EA044932B1 - SUBSTITUTED OXOPYRIDINE DERIVATIVES - Google Patents

Description

The present invention relates to substituted oxopyridine derivatives and methods for their preparation, as well as their use for the preparation of medicinal products for the treatment and/or prevention of diseases, in particular vascular disorders, preferably thrombotic or thromboembolic disorders, and/or thrombotic or thromboembolic complications.

Hemostasis is a protective mechanism of the body that helps quickly and reliably close leaking damage in the wall of blood vessels. In this way, excessive blood loss can be avoided or minimized. After injury to a blood vessel, hemostasis occurs mainly through the activation and aggregation of platelets and the activation of the coagulation system, which consists of a waterfall enzymatic cascade leading one after another to the activation of the next coagulation factor until thrombin is formed, which leads to the formation of insoluble fibrin , which is an important part of the clot.

Recently, the traditional theory of two separate starting points of the coagulation cascade (extrinsic and intrinsic pathways) has been modified by new discoveries: in these models, coagulation is initiated by the binding of activated factor VIIa to tissue factor (TF). The resulting complex activates factor X, which in turn leads to the formation of thrombin with subsequent formation of fibrin and activation of platelets (via PAR-1) as the end products of hemostasis, sealing the damage. Compared to the subsequent amplification/propagation phase, the rate of thrombin production in this first phase is low and time-limited as a result of the emergence of TFPI as an inhibitor of the TF-FVIIa-FX complex. A central component of the transition from initiation to amplification of coagulation and thus thrombus propagation is factor XIa: in positive feedback loops, thrombin activates not only factor V and factor VIII, but also factor XI to factor XIa, which in turn converts factor IX to factor IXa, which in turn, in the factor IXa/factor VIIIa complex, generates factor Xa and, finally, a large amount of thrombin, which leads to strong thrombus growth and stabilization of the thrombus. This is supported by TAFIa and FXIIIa, which are also activated by thrombin and lead to inhibition of clot lysis and further stabilization of the clot.

In addition to stimulation by tissue factor, the coagulation system can be activated in particular on negatively charged surfaces, which include not only the surface structures of foreign cells (eg bacteria), but also artificial surfaces such as vascular prostheses, stents and extracorporeal circulation. On these surfaces, factor XII (FXII) is activated to factor XIIa, which then activates factor XI to factor XIa. This leads to further activation of the coagulation cascade as described above. In addition, factor XIIa also activates bound plasma prokallikrein to plasma kallikrein (KK), which in a potentiation loop first leads to further activation of factor XII, which overall leads to amplification of the initiation of this internal part of the coagulation cascade.

Uncontrolled activation of the coagulation system or impaired inhibition of activation processes can lead to the formation of local thrombi or emboli in vessels (eg, arteries, veins, lymphatic vessels) or in organ cavities (eg, atrium of the heart). In addition, systemic hypercoagulability can lead to system-wide microthrombi formation and ultimately to consumptive coagulopathy in the context of disseminated intravasal coagulation. Thromboembolic complications can also occur in extracorporeal circulatory systems such as hemodialysis, as well as in vascular prostheses or prosthetic heart valves and stents.

In many cardiovascular and metabolic disorders, an increased tendency for platelet clotting and activation occurs either due to systemic factors such as hyperlipidemia, diabetes, inflammation, infection or smoking, or due to changes in blood flow with stasis, such as in the affected veins of the legs or with atrial fibrillation, or due to pathological changes in the walls of blood vessels, for example, endothelial dysfunction or atherosclerosis. This unwanted and excessive activation of coagulation can, through the formation of fibrin- and platelet-rich thrombi, lead to thromboembolic disorders and thrombotic complications with often life-threatening events. Inflammatory processes may also be involved by triggering the blood coagulation system. On the other hand, thrombin is also known to activate inflammatory pathways.

Accordingly, thromboembolic disorders continue to be the most common cause of morbidity and mortality in most industrialized countries.

Anticoagulants known in the art, that is, substances for inhibiting or preventing blood clotting, have various disadvantages. Accordingly, effective methods for treating or preventing thrombotic/thromboembolic disorders have proven difficult and unsatisfactory when put into practice.

In the treatment and prevention of thromboembolic disorders, heparin is used primarily, which is administered parenterally or subcutaneously. Due to its more favorable pharmacokinetic properties, low molecular weight heparin is now increasingly preferred, however, the known disadvantages encountered with heparin therapy, described below, also cannot be avoided in this way. Thus, heparin is ineffective when taken orally and has a relatively short half-life. In addition, there is a high risk of bleeding, in particular there may be cerebral and gastrointestinal hemorrhages, and thrombopenia, drug-induced alopecia or osteoporosis may occur.

Low molecular weight heparins are less likely to cause heparin-induced thrombocytopenia, but they can also only be administered subcutaneously. This also applies to fondaparinux, a synthetic selective factor Xa inhibitor with a long half-life.

The second class of anticoagulants are vitamin K antagonists. These include, for example, 1,3-indanediones and, in particular, compounds such as warfarin, phenprocoumon, dicoumarol and other coumarin derivatives, which non-selectively inhibit the synthesis of various products of vitamin K-dependent coagulation factors in liver. Due to the mechanism of action, the onset of action is very slow (latency to onset of action is 36 to 48 hours). The compounds can be administered orally, however, due to the high risk of bleeding and narrow therapeutic index, complex individual adjustments and patient monitoring are required. In addition, other side effects have been described, such as gastrointestinal problems, hair loss and skin necrosis.

Today, non-vitamin K-dependent oral anticoagulant (NOAC) approaches are in clinical practice and have demonstrated their effectiveness in various studies. However, these medications may also cause bleeding, especially in predisposed patients.

Thus, for antithrombotic drugs, the therapeutic window is of central importance: the interval between the therapeutically active dose for inhibition of coagulation and the dose at which bleeding may occur should be as large as possible so that maximum therapeutic activity is achieved with a minimum risk profile.

In various in vitro and in vivo models with, for example, antibodies as factor XIa inhibitors, as well as factor XIa knockout animal models, an antithrombotic effect with little/no prolongation of bleeding time or increase in blood volume has been confirmed. In clinical studies, increased concentrations of factor XIa were associated with an increased incidence of thrombotic events. In contrast, factor XI deficiency (hemophilia C) did not result in spontaneous bleeding and was only seen during surgery and trauma, but did show protection against some thromboembolic events.

In many disorders, a combination of antithrombotic and anti-inflammatory principles may also be particularly attractive in preventing mutual enhancement of coagulation and inflammation.

It is therefore an object of the present invention to provide novel compounds for the treatment of cardiovascular disorders, in particular thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications, in humans and animals, where the compounds have a wide therapeutic window.

WO 2006/030032, among other things, describes substituted pyridinones as allosteric modulators of the mGluR2 receptor, and WO 2008/079787 describes substituted pyridin-2-ones and their use as glucokinase activators. In WO 2014/154794, WO 2014/160592, WO 2015/011087, WO 2015/063093, WO 2016/046158, WO 2016/046157, WO 2016/046159, WO 2016/046164, W O 2016/046166, WO 2016/046156 , WO 2017/005725 and WO 2017/037051 describe substituted pyridin-2-ones and their use as factor XIa inhibitors.

The present invention provides compounds of formula wherein R ¹ is methyl, ethyl, difluoromethyl or trifluoromethyl,

R ² is hydrogen, methyl, difluoromethyl or trifluoromethyl, or

R ¹ and R ² , together with the carbon atoms to which they are attached, form a cyclobutyl ring

R ³ represents methyl, ethyl or n-propyl, where methyl may be replaced by one substituent selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydro- 2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl and 1,4-dioxan-2-yl, where oxetan-2-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and 1 ,4-dioxan-2-yl may be substituted with 1 or 2 substituents independently selected from the group consisting of fluorine and methyl, or

- 2 044932 where methyl may be replaced by one substituent of the formula group

where * indicates the place of attachment to the methyl group,

R ⁹ is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl,

R ¹⁰ represents methyl or difluoromethyl, and wherein ethyl may be replaced by one substituent selected from the group consisting of methoxy, ethoxy, isopropoxy, t-butoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2trifluoroethoxy, cyclopropyloxy and cyclobutyloxy, wherein cyclopropyloxy and cyclobutyloxy may be substituted by one substituent selected from the group consisting of fluorine and methyl,

R ⁴ represents hydrogen,

R ⁵ represents a group of the formula

where # indicates the site of attachment to the nitrogen atom,

R ¹¹ represents hydrogen or fluorine,

R ¹² represents methyl, difluoromethyl or trifluoromethyl,

R ¹³ represents methyl, difluoromethyl or trifluoromethyl,

R ¹⁴ represents hydrogen or methyl,

R ¹⁵ represents hydrogen or methyl,

R ¹⁶ represents hydrogen or methyl,

R ¹⁷ represents hydrogen or methyl,

R ⁶ , R ⁷ and R ⁸ have the following meanings:

R ⁶ represents hydrogen, fluorine or chlorine,

R ⁷ represents hydrogen,

R ⁸ represents hydrogen, or

R ⁶ represents hydrogen,

R ⁷ represents fluorine or chlorine,

R ⁸ represents hydrogen, or

R ⁶ represents hydrogen,

R ⁷ represents hydrogen,

R ⁸ represents fluorine, and their salts.

The compounds of the present invention are the compounds of formula (I) and their salts, as well as the compounds covered by formula (I) and listed below as working example(s), and their salts, to the extent that the compounds covered by formula (I ) and those listed below are not yet salts.

The compounds of the present invention may, depending on their structure, exist in different stereoisomeric forms, that is, in the form of configurational isomers or, if necessary, in the form of conformational isomers (enantiomers and/or diastereomers, including in the case of rotamers and atropisomers). Thus, the present invention covers enantiomers and diastereomers and their corresponding mixtures. Stereoisomerically homogeneous components can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; For this purpose, chromatographic methods are preferably used, especially HPLC chromatography on achiral or

- 3 044932 chiral phase.

While the compounds of the present invention may be in tautomeric forms, the present invention covers all tautomeric forms.

In the context of the present invention, the term enantiomerically pure should be understood to mean that the compound in question, with respect to the absolute configuration of the chiral center, is present in an enantiomeric excess of greater than 95%, preferably greater than 97%. The enantiomeric excess (ee value) is calculated in the context of the present invention by evaluating the corresponding HPLC chromatogram on the chiral phase using the formula below:

ee = [E ^A (% by area) - E ⁱⁿ (% by area)] x100% / [E ^A (% by area) + E ⁱⁿ (% by area)] (E ^A : enantiomer in excess, E ^B : enantiomer in deficiency).

The present invention also includes all suitable isotopic variants of the compounds of the present invention. By isotopic variant of a compound of the present invention, in the context of the present invention, is meant a compound in which at least one atom in the compound of the present invention has been replaced by another atom with the same atomic number, but with a different atomic mass than the atomic mass that is normally or predominantly found in nature. Examples of isotopes that can be included in the compound of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ^2H (deuterium), ^3H (tritium), ¹³ С, ¹⁴ С, ¹⁵ N ^{, 17} О, ^{18 О} , 32 Р, ³³ Р, ³³ S, 34 S, 35 S, ³⁶ S, ¹⁸ F, ³⁶ Cl ^{, 82} Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Particular isotopic variants of a compound of the present invention, especially those in which one or more radioactive isotopes have been included, may be preferred, for example, to study the mechanism of action or distribution of the active compound in the body; Due to their comparative ease of preparation and determination, compounds labeled with ³ H- or ¹⁴ Sisotopes are particularly suitable for these purposes. In addition, the inclusion of isotopes such as deuterium may lead to particular therapeutic benefits due to greater metabolic stability of the compound, such as increasing the half-life in the body or reducing the required active dose; Therefore, such modifications of the compounds of the present invention may, in some cases, also represent a preferred embodiment of the application of the present invention. Isotopic variants of the compounds of the present invention can be obtained by methods known to those skilled in the art, for example, the methods described below and the procedures described in the working examples, through the use of appropriate isotopic modifications of the appropriate reagents and/or starting compounds.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the present invention. However, the present invention also includes salts that are not themselves suitable for pharmaceutical use, but may be used, for example, to isolate or purify the compounds of the present invention.

Physiologically acceptable salts of the compounds of the present invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid , acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, citric acid, malic acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds of the present invention also include salts of conventional bases, for example and preferably alkali metal salts (for example, sodium and potassium salts), alkaline earth metal salts (for example, calcium and magnesium salts) and ammonium salts, derivatives of ammonia or organic amines, containing from 1 to 16 carbon atoms, by way of example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline .

Solvates are described as those forms of compounds that form a complex in the solid or liquid state through coordination with solvent molecules. Hydrates are a special form of solvate in which coordination occurs with water.

The present invention further also covers prodrugs of the compounds of the present invention. The term prodrugs covers compounds that may or may not be biologically active in their own right, but are converted during their presence in the body into the compounds of the present invention (eg, by metabolism or hydrolysis).

In the context of the present invention, the term treat or treat includes inhibiting, slowing, checking, alleviating, attenuating, limiting, reducing, suppressing, eliminating or healing a disease, condition, disorder, injury or health or developmental problem, the course or progression of such conditions and/or symptoms of such conditions. The term therapy is used herein synonymously with the term treatment.

- 4 044932

The terms prevention, prophylaxis and prevention are used interchangeably in the context of the present invention and refer to preventing or reducing the risk of developing, experiencing, suffering from or having a disease, condition, disorder, injury or health problem, or the development or progression of such conditions and/or symptoms such states.

Treatment or prevention of a disease, condition, disorder, injury or health problem may be partial or complete.

In formulas for a group that may represent a methyl group substituent on R ³ , the end point of the line marked * in each case does not represent a carbon atom or a CH2 group, but is part of a bond to the atom to which the group is attached.

In formulas of a group that may represent R ⁵ , the end point of the line designated # in each case does not represent a carbon atom or a CH 2 group, but is part of a bond to the atom to which R ⁵ is attached.

Preferred are compounds of formula (I) in which

R ¹ represents methyl, ethyl or trifluoromethyl,

R ² represents hydrogen or methyl, or

R ¹ and R ² , together with the carbon atoms to which they are attached, form a cyclobutyl ring,

R ³ represents methyl, ethyl or n-propyl, where methyl may be replaced by one substituent selected from the group consisting of cyclobutyl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and 1,4-dioxan- 2-yl, wherein tetrahydrofuran-2-yl may be substituted with 1 or 2 methyl substituents, or where methyl may be substituted with one group substituent of the formula

R ¹ ' R ¹³ OH o ° jl ^{f Ι£ΤΠΙ} OR

ΓΧ Η I where * indicates the place of attachment to the methyl group,

R ⁹ is methyl, cyclopropyl, difluoromethyl or trifluoromethyl,

R ¹⁰ represents methyl or difluoromethyl, and wherein ethyl may be replaced by one substituent selected from the group consisting of methoxy, isopropoxy, t-butoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, cyclopropyloxy and cyclobutyloxy, wherein cyclopropyloxy and cyclobutyloxy may be replaced by one substituent selected from the group consisting of fluorine and methyl,

R ⁴ represents hydrogen,

R ⁵ represents a group of the formula

where # indicates the site of attachment to the nitrogen atom, R ¹¹ represents hydrogen or fluorine,

R ¹² represents difluoromethyl or trifluoromethyl,

R ¹³ represents methyl,

R ¹⁴ represents hydrogen or methyl,

R ¹⁵ represents hydrogen or methyl,

R ¹⁶ represents hydrogen,

R ¹⁷ represents hydrogen,

R ⁶ , R ⁷ and R ⁸ have the following meanings:

R ⁶ represents hydrogen, fluorine or chlorine,

R ⁷ represents hydrogen,

- 5 044932

R ⁸ represents hydrogen, and their salts.

Also preferred are compounds of formula (I) in which

R ¹ represents methyl, ethyl or trifluoromethyl,

R ² represents hydrogen or methyl, or

R ¹ and R ² , together with the carbon atoms to which they are attached, form a cyclobutyl ring,

R ³ represents methyl, ethyl or n-propyl, where methyl may be replaced by one substituent selected from the group consisting of cyclobutyl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and 1,4-dioxan- 2-yl, wherein tetrahydrofuran-2-yl may be substituted with 1 or 2 methyl substituents, or where methyl may be substituted with one group substituent of the formula

R ¹⁰ R ¹⁰ OH

О ° 1 F ^1ИШ OR ri Н । where * indicates the place of attachment to the methyl group,

R ⁹ is methyl, cyclopropyl, difluoromethyl or trifluoromethyl,

R ¹⁰ represents methyl or difluoromethyl, and wherein ethyl may be replaced by one substituent selected from the group consisting of methoxy, isopropoxy, t-butoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, cyclopropyloxy and cyclobutyloxy, wherein cyclopropyloxy and cyclobutyloxy may be replaced by one substituent selected from the group consisting of fluorine and methyl,

R ⁴ represents hydrogen,

R ⁵ represents a group of the formula

where # indicates the site of attachment to the nitrogen atom,

R ¹¹ represents hydrogen or fluorine,

R ¹² represents difluoromethyl or trifluoromethyl,

R ¹³ represents methyl,

R ¹⁵ represents hydrogen or methyl,

R ¹⁶ represents hydrogen,

R ⁶ , R ⁷ and R ⁸ have the following meanings:

R ⁶ represents hydrogen or fluorine,

R ⁷ represents hydrogen,

R ⁸ represents hydrogen, and their salts.

Also preferred are compounds of formula (I) in which

R ¹ represents methyl or trifluoromethyl,

R ² represents hydrogen, or

R ¹ and R ² , together with the carbon atoms to which they are attached, form a cyclobutyl ring,

R ³ represents methyl or ethyl, where methyl is substituted with one substituent selected from the group consisting of tetrahydro-2H-pyran2-yl and 1,4-dioxan-2-yl, or where methyl is substituted with one substituent of the formula

- 6 044932 where * indicates the place of attachment to the methyl group,

R ⁹ represents methyl,

R ¹⁰ represents methyl or difluoromethyl, and wherein ethyl is substituted with one substituent selected from the group consisting of methoxy, isopropoxy, tert-butoxy, difluoromethoxy and cyclopropyloxy, wherein cyclopropyloxy may be substituted with one substituent selected from the group consisting of fluorine and methyl ,

R ⁴ represents hydrogen,

R ⁵ represents a group of the formula where # indicates the site of attachment to the nitrogen atom,

R ¹¹ represents hydrogen or fluorine,

R ¹³ represents methyl,

R ¹⁵ represents hydrogen or methyl,

R ¹⁶ represents hydrogen,

R ⁶ , R ⁷ and R ⁸ have the following meanings:

R ⁶ represents hydrogen or fluorine,

R ⁷ represents hydrogen,

R ⁸ represents hydrogen, and their salts.

Also preferred are compounds of formula (I) in which R ¹ represents methyl or trifluoromethyl,

R ² represents hydrogen,

R ³ represents methyl, where methyl is replaced by one group substituent of the formula

where * indicates the place of attachment to the methyl group,

R ⁹ represents methyl,

R ¹⁰ represents methyl or difluoromethyl,

R ⁴ represents hydrogen,

R ⁵ represents a group of the formula ,nh ₂ where # indicates the site of attachment to the nitrogen atom,

R ¹¹ represents hydrogen,

R ⁶ , R ⁷ and R ⁸ have the following meanings:

R ⁶ represents hydrogen or fluorine,

R ⁷ represents hydrogen,

R ⁸ represents hydrogen, and their salts.

Also preferred are compounds of formula (I) in which R ⁶ , R ⁷ and R ⁸ have the following meanings: R ⁶ represents hydrogen or fluorine,

R ⁷ represents hydrogen,

R ⁸ represents hydrogen.

Also preferred are compounds of formula (I) in which R ⁶ , R ⁷ and R ⁸ have the following meanings:

- 7 044932

R ⁶ represents hydrogen,

R ⁷ represents hydrogen,

R ⁸ represents hydrogen.

Also preferred are compounds having formula (Ia)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ have the meanings as defined above.

Also preferred is the compound 4-({(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino [2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (single stereoisomer) of the formula below

or one of its salts.

Also preferred is the compound 4-({(2S,4S)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7(trifluoromethyl)-2,6,7,8-tetrahydro-3H- [3]benzoxocino[2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (single stereoisomer) of formula below o'

CI or one of its salts.

The present invention also relates to a process for the preparation of compounds of formula (I) or salts thereof, wherein

[A] compounds of formula

in which R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are as defined above are reacted with compounds of the formula

R ⁴

A 5 R in which R ⁴ and R ⁵ are as defined above, in the presence of a dehydrating agent to obtain compounds of formula (I) or

[B] compounds of formula (II) are converted in a one-pot reaction to the acid chloride of compounds of formula (II), and then the acid chlorides are reacted with compounds of formula (III) to produce compounds of formula (I) or

[C] compounds of formula

- 8 044932 in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ have the meanings as defined above, are reacted with a compound

niami formulas

wherein X ¹ is bromine, iodoyl trifluoromethanesulfonyloxy, in the presence of a base to give compounds of formula (I).

The reaction according to method [A] is generally carried out in inert solvents, if appropriate, in the presence of a base, preferably in the temperature range from -20°C to 80°C at atmospheric pressure.

Alternatively, the reaction can also be carried out without solvent in the base only, if the base is liquid at room temperature.

Suitable dehydrating agents according to the present invention are, for example, carbodiimides such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl-, N,N'dicyclohexylcarbodiimide, N-(3-dimethylaminoisopropyl )-N-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'propyloxymethyl-polystyrene (PS-carbodiimide), or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl chloroformate, or bis-(2-oxo-3oxazolidinyl)phosphoryl chloride or benzotriazolyloxytri(dimethylamino)-phosphonium hexafluorophosphate, or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) , 2-(2-oxo-1-(2H)pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), (benzotriazol-1yloxy)bisdimethylaminomethylium fluoroborate (TBTU) or O-(7-azabenzotriazol-1- yl)-N,N,N',N'tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1yloxytris(dimethyl-amino)phosphonium hexafluorophosphate (BOP), or ethylcyano(hydroxyimino)acetate (Oxyma) , or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), or N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b] pyridin-3-yloxy)methylidene]-Nmethylmethanaminium hexafluorophosphate, or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan-2,4,6trioxide (T3P), or mixtures thereof with bases, with condensation with HATU or T3P being preferred.

The bases are, for example, organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or pyridine, preferably condensation with diisopropylethylamine or pyridine.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as 1,4-dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile, or mixtures of solvents, preferably N,Ndimethylformamide or tetrahydrofuran.

The reaction according to method [B] is generally carried out in inert solvents, in the presence of a chlorinating agent, preferably in the temperature range from -20 to 80°C at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as 1,4-dioxane, diethyl ether, tetrahydrofuran, ethyl acetate or N,Ndimethylformamide, or mixtures of solvents , preference is given to dichloromethane.

Chlorinating agents are, for example, 1-chloro-N,N,2-trimethylprop-1-en-1-amine, oxalyl chloride, sulfur dichloride, with preference given to 1-chloro-N,N,2-trimethylprop-1-en- 1-amine.

The reaction according to method [C] is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux temperature of the solvents at atmospheric pressure.

The bases are, for example, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium carbonate or potassium carbonate, or potassium tert-butoxide or sodium tert-butoxide, sodium hydride or a mixture of these bases or a mixture of sodium hydride and lithium bromide, or organic bases such as 1,1,3,3-tetramethylguanidine or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro1,3, 2-diazaphosphorine (BEMP), preference is given to potassium carbonate or sodium hydride or 1,1,3,3tetramethylguanidine.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol, ethanol or 2-propanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane or tetrahydrofuran, or other solvents such as N,Ndimethylformamide, N,N-dimethylacetamide, acetonitrile, pyridine or acetone, or mixtures of solvents or mixtures of solvents with water, preference is given N,N-dimethylformamide or a mixture of acetone and 2-propanol.

The compounds of formula (III) are known or can be synthesized from the corresponding starting compounds by known methods.

The compounds of formula (V) are known and can be synthesized from the corresponding starting compounds by known methods or can be prepared analogously to the methods described in the Examples section.

Compounds of formula (II) are known or can be prepared by reacting [D] compounds of formula

in which R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are each as defined above, and R ¹⁸ is tert-butyl,

With acid to obtain compounds of formula (II), or

[E] compounds of formula

in which R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ each have the meanings as defined above, and

R ¹⁸ is methyl, ethyl, tert-butyl or benzyl, with a base to give compounds of formula (II).

The reaction according to method [D] is generally carried out in inert solvents, preferably in the temperature range from 0 to 60° C. at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or ethers such as tetrahydrofuran or 1,4-dioxane, with preference given to dichloromethane.

The acids are, for example, trifluoroacetic acid or the hydrochloride in 1,4-dioxane, preferably trifluoroacetic acid.

The reaction according to method [E] is generally carried out in solvents, preferably in a temperature range from room temperature to the reflux temperature of the solvents at atmospheric pressure.

Inert solvents are, for example, alcohols such as methanol or ethanol, ethers such as diethyl ether, tert-butyl ether, 1,2-dimethoxyethane, 1,4dioxane or tetrahydrofuran, or mixtures of solvents, or mixtures of solvents with water , preference is given to a mixture of tetrahydrofuran and water.

The bases are, for example, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium carbonate or potassium carbonate, with preference being given to lithium hydroxide.

The compounds of formula (VIa) and (VIb) together form the group of compounds of formula (VI).

Compounds of formula (VIa) are known or can be prepared by reacting compounds of formula

- 10 044932

in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ each have the meanings as defined above, and

R ¹⁸ is tert-butyl, with compounds of the formula

R—X ² (VIII), in which R ³ has the meanings as defined above, and

X ² represents chlorine, bromine, iodine or trifluoromethanesulfonyloxy.

The reaction is generally carried out in inert solvents, in the presence of a base, preferably in the temperature range from -78°C to room temperature at atmospheric pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxypetane, 1,4-dioxane or tetrahydrofuran, or mixtures of solvents, or mixtures of solvent with water, tetrahydrofuran being preferred .

The bases are, for example, potassium tert-butoxide or sodium tert-butoxide, sodium hydride, n-butyllithium, lithium bis(trimethylsilyl)amide or sodium bis(trimethylsilyl)amide, preferably lithium bis(trimethylsilyl)amide or bis(trimethylsilyl)amide sodium

The compounds of formula (VIII) are known or can be synthesized from the corresponding starting compounds by known methods.

Compounds of formula (VII) are known or can be prepared by reacting compounds of formula

in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ are as defined above with compounds of the formula

in which X ³ represents chlorine, bromine, iodine, methanesulfonyloxy or trifluoromethanesulfonyloxy, and

R ¹⁸ is tert-butyl. The reaction is carried out as described for method [C].

The compounds of formula (IX) are known or can be synthesized from the corresponding starting compounds by known methods.

In an alternative method, compounds of formula (VI) can be prepared by reacting compounds of formula (IV) with compounds of formula

R ³

in which R ³ has the meanings as defined above,

X ⁴ is chlorine, bromine, iodine, methanesulfonyloxy or trifluoromethanesulfonyloxy, and

R ¹⁸ is methyl, ethyl, tert-butyl or benzyl. The reaction is carried out as described for method [C].

The compounds of formula (X) are known and can be synthesized from the corresponding starting compounds by known methods or can be prepared analogously to the methods described in the examples.

Compounds of formula (IV) are known or can be prepared by reacting compounds of formula

- 11 044932 in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ have the meanings as defined above, with pyridinium hydrochloride

or pyridinium hydrobromide or sodium iodide and acid or lithium iodide and acid or with a thiol such as ethanethiol and a base.

The reaction is generally carried out in an inert temperature of 80 to 120°C at atmospheric pressure.

Inert solvents are, for example, hydrocarbons such as benzene, or alcohols such as methanol, ethanol or 1-butanol, or other solvents such as nitromethane, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or acetonitrile, or a mixture of solvents, preferably N,N-dimethylformamide or 1-butanol.

The acids are, for example, 4-toluenesulfonic acid monohydrate, formic acid, acetic acid, trifluoroacetic acid, and acetic acid and 4-toluenesulfonic acid monohydrate are preferred.

The bases are, for example, potassium tert-butoxide or sodium tert-butoxide or sodium hydride, with sodium hydride being preferred.

Compounds of formula (XI) are known or can be prepared by reacting compounds of formula

in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ are as defined above, with a base in the presence of a catalyst.

The reaction is generally carried out in inert and degassed solvents, preferably in the temperature range from 80 to 150°C at atmospheric pressure.

The bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, organic bases such as sodium pivalate, potassium pivalate, cesium pivalate, sodium acetate, potassium acetate, cesium acetate, with preference being given to potassium pivalate or potassium acetate.

The catalysts are, for example, palladium-based catalysts customary for CH activation conditions, such as dichlorobis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium(0), palladium (II) acetate/triscyclohexylphosphine, bis(tri-tert-butylphosphine)palladium( 0), tris(dibenzylidene-acetone)dipalladium, bis(diphenylphosphaneferrocenyl)palladium(P) chloride, 1,3bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium dimer, allyl(chlorine) (1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)palladium, palladium(P) acetate/dicyclohexyl(2',4',6'triisopropyl-biphenyl-2-yl)phosphine, XPhos precatalyst [ (2'-aminobiphenyl-2-yl)(chloro)palladium dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphane (1:1)], DavePhos precatalyst [Methanesulfonato 2-dicyclohexylphosphino-2-( N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl) palladium(P)], PEPPSI® catalysts such as [1,3-bis(2,6-di- 3-pentylphenyl)imidazol-2-ylidene](3chloropyridyl)palladium(II) dichloride or [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3chloropyridyl)palladium(II) dichloride, with preference being tetrakis(triphenylphosphine)palladium(0) or [1,3-bis(2,b-di-3-pentylphenyl)imidazol-2-ylidene](3chloropyridyl)palladium(II) dichloride.

Inert solvents are, for example, ethers such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxypetane, hydrocarbons such as benzene, xylene or toluene, or carboxamides such as N,N-dimethylformamide or N,N- dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, or mixtures of solvents with water, preferably N,N-dimethylformamide or N,N-dimethylacetamide.

Alternatively, compounds of formula (XI) can be prepared by reacting compounds of formula

- 12 044932 in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ are as defined above, with bis(pinacolato)diborane in the presence of a base and a catalyst.

The reaction is generally carried out in inert solvents, preferably in the temperature range from room temperature to 150°C at atmospheric pressure.

The catalysts are, for example, palladium-based catalysts standard for Suzuki reaction conditions, with preferred catalysts such as dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), bis(tri-tert-butylphosphine)palladium(0), palladium acetate(H) , palladium(P) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphaneferrocenyl)palladium(P) chloride, 1,3-bis(2,6diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium dimer, allyl(chloro)(1,3-dimesityl-1,3dihydro-2H-imidazol-2-ylidene)palladium, palladium(II) acetate/dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine, adduct of [1,1-bis(diphenylphosphino)-ferrocene]palladium(P) chloride and monodichloromethane or XPhos precatalyst [(2'-aminobiphenyl-2-yl)(chloro)palladium dicyclohexyl(2',4',6'triisopropylbiphenyl- 2-yl)phosphane (1:1)], with palladium(P) acetate or palladium(P) acetate/triscyclohexylphosphine or tetrakistriphenylphosphine palladium(0) being preferred.

The bases are, for example, alkali metal carbonates such as cesium carbonate, potassium carbonate or sodium carbonate, alkali metal bicarbonates such as sodium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide or potassium acetate, tert. -potassium butoxide or potassium phosphate, when they may be present in aqueous solution, preference is given to an aqueous solution of sodium bicarbonate or potassium acetate.

Inert solvents are, for example, ethers such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxypetane, hydrocarbons such as benzene, xylene or toluene, or carboxamides such as N,N-dimethylformamide or N,N- dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, or N-methylpyrrolidone or acetonitrile, or mixtures of solvents with alcohols such as methanol or ethanol and/or water, with preference given to N,N-dimethylformamide.

Compounds of formula (XII) are known or can be prepared by reacting compounds of formula

in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ are as defined above, with a compound of the formula

The reaction is carried out in the presence of (tributylphosphoranylidene)-acetonitrile, in inert solvents such as benzene, xylene or toluene, preferably toluene, optionally by microwave treatment, preferably in the temperature range from 80°C to 160°C, at atmospheric pressure up to 3 bar or higher than 3 bar, using microwaves, or the reaction is carried out in the presence of an azodicarboxylic acid ester such as diisopropyl azodicarboxylate (DIAD) and organophosphates such as triphenylphosphine, in inert solvents such as tetrahydrofuran, 1,4-dioxane or dichloromethane, in the temperature range from 0°C to room temperature, at atmospheric pressure.

The compounds of formulas (XIV) and (XV) are known and can be synthesized from the corresponding starting compounds by known methods or can be prepared analogously to the methods described in the examples.

Compounds of formula (XIII) are known or can be prepared by reacting compounds of formula

in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ are as defined above with the compound of formula (XV).

The reaction is carried out as described for the reaction of compounds of formula (XIV) with compounds of formula (XV).

The compounds of formula (XVI) are known and can be synthesized from the corresponding starting compounds by known methods or can be prepared analogously to the methods described in the examples.

The preparation of the starting compounds and compounds of formula (I) can be illustrated by the following synthesis scheme.

- 13 044932

Scheme

The compounds of the present invention have an unexpected range of beneficial pharmacological activities and good pharmacokinetic properties. These are compounds that affect the proteolytic activity of serine protease factor XIa (FXIa). The compounds of the present invention inhibit the enzymatic degradation of FXIa substrates such as factor IX (FIX), which plays an important role in the activation of blood coagulation, in blood platelet aggregation through activation of platelet PAR-1, and in inflammatory processes, which in particular are associated with an increase in vascular permeability.

Thus, the present invention relates to a biologically active agent having FXIa inhibitor properties, which is a compound of formula (I).

They are therefore suitable for use as medicinal products for the treatment and/or prevention of diseases in humans and animals.

Furthermore, the present invention relates to the use of the compounds of the present invention for the treatment and/or prevention of disorders, in particular vascular disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications.

Factor XIa (FXIa) is an important enzyme in the context of blood coagulation that can be activated by both thrombin and factor XIIa (FXIIa), and is therefore involved in two major coagulation processes. It is a central component of the transition from initiation to amplification of coagulation and clot propagation: in positive feedback loops, thrombin activates, in addition to factor V and factor VIII, also factor XI into factor XIa, whereby factor IX is converted into factor IXa, and through the complex thus formed factor IXa/factor VIIIa are formed by factor Xa and then thrombin, which leads to strong thrombus growth and stabilization of the clot.

Moreover, factor XIa is an important component for the intrinsic initiation of blood coagulation: in addition to stimulation through tissue factor (TF) in the extrinsic pathway, the blood coagulation system can also be activated, in particular on negatively charged surfaces, which include not only surface structures, foreign cells (for example, bacteria), as well as artificial surfaces such as vascular prostheses, stents and parts of extracorporeal circulatory systems. On these surfaces, factor XII (FXII) is activated to factor XIIa (FXIIa), which then activates FXI to FXIa. This leads to further activation of the coagulation cascade as described above.

- 14 044932

In contrast, thrombin generation, triggered by TF factor Vila through activation of factor X, and finally thrombin generation, which is an early physiological response to damage to the vascular wall, remains unaffected. This may explain why an increase in bleeding time was not found in FXIa knockout mice, as in rabbits and other species, when administered an FXIa inhibitor. This low bleeding tendency caused by the substance is of great advantage for use in humans, especially in patients with an increased risk of bleeding.

Accordingly, the compounds of the present invention are suitable for the treatment and/or prevention of disorders or complications that may arise as a result of clot formation.

In the context of the present invention, thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications include disorders and complications that occur in the arterial, venous vascular system and lymphatic system, which can be treated with the compounds of the present invention. These include, but are not limited to, coronary artery disorders such as acute coronary syndrome (ACS), ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, stent thrombosis, reocclusion and restenosis after coronary interventions such as angioplasty, stent implantation or coronary artery bypass grafting, cerebrovascular disorders such as transient ischemic attack (TIA), ischemic strokes including cardioembolic strokes such as strokes due to atrial fibrillation, non-cardioembolic strokes such as lacunar stroke, strokes as a result of large or small artery disease or strokes of unknown cause, cryptogenic strokes, embolic strokes, embolic strokes of unknown origin or events of thrombotic and/or thromboembolic origin leading to stroke or TIA, as well as peripheral arterial disorders leading to peripheral artery disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusion and restenosis after procedures such as angioplasty, stent implantation or surgery or bypass.

In addition, it includes thrombotic or thromboembolic disorders, in particular in the veins of the extremities, kidneys, mesentery, liver, brain and eye, leading to pulmonary embolism, venous thromboembolism and/or venous thrombosis.

Stimulation of the coagulation system can occur for various reasons or related disorders. In the context of surgery, immobility, bedriddenness, infection, inflammation or cancer or cancer therapy, among others, the coagulation system may be highly activated and there may be thrombotic complications, in particular venous thrombosis. The compounds of the present invention are therefore suitable for the prevention of thrombosis in the context of surgical interventions in patients suffering from cancer. Thus, the compounds of the present invention are also suitable for the prevention of thrombosis in patients having an activated coagulation system, for example in the stimulation situations described.

The compounds of the present invention are therefore also suitable for the prevention and treatment of cardiogenic thromboembolism, for example cerebral ischemia, stroke and systemic thromboembolism and ischemia, in patients with acute, intermittent or persistent cardiac arrhythmias, for example atrial fibrillation, and in patients undergoing electrical shock pacing , as well as in patients with heart valve disorders or artificial heart valves.

In addition, the liquid compounds according to the present invention are suitable for the treatment and prevention of generalized thrombohemorrhagic syndrome (DIC), which can occur, in particular in connection with sepsis, but also due to surgical interventions, neoplastic disorders, burns or other injuries and can lead to serious organ damage due to microthrombosis.

In addition, thromboembolic complications occur in microangiopathic hemolytic anemias and in contact of blood with foreign surfaces in the context of extracorporeal circulation, for example, hemodialysis, ECMO (extracorporeal membrane oxygenation), LVAD (left ventricular assist device) and similar methods, AV fistulas, vascular grafts and heart valves.

Moreover, the compounds of the present invention are suitable for the treatment and/or prevention of disorders involving microclot formation or fibrin deposition in the blood vessels of the brain, which can lead to dementia disorders such as vascular dementia or Alzheimer's disease. Here the clot may contribute to the disorder, both through occlusion and by binding to other disease-related factors.

Moreover, the compounds of the invention are suitable for the treatment and/or prevention of disorders where, in addition to the procoagulant component, the proinflammatory component also plays an important role. The mutual enhancement of coagulation and inflammation, in particular, can be prevented by the compounds of the present invention, thereby decisively reducing the likelihood of thrombotic

- 15 044932 complications. Therefore, the compounds of the present invention are suitable for the treatment and/or prevention in the context of atherosclerotic vascular disorders, inflammatory diseases such as rheumatic musculoskeletal disorders, inflammatory lung diseases such as pulmonary fibrosis, inflammatory kidney diseases such as glomerulonephritis, inflammatory diseases bowel disease, such as Crohn's disease or ulcerative colitis, or disorders that may be present in the context of an underlying diabetic disease, such as diabetic retinopathy or nephropathy.

Moreover, the compounds of the present invention can be used to inhibit tumor growth and metastasis formation, as well as to prevent and/or treat thromboembolic complications, for example, venous thromboembolism in cancer patients, in particular those undergoing major surgery or chemotherapy or radiation therapy.

In addition, the compounds of the present invention are also suitable for the prevention and/or treatment of pulmonary hypertension.

In the context of the present invention, the term pulmonary hypertension includes pulmonary arterial hypertension, pulmonary hypertension associated with left heart disorders, pulmonary hypertension associated with pulmonary disorders, and/or hypoxia and pulmonary hypertension due to chronic thromboembolism (STERN).

Pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, formerly also called primary pulmonary hypertension), hereditary pulmonary arterial hypertension (FPAH) and associated pulmonary arterial hypertension (APH), which is associated with collagen diseases, congenital pulmonary artery bypass grafting, and portal hypertension , HIV infections, taking certain drugs and medications, with other disorders (thyroid diseases, glycogen storage disorders, Gaucher syndrome, hereditary telangiectasia, hemoglobinopathy, myeloproliferative disorders, splenectomy), with disorders that have a significant venous/capillary contribution, such as pulmonary veno-occlusive disorder and pulmonary capillary angiomatosis, as well as persistent pulmonary hypertension of newborns.

Pulmonary hypertension associated with disorders of the left side of the heart includes disease of the left atrium or ventricle, and defects of the mitral or aortic valve.

Pulmonary hypertension due to chronic thromboembolism (PTER) includes thromboembolic occlusion of the proximal pulmonary arteries, thromboembolic occlusion of the peripheral pulmonary arteries, and nonthrombotic pulmonary emboli (tumors, parasites, foreign bodies).

The present invention also provides the use of the compounds of the present invention for the preparation of medicaments for the treatment and/or prevention of pulmonary hypertension associated with sarcoidosis, histiocytosis X and lymphangiomatosis.

In addition, the compounds of the present invention may also be suitable for the treatment of fibrosis of the lungs, liver and kidneys.

The compounds of the present invention are also suitable for the primary prevention of thrombotic or thromboembolic disorders and/or thromboinflammatory disorders and/or hypervascular permeability disorders in patients in whom gene mutations lead to increased enzyme activity or increased levels of zymogens, and they are established appropriate tests/measurements of enzyme activity or zymogen concentrations.

The present invention also provides the use of the compounds of the present invention for the treatment and/or prevention of disorders, especially the disorders mentioned above.

The present invention also provides the use of the compounds of the present invention for the preparation of a medicament for the treatment and/or prevention of disorders, especially the disorders mentioned above.

The present invention also provides a method of treating and/or preventing disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound of the present invention.

The present invention also provides the compounds of the present invention for use in a method of treating and/or preventing disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound of the present invention.

In addition, the present invention provides medicaments containing a compound of the present invention and one or more other active compounds.

In addition, the compounds of the present invention can also be used to prevent coagulation ex vivo, for example, to protect organs to be transplanted from organ damage caused by clot formation and to protect the recipient organ from thromboembolism from the transplanted organ, to preserve blood products and plasma, for cleaning/pretreating catheters and other medical aids and instruments, for coating synthetic surfaces of medical aids and instruments used in vivo or ex vivo, or for biological samples that may contain the factor

- 16 044932

XIa.

The present invention further provides a method of preventing coagulation of blood in vitro, in particular in blood banks or biological samples that may contain factor XIa, the method characterized in that an anticoagulantly effective amount of a compound of the present invention is added.

The present invention also relates to medicinal products containing a compound according to the present invention and one or more additional active compounds, in particular for the treatment and/or prevention of the disorders mentioned above. Preferred examples of active compounds suitable for combination include:

lipid-lowering agents, especially HMG-CoA (3-hydroxy-3methylglutaryl-coenzyme A) reductase inhibitors, such as lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), fluvastatin (Lescol) and atorvastatin (Lipitor);

coronary therapies/vasodilators, especially ACE (angiotensin-converting enzyme) inhibitors, eg captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or AII receptor antagonists (angiotensin II), eg embusartan, losartan, valsartan , irbesartan, candesartan, eprosartan and temisartan, or β-adrenergic receptor antagonists, for example, carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, cartolol, metoprolol, nadolol, penbutolol, pindolol, propanolol and timolol, or alpha-1-adrenergic receptor antagonists , for example prazosin, bunazosin, doxazosin and terazosin, or diuretics, for example hydrochlorothiazide, furosemide, bumetanide, pyretanide, torsemide, amiloride and dihydralazine, or calcium channel blockers, for example verapamil and diltiazem, or dihydropyridine derivatives, for example nifedipine (Adalat ) and nitrendipine (Bayotensin) or nitro-drugs, such as isosorbide-5 mononitrate, isosorbide dinitrate and glycerol trinitrate, or substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulators, such as riociguat;

plasminogen activators (thrombolytics/fibrinolytics) and compounds that promote thrombolysis/fibrinolysis, such as plasminogen activator inhibitor inhibitors (PAI inhibitors) or thrombin-activated fibrinolysis inhibitor inhibitors (TAFI inhibitors), such as, for example, tissue plasminogen activator (t-PA , for example, Actilyse®), streptokinase, reteplase and urokinase, or plasminogen modulating substances causing increased plasmin formation;

anticoagulants (anticoagulants), eg heparin (UFH), low molecular weight heparins (LMW), eg tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin ( M118) and EP42675/ORG42675;

direct thrombin inhibitors (DTIs), such as, for example, Pradaxa (dabigatran), atecegatran (AZD0837), DP-4088, SSR-182289A, argatroban, bivalirudin and tanogitran (BIBT-986 and prodrug BIBT1011), hirudin;

direct factor Xa inhibitors, for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673/RPR-130673), letaxaban (TAK442 ), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux, substances that inhibit platelet aggregation (blood cell aggregation inhibitors, platelet aggregation inhibitors) , such as e.g. acetylsalicylic acid (e.g. aspirin), P2Y12 antagonists such as e.g. ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor, elinogrel, PAR-1 antagonists such as e.g. vorapaxar, PAR-4 antagonists, EP3 antagonists, such as, for example, DG041;

platelet adhesion inhibitors, such as GPVI and/or GPIb antagonists, such as, for example, Revacept or caplacizumab;

fibrinogen receptor antagonists (glycoprotein-IIb/IIIa antagonists), for example abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban;

recombinant activated human protein C, such as, for example, Xigris or recombinant thrombomudulin;

as well as antiarrhythmic drugs.

Combinations in the context of the present invention mean not only dosage forms that contain all the components (so-called fixed combinations) and combination packs that contain components separate from each other, but also components that are administered simultaneously or sequentially, provided that they are used for the prevention and/or treatment of the same disease. It is also possible to combine two or more active ingredients with each other, which means that each of them is thus in two-component or multi-component combinations.

The compounds of the present invention may act systemically and/or locally. For this purpose they can be administered by a suitable route, for example, oral, parenteral, pulmonary,

- 17 044932 by the nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or auricular route, or as an implant or stent.

The compounds of the present invention can be administered in administration forms suitable for these routes of administration.

For oral administration, suitable dosage forms are in accordance with the prior art and deliver the compound according to the invention quickly and/or in a modified manner and which contain the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as, for example, tablets (uncoated or coated, e.g. gastric acid-resistant or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films/wafers, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may bypass the absorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or involve absorption (eg, intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Suitable forms of administration for parenteral administration include, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Oral administration is preferred.

Other methods of administration include, for example, dosage forms for inhalation (including powder inhalers, nebulizers), drops, solutions or nasal sprays, taken on the tongue, sublingually or buccally tablets, films/wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, mash), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg, patch), milks, pastes, foams, powders, implants or stents.

The compounds of the present invention can be converted into the indicated forms of use. This can be carried out in a known manner by mixing with inert, non-toxic, pharmaceutically acceptable excipients. Such excipients include, but are not limited to, carrier substances (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersing or wetting agents (e.g. sodium dodecyl sulfate, polyoxysorbitan oleate), binders ( for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxide) and improving substances taste and/or smell.

The present invention further provides medicaments containing at least one compound of the present invention, preferably together with one or more inert, non-toxic, pharmaceutically acceptable excipients, and their uses for the above purposes.

In the case of parenteral administration, it has generally been found that to achieve effective results, it is preferable to administer amounts of from about 5 to 250 mg every 24 hours. In the case of oral administration, the amount is from about 5 to 500 mg every 24 hours.

However, deviations from the amounts indicated may be necessary if necessary, in particular depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval of administration.

Unless otherwise noted, percentages in the tests and examples that follow are percentages by weight; parts are mass parts. Solvent ratios, dilution factors and concentration data for liquid/liquid solutions are based on volume in each case. Mac./rev. means mass/volume. For example, 10 w/v% means: 100 ml of solution or suspension contains 10 g of substance.

A. Examples.

Abbreviations:

Boc - tert-butyloxycarbonyl;

br s - wide singlet (in NMR);

br d - wide doublet (in NMR);

br t - wide triplet (in NMR);

Cv - column volume;

d - day (days), doublet (in NMR);

TLC - thin layer chromatography;

DCI - direct chemical ionization (in MS);

Dd - doublet of doublets (in NMR);

Ddd - doublet of doublets of doublets (in NMR);

- 18 044932

DMSO - dimethyl sulfoxide;

eq. - equivalent(s);

ESI - electrospray ionization (in MS);

h - hour (hours);

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

HPLC - high-performance liquid chromatography, high pressure;

LC/MS - liquid chromatography combined with mass spectroscopy;

M - multiplet (in NMR);

min - minute (minutes);

MS - mass spectroscopy;

NMR - nuclear magnetic resonance spectroscopy;

Q - quartet or quadruplet (in NMR);

Quin - quintet (in NMR);

RP - reverse phase (in HPLC);

RT - room temperature;

Rt - retention time (in HPLC);

S - singlet (in NMR) Sxt sextet (in NMR);

SFC - supercritical liquid chromatography (with supercritical carbon dioxide as an eluent);

T - triplet (in NMR);

TFA - trifluoroacetic acid;

T3P - 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide.

HPLC, LC-MS and GC methods.

Method 1. Device: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 C18 1.8 µm, 50 mmx1.0 mm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile + 0.025% formic acid; gradient: 0.0 min 10% B ^ 1.2 min 95% B ^ 2.0 min 95% B; oven: 50°C; flow rate: 0.40 ml/min; UV detection: 210-400 nm.

Method 2. Device: Thermo Scientific DSQII; GC: Thermo Scientific Trace GC Ultra; column: Restek RTX-35MS, 15 mx200 µmx0.33 µm; constant helium flow rate: 1.20 ml/min; oven: 60°C; input: 220°C; gradient: 60°C, 30°C/min ^ 300°C (maintained for 3.33 min).

Method 3. Device: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 C18 1.8 µm, 50 mmx1.0 mm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile + 0.025% formic acid; gradient: 0.0 min 5% B ^ 6.0 min 95% B ^ 7.5 min 95% B; oven: 50°C; flow rate: 0.35 ml/min; UV detection: 210-400 nm.

Method 4. Device: Thermo Scientific FT-MS; CVLC: Thermo Scientific UltiMate 3000; column: Waters HSS T3 C18 1.8 µm, 75 mmx2.1 mm; eluent A: water + 0.01% formic acid; eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B ^ 2.5 min 95% B ^ 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210-400 nm.

Method 5. Device: Agilent MS Quad 6150; HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8 µm, 50 mmx2.1 mm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile + 0.025% formic acid; gradient: 0.0 min 10% B ^ 0.3 min 10% B ^ 1.7 min 95% B ^ 3.0 min 95% B; oven: 50°C; flow rate: 1.20 ml/min; UV detection: 205-305 nm.

Method 6. Device: Waters MS SQ detector 2; GC: Agilent A7890; column: Restek RTX-35 MS, 15 mx200 µmx0.33 µm, gas: helium; oven: 60°C; flow rate: 1.20 ml/min; input: 240°C; gradient: 30°C/min ^ 300°C.

Method 7. Device: Shimadzu LCMS-2020; column: CORTECS C18 2.7 µm, 50 mmx2.1 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid, gradient: 0.0 min 5% B ^ 2.0 min 95% B ^ 3.0 min 95% B; oven: 40°C; flow rate: 1.0 ml/min; UV detection: 210-400 nm.

Method 8: Device: Shimadzu LCMS-2020; column: CORTECS C18 2.7 µm, 2.1 mmx50 mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid, gradient: 0.0 min 5% B ^ 1.2 min 100% B ^ 2.0 min 100% B; oven: 40°C; flow rate: 1.0 ml/min; UV detection: 210-400 nm.

Method 9. Device: Shimadzu LCMS-2020; column: Kinetex EVO-C18 2.6 µm, 3.0 mmx50 mm; eluent A: water + 0.2% ammonium hydroxide, eluent B: acetonitrile, gradient: 0.0 min 10% B ^ 2.0 min 95% B ^ 3.0 min 95% B; oven: 45°C; flow rate: 1.2 ml/min; UV detection: 210-400 nm.

Method 10. Device: Shimadzu LCMS-2020; column: CORTECS C18 2.7 µm, 50 mmx2.1 mm; eluent A: water + 0.09% formic acid, eluent B: acetonitrile + 0.1% formic acid, gradient: 0.0 min 5% B ^ 1.2 min 100% B ^ 2.0 min 100% B; oven: 40°C; flow rate: 1.0 ml/min; UV detection: 210-400 nm.

- 19 044932

Method 11. Device: Shimadzu LC-MS-2020; column: Ascentis Express C18 2.7 µm, 50 mmx2.1 mm; eluent A: water with 0.05% trifluoroacetic acid, eluent B: acetonitrile with 0.05% trifluoroacetic acid; gradient: 0.0 min 5% B ^ 1.2 min 100% B ^ 1.7 min 100% B ^ 1.75 min 5% B ^ 2.0 min 5%

IN; oven: 40°C; flow rate: 1.5 ml/min; UV detection: 210-400 nm.

Method 12. Device: Shimadzu LC-MS-2020; column: Ascentis Express C18 2.7 µm, 50 mmx3.0 mm; eluent A: water with 0.05% trifluoroacetic acid, eluent B: acetonitrile with 0.05% trifluoroacetic acid; gradient: 0.0 min 5% B ^ 1.2 min 95% B ^ 1.7 min 95% B ^ 1.8 min 5% B ^ 2.0 min 5% B; oven: 40°C; flow rate: 1.5 ml/min; UV detection: 210-400 nm.

Method 13. Device: Shimadzu LCMS-2020; column: Kinetex EVO C18 2.6 µm, 50 mmx3.0 mm; eluent A: water + 0.03% ammonium hydroxide, eluent B: acetonitrile, gradient: 0.0 min 10% B ^ 1.1 min 95% B ^ 2.0 min 95% B; oven: 40°C; flow rate: 1.2 ml/min; UV detection: 210-400 nm.

Method 14. Device: Shimadzu LCMS-2020; column: Kinetex EVO C18 2.6 µm, 50 mmx3.0 mm; eluent A: water + 0.03% ammonium hydroxide, eluent B: acetonitrile, gradient: 0.0 min 10% B ^ 2.0 min 95% B ^ 3.0 min 95% B; oven: 40°C; flow rate: 1.2 ml/min; UV detection: 210-400 nm.

Method 15. Device: Waters Single Quad MS; HPLC: Waters UPLC Acquity; column: Waters VEN C18 1.7 µm, 50 mmx2.1 mm; eluent A: water + 0.025% ammonia, eluent B: acetonitrile; gradient: 0.0 min 8% B ^ 0.1 min 8% B ^ 1.8 min 95% B ^ 3.5 min 95% B; oven: 50°C; flow rate: 0.45 ml/min; UV detection: 210-400 nm.

Method 16. Device: Waters TOF Device; UPLC: Waters Acquity I-CLASS; column: Waters HSST3 C18 1.8 µm, 50 mmx2.1 mm; eluent A: water + 0.01% formic acid; eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 2% B ^ 0.5 min 2% B ^ 7.5 min 95% B ^ 10.0 min 95% B; oven: 50°C; flow rate: 1.00 ml/min; UV detection: 210-400 nm.

Method 17. Device: Waters TOF Device; UPLC: Waters Acquity I-CLASS; column: Waters Acquity UPLC Peptide VEN C18, 300 A, 1.7 µm; 150 mmx2.1 mm; eluent A: water + 0.01% formic acid, eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 90% A ^ 0.25 min 90% A ^ 8.0 min 45% A ^ 10.0 min 2% A ^ 12.0 min 2% A; oven: 50°C; flow rate: 0.475 ml/min; UV detection: 210 nm.

Method 18. Device: Waters TOF Device; UPLC: Waters Acquity I-CLASS; column: Waters Acquity UPLC HSS T3, 1.8 µm, 50 mmx1 mm; eluent A: water + 0.01% formic acid, eluent B: acetonitrile + 0.01% formic acid; gradient: 0.0 min 95% A ^ 6.0 min 5% A ^ 7.5 min 5% A; oven: 50°C; flow rate: 0.35 ml/min; UV detection: 210 nm.

Method 19. Device: Shimadzu LCMS-2020; column: Poroshell HPH C18 2.7 µm, 50 mmx3.0 mm; eluent A: water 6.5 mm ammonium carbonate, eluent B: acetonitrile, gradient: 0.0 min 10% B ^ 2.1 min 95% B ^ 2.7 min 95% B ^ 2.75 min 10% B; oven: 40°C; flow rate: 1.2 ml/min; UV detection: 190-400 nm.

Microwave. The microwave reactor used was a single module type Emrys™ Optimizer.

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

In the case of the synthesis of intermediates and working examples of the present invention described below, any compound indicated in the form of a salt of the corresponding base or acid is usually a salt of unknown exact stoichiometric composition obtained by an appropriate method of preparation and/or purification. Unless specified in more detail, additions to names and structural formulas such as hydrochloride, trifluoroacetate, sodium salt or xHCl, xCF3COOH, xNa+ should therefore not be understood in a stoichiometric sense in the case of such salts as they are descriptive only in relation to the salt-forming components present in them.

This applies accordingly if the synthetic intermediates or working examples or salts thereof have been prepared in the form of solvates, eg hydrates, of unknown stoichiometric composition (if they are of a particular type) by the preparation and/or purification methods described.

In NMR spectra of mixtures of stereoisomers, numbers marked with / indicate that the stereoisomers exhibit separate signals for the corresponding hydrogen atom, i.e. .../.....(2s,

1H) means that one hydrogen atom is represented by two singlets, each singlet from one or more different stereoisomers.

General methods of synthesis.

- 20 044932

General method 1. Esterification using sodium hydride.

The corresponding alcohol (1.0 eq.) and the corresponding bromide (1.0-1.25 eq.) were dissolved in tetrahydrofuran (0.2-0.4 M) and cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 1.5-3.0 eq.) was then added and stirring was continued for 1-3 hours at 0°C and overnight at room temperature. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride, then washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified either by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate or dichloromethane/methanol mixtures) or preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients) .

General method 2. Mitsunobu reaction using (tributylphosphoranilidene)acetonitrile.

(Tributylphosphoranylidene)acetonitrile (1.5-3.0 eq.) was added to a solution of the appropriate primary or secondary alcohol (1.0 eq.) and the appropriate phenol (1.0-1.5 eq.) in toluene (0.1-0.5 M) in a microwave vessel. The reaction vessel was then sealed, placed in a microwave reactor, irradiated at 100 to 160° C. and stirred at this temperature for 1-8 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified either by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate or dichloromethane/methanol mixtures) or by preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients).

General method 3a. Ring closure using the Miyaura borylation reaction and the Suzuki reaction.

The corresponding ether (1.0 eq.), bis(pinacolato)diborone (1.25-2.0 eq.), palladium(P) acetate (0.03-0.1 eq.), tricyclohexylphosphine (0.1-0.15 eq.) and potassium acetate (3.0-4.5 eq.) was dissolved in N,N-dimethylformamide (0.25-0.4 M), and argon was passed through the resulting suspension for 10 min. The reaction mixture was heated to 80-100°C and stirred at this temperature overnight, followed by the addition of a saturated aqueous solution of sodium bicarbonate (5-7 ml/mmol of the appropriate ether) and tetrakis(triphenylphosphine)palladium(0) (0.03-0.05 equiv .). Stirring was then continued at 80-100°C for a further 2-72 hours, and the reaction mixture was either filtered through silica gel and diluted with dichloromethane, or extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified either by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate or dichloromethane/methanol mixtures) or preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients) .

General method 3b. Ring closure using CH activation.

The appropriate ether (1.0 eq.) and potassium pivalate or potassium acetate (2.0-6.0 eq.) in N,Ndimethylacetamide (0.01-0.1 M) and argon were passed through the mixture for 10 min. Then tetrakis(triphenylphosphine)palladium(0) (0.05-0.2 eq.). was added and the mixture was stirred for 2-48 hours at 100-150°C. The residue was diluted with water and extracted with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified either by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate or dichloromethane/methanol mixtures) or by preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients).

General Method 4: Formation of pyridinone using acetic acid and sodium iodide.

The corresponding 2-methoxypyridine derivative (1.0 eq.) was dissolved in acetic acid (0.05-0.2 M), sodium iodide (2.0-4.0 eq.) was added and the resulting mixture was stirred at 80-100°C for 2-24 hours. Then dichloromethane and a saturated aqueous sodium bicarbonate solution was added and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified either by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate or dichloromethane/methanol mixtures) or preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients), or used in the subsequent reaction without further purification.

General Method 5: Formation of pyridinone using 4-toluenesulfonic acid monohydrate and lithium iodide.

The corresponding 2-methoxypyridine derivative (1.0 eq.) was dissolved in 1-butanol (0.1-0.25 M), 4-toluenesulfonic acid monohydrate (1.5-2.5 eq.) and lithium iodide (5.0-10.0 eq.) were added and the resulting mixture was stirred at 80-100°C for 2-6 hours. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Unrefined product

- 21 044932 was purified either by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures), or by preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients), or used in the subsequent reaction without further purification.

General Method 6: Formation of pyridinone using ethanethiol and sodium hydride.

The corresponding 2-methoxypyridine derivative (1.0 eq.) was dissolved in N,Ndimethylformamide (0.1-0.25 M) followed by the addition of ethanethiol (6.0-10.0 eq.). The mixture was cooled to 0°C, sodium hydride (60% dispersion in mineral oil, 3.0-5.0 eq.) was added, stirring was continued at 0°C for 10-20 minutes and then heated to 80-100°C overnight. Then, water was added, the mixture was neutralized to pH 7 by slowly adding aqueous hydrochloric acid (1 N) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients).

General Method 7. Alkylation of pyridinone derivatives with α-bromo-ester and α-bromoamide derivatives.

The corresponding pyridinone derivative (1.0 eq.) was dissolved in a 4:1 mixture of 2-propanol and acetone (0.05-0.15 M), and 1,1,3,3-tetramethylguanidine (3.0-5.0 eq.) was added at room temperature. After stirring or shaking for 15 minutes, the appropriate α-bromo-ester or α-bromo-amide derivative (1.0-2.5 eq.) was added and stirring or shaking was continued overnight at room temperature. The crude mixture was then directly purified by preparative HPLC or concentrated under reduced pressure, and the crude mixture was purified by preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients).

General method 8. Synthesis of triflate derivatives.

A solution of trifluoromethanesulfonic acid anhydride (1.1-1.3 eq.) in dichloromethane (0.1-0.25 M) in an argon atmosphere was cooled to -78°C and a solution of the corresponding alcohol (1.0 eq.) and trimethylamine or pyridine (1.1-1.5 eq.) in dichloromethane (0.75-1.0 M) was added slowly. Stirring was continued at -78°C for 0.5-2 hours before the mixture was warmed to room temperature, diluted with methyl tert-butyl ether and washed with a 3:1 mixture of saturated aqueous sodium chloride and aqueous hydrochloric acid (1N). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was used in the subsequent reaction without further purification.

General method 9. α-alkylation of N-substituted pyridinone derivatives with triflate or bromide derivatives.

Under an argon atmosphere, the corresponding N-substituted pyridinone derivative (1.0 eq.) was dissolved in tetrahydrofuran (0.1-0.2 M). At -78°C, a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 1.15-1.5 eq.) was added dropwise. After 20-30 min, the corresponding triflate or bromide derivative (1.15-1.5 eq.), dissolved in tetrahydrofuran (0.2-0.4 M), was added slowly. The mixture was stirred at -78°C for 15-30 minutes and for 0.5-1.0 hours at room temperature. The mixture was then cooled to -78°C before glacial acetic acid (1.5-3.0 eq.) was added. The reaction mixture was concentrated under reduced pressure and the crude product was purified either by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate or dichloromethane/methanol mixtures) or preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients ), or used in the subsequent reaction without further purification.

General Method 10: Ester cleavage using lithium hydroxide.

The appropriate ester (1.0 eq.) was dissolved in tetrahydrofuran (0.05-0.15 M) and an aqueous solution of lithium hydroxide or sodium hydroxide (0.3-1.0 M, 5.0-10.0 eq.) was added. The reaction mixture was stirred at room temperature for 2 hours to overnight and acidified by adding aqueous hydrochloric acid (1N). The corresponding crude product was filtered and then washed with water and cyclohexane or directly concentrated under reduced pressure. The residue was then purified by preparative HPLC (reverse phase, eluent: water/acetonitrile or water/methanol gradients), or used in the subsequent reaction without further purification.

General method 11. Amide coupling using T3R/pyridine.

T3P (50% solution in N,N-dimethylformamide or ethyl acetate, 1.54.0 eq.) was added to a solution of the corresponding carboxylic acid (1 eq.) and the corresponding amine (1.1-1.5 eq.) in pyridine (about 0.1 M) at room temperature, and the mixture was then stirred at room temperature or heated to 50-80°C. Alternatively, to a solution of the corresponding carboxylic acid (1.0 eq.) in pyridine (about 0.1 M) was added T3P (50% solution in N,N-dimethylformamide or ethyl acetate, 1.5-4 eq.), and

- 22 044932 the solution was stirred for 1-10 minutes at room temperature. The appropriate amine (1.1-1.5 eq.) was then added and the reaction mixture was stirred at room temperature or heated to 50-80°C. After stirring at the appropriate temperature for 1-48 hours, the reaction mixture was cooled to room temperature and either directly concentrated under reduced pressure or diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified either by column chromatography (cyclohexane/ethyl acetate or dichloromethane/methanol) or preparative HPLC (reverse phase, eluent: water/acetonitrile gradients or water/methanol gradients).

Initial compounds example 1.1 A.

4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (single stereoisomer) ₌ /CH ₃ nh ₂ (2R)-2-bromobutanoic acid (single stereoisomer) (3.5 g, 21.2 mmol, 1.1 eq. ), pyridine (1.7 ml, 21.2 mmol, 1.1 eq.) and T3P (17.2 ml, 50% solution in ethyl acetate, 28.9 mmol, 1.5 eq.) were added under argon at 0-5°C to a suspension of 4-amino-2 -fluorobenzamide (3.0 g, 19.3 mmol) in tetrahydrofuran (30 ml). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was then cooled to 10°C, mixed dropwise with water (35 ml), stirred for 15 minutes, followed by the addition of more water (25 ml), and stirred for 30 minutes. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 5.23 g (90% of theoretical yield). A precipitate then formed from the combined filtrates, which was filtered, washed with water and dried in vacuum. Yield: 0.5 g (9% of theoretical yield).

Both batches: LC-MS (method 4): R _t =1.25 min; MS (ESIpos): m/z=303 [M+H]+.

Example 1.2A.

4-{[(2R)-2-Bromobutanoyl]amino}benzamide (single stereoisomer)

(2R)-2-Bromobutanoic acid (single stereoisomer) (3.97 g, 23.8 mmol, 1.1 eq.) was added slowly under argon to an ice-cooled suspension of 4-aminobenzamide (3.00 g, 21.6 mmol) in tetrahydrofuran (22 mL), with followed by the addition of pyridine (1.9 ml, 23.8 mmol, 1.1 eq.) and T3P (19 ml, 50% solution in ethyl acetate, 32.4 mmol, 1.5 eq.) at a temperature of 0-5°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. Water (35 ml) was added dropwise at 10°C. The reaction mixture was stirred for 15 minutes, followed by the addition of more water (25 ml), and stirred for another 30 minutes. The resulting precipitate was filtered, washed with water and dried in vacuum. The precipitate was suspended in dichloromethane/ethyl acetate, filtered (the filtrate was discarded), suspended in tetrahydrofuran, filtered and dried in vacuo. Yield: 5.72 g (93% of theoretical yield). Further crystallization from the second filtrate gave a further 210 mg (3% of theoretical yield).

Main batch: LC-MS (method 4): R _t =1.12 min; MS (ESIpos): m/z=285 [M+H] ⁺ .

Main batch: 1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.52 (s, 1H), 7.94-7.81 (m, 3H), 7.66 (d, 2H), 7.26 (br s, 1H ), 4.48 (t, 1H), 2.17-1.88 (m, 2H), 0.96 (t, 3H).

Example 1.3A.

(2R)-2-Bromo-N-(2-methyl-2H-benzotriazol-5-yl)butanamide (sole stereoisomer)

(2R)-2-Bromobutanoic acid (single stereoisomer) (695 mg, 4.16 mmol, 1.1 eq.) was added slowly under argon to an ice-cooled suspension of 2-methyl-2H-benzotriazol-5-amine (590 mg, 3.78 mmol) in tetrahydrofuran (3.8 ml), followed by the addition of pyridine (337 µl, 4.16 mmol, 1.1 eq.) and T3P (3.38 ml, 50% solution in ethyl acetate, 5.67 mmol, 1.5 eq.) at a temperature of 0-5°C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 30 minutes. Water (25 ml) was added dropwise at 10°C. The reaction mixture was stirred for 15 min, followed by the addition of ethyl acetate (15 ml). After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine (15 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 980 mg (85% of theoretical yield).

LC-MS (method 1): R _t =0.82 min; MS (ESIpos): m/z=297 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.55 (s, 1H), 8.36 (d, 1H), 7.89 (d, 1H), 7.43 (dd, 1H), 4.51 (t, 1H), 4.46 (s, 3H), 2.19-1.91 (m, 2H), 0.98 (t, 3H).

Example 1.4A.

(2R)-2-Bromo-N-[2-(difluoromethyl)-2H-indazol-5-yl]butanamide (sole stereoisomer)

General method 11 was performed with 2-(difluoromethyl)-2H-indazol-5-amine hydrochloride (24.0 mg, 109 µmol, 1.0 eq.), (2R)-2-bromobutanoic acid (single stereoisomer) (20.1 mg, 120 µmol, 1.1 eq.), pyridine (9.7 µl, 120 µmol, 1.1 eq.) and T3P (98 µl, 50% solution in ethyl acetate, 160 µmol, 1.5 eq.) in tetrahydrofuran (300 µl), including the following variations of the procedure: The mixture was stirred at 0°C during the addition of reagents and at room temperature for 30 minutes. Water was added at 10°C to the reaction mixture and stirring was continued for 15 minutes. The crude mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and used in the subsequent reaction without further purification. Yield: 59.0 mg (quantitative theoretical yield).

LC-MS (method 5): Rt=1.12 min; MS (ESIpos): m/z=332 [M+H]+.

Example 1.5A.

(2R)-2-Bromo-N-[2-(trifluoromethyl)-2H-indazol-5-yl]butanamide (sole stereoisomer)

General method 11 was performed with 2-(trifluoromethyl)-2H-indazol-5-amine hydrochloride (65.3 mg, 272 µmol, 1.0 eq.), (2R)-2-bromobutanoic acid (single stereoisomer) (50.0 mg, 299 µmol, 1.1 eq.), pyridine (24 µl, 300 µmol, 1.1 eq.) and T3P (240 µl, 50% solution in ethyl acetate, 410 µmol, 1.5 eq.) in tetrahydrofuran (500 µl), including the following variations of the procedure: The mixture was stirred at 0°C during the addition of reagents and at room temperature for 30 minutes. Then, additional amounts of (2R)-2-bromobutanoic acid (22.7 mg, 136 µmol, 0.5 eq.) and T3P (81 µl, 50% solution in ethyl acetate, 136 µmol, 0.5 eq.) were added and stirring was continued for 30 min. Water was added at 10°C to the reaction mixture and stirring was continued for 15 minutes. The crude mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and used in the subsequent reaction without further purification. Yield: 181 mg (quantitative theoretical yield).

LC-MS (method 5): R _t =1.25 min; MS (ESIpos): m/z=350 [M+H]+.

Example 1.6A.

Ethyl 3-cyclobutylpropanoate o

To a solution of 3-cyclobutylpropanoic acid (1.00 g, 7.80 mmol, 1.0 eq.) in ethanol (15 ml) was added thionyl chloride (850 μl, 12 mmol, 1.5 eq.) at 0°C. The resulting mixture was then warmed to room temperature and stirred overnight. The crude mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

The crude product was used in the subsequent reaction without further purification. Yield: 1.02 g (84% of theoretical yield).

GC-MS (method 6): R _t =3.15 min; MS (APCIpos): m/z=157 [M+H]+.

Example 1.6V.

Ethyl 2-bromo-3-cyclobutylpropanoate (racemate)

- 24 044932

To a solution of diisopropylamine (1.3 ml, 9.0 mmol, 1.4 equiv.) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium (3.1 ml, 2.5 M in hexane, 7.7 mmol, 1.2 equiv.) at 0°C. After stirring at this temperature for 30 minutes, the mixture was cooled to -78°C and a solution of ethyl 3-cyclobutylpropanoate (1.00 g, 6.40 mmol, 1.0 eq.) in tetrahydrofuran (20 ml) was added dropwise. The mixture was stirred at 78°C for 45 min, followed by the addition of 1,2-dibromo-1,1,2,2-tetrachloroethane (2.50 g, 7.68 mmol, 1.2 eq.) in tetrahydrofuran (10 ml). The resulting mixture was allowed to warm to room temperature over a period of 1 hour, quenched by adding saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 98:2 -9:1). Yield: 540 mg (41% purity, 15% theoretical yield).

GC-MS (method 6): Rt=4.33 min; MS (APCIpos): m/z=235 [M+H]+.

Example 1.6C.

2-Bromo-3-cyclobutylpropanoic acid (racemate)

General method 10 was performed with ethyl 2-bromo-3-cyclobutylpropanoate (racemate) (530 mg, 41% purity, 924 µmol, 1.0 eq) and lithium hydroxide (111 mg, 4.62 mmol, 5.0 eq) in tetrahydrofuran/water (2:1, 9 ml), including the following variations of the procedure: The reaction mixture was stirred at room temperature for 2 hours, then acidified by adding aqueous hydrochloric acid (1N) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the subsequent reaction without further purification.

Example 1.6D.

4-(2-Bromo-3-cyclobutylpropanamido)-2-fluorobenzamide (racemate)

General method 11 was performed twice with the crude product of 2-bromo-3-cyclobutylpropanoic acid (racemate) (50.0 mg, 0.24 mmol, 1.0 eq.), 4-amino-2-fluorobenzamide (55.8 mg, 0.36 mmol, 1.5 eq.) and T3P (0.56 ml, 50% solution in ethyl acetate, 0.97 mmol, 4.0 eq.) in pyridine (3 ml) and the crude product of 2-bromo-3-cyclobutylpropanoic acid (racemate) (410 mg, 1.98 mmol, 1.0 eq.) , 4-amino-2fluorobenzamide (458 mg, 2.97 mmol, 1.5 eq.) and T3P (4.6 mL, 50% solution in ethyl acetate, 7.9 mmol, 4.0 eq.) in pyridine (20 mL), including the following variations of the procedure: Two reactions the mixtures were combined, washed with saturated aqueous ammonium chloride and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 33.0 mg (91% purity, 4% theoretical yield).

LC-MS (method 5): R _t =1.16 min; MS (ESIpos): m/z=343 [M+H] ⁺ .

Example 1.7A.

tert-Butyl 3-(tetrahydro-2H-pyran-2-yl)propanoate (racemate)

Tetrahydro-2H-pyran-2-ylmethanol (racemate) (20.0 g, 172 mmol, 1.0 eq.), tert-butyl acetate (230 ml, 1.7 mol, 10.0 eq.), bis(1,5-cyclooctadiene)diiridium ( I) dichloride (5.78 g, 8.61 mmol, 0.1 eq.), triphenylphosphine (6.77 g, 25.8 mmol, 0.2 eq.) and potassium tert-butanolate (38.6 g, 344 mmol, 2.0 eq.) were dissolved in degassed tert-butanol ( 200 ml) and stirred at 100°C for 6 days. The reaction mixture was filtered and washed again with ethyl acetate. After removal of volatile compounds under reduced pressure, the crude mixture was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate with 0.1% K,K-diisopropylethylamine: 100:0 - 98:2 - 96:4). Yield: 8.40 g (23% of theoretical yield).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.88-3.80 (m, 1H), 3.32-3.24 (m, 1H), 3.20-3.13 (m, 1H), 2.292.13 (m , 2H), 1.78-1.67 (m, 1H), 1.63-1.49 (m, 3H), 1.47-1.35 (m, 3H), 1.39 (s, 9H), 1.18-1.06 (m, 1H).

Example 1.7V.

tert-Butyl 2-bromo-3-(tetrahydro-2H-pyran-2-yl)propanoate (mixture of stereoisomers)

X O CH ₃

Вг γ X

II 1^сн ₃ о сн ₃ ³

N,K-Diisopropylamine (7.7 ml, 55 mmol, 1.4 eq.) was dissolved in tetrahydrofuran (120 ml) and cooled to 0°C before n-butyllithium solution (19 ml, 2.5 M in hexane, 47 mmol, 1.2 eq. .) added. The mixture was stirred at 0°C for 30 min, then cooled to -78°C, followed by dropwise addition of tert-butyl 3-(tetrahydro-2H-pyran-2-yl)propanoate (racemate) (8.40 g, 39.2 mmol , 1.0 eq.) in tetrahydrofuran (62 ml). Stirring was continued at -78°C for 45 min, 1,2-dibromo-1,1,2,2tetrafluoroethane (12.2 g, 47.0 mmol, 1.2 eq.) in tetrahydrofuran (62 ml) was added dropwise and the mixture was heated to room temperature for 1 hour. After adding a saturated aqueous ammonium chloride solution, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate with 0.1% K,K-diisopropylethylamine: 100:0 - 96:4 - 70:30). Yield: 7.00 g (61% of theoretical yield).

GC-MS (method 6): R _t =5.38/5.50 min; MS (APCIpos): m/z=239 [M-tBu+H]+.

Example 1.7C.

2-Bromo-3-(tetrahydro-2H-pyran-2-yl)propanoic acid (mixture of stereoisomers) o

tert-Butyl 2-bromo-3-(tetrahydro-2H-pyran-2-yl)propanoate (mixture of stereoisomers) (7.00 g, 23.9 mmol, 1.0 eq.) was dissolved in trifluoroacetic acid (140 ml) and stirred at room temperature in for 2 hours. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene three times. The crude product was used in the subsequent reaction without further purification. Yield: 5.65 g (quantitative theoretical yield).

GC-MS (method 6): R _t =5.53 min; MS (APCIpos): m/z=239 [M+H]+.

Example 1.7D.

4-({(2R)-2-Bromo-3-[(2S)-tetraαhydro-2H-pyran-2-yl]propαnoyl}amino)-2-fluorobenzamide (sole stereoisomer)

General method 11 was performed with 4-amino-2-fluorobenzamide (3.68 g, 23.9 mmol, 1.0 eq.), 2-bromo-3(tetrahydro-2H-pyran-2-yl)propanoic acid (stereoisomer mixture) (5.66 g, 23.9 mmol, 1.0 eq.), pyridine (2.1 ml, 26 mmol, 1.1 eq.) and T3P (21 ml, 50% solution in ethyl acetate, 36 mmol, 1.5 eq.) in tetrahydrofuran (43 ml), including the following variations of the procedure : After stirring at room temperature overnight, the reaction mixture was worked up by adding water, extracted with ethyl acetate, washed with brine, dried and concentrated under reduced pressure. Separation of the stereoisomers of the crude mixture gave:

single stereoisomer 1 (chiral SFC: R _t =1.52 min): 1.87 g, single stereoisomer 2 (title compound 1.7D) (chiral SFC: R _t =1.66 min, 99% de): 1.90 g (21% of theoretical yield), the only stereoisomer 3 (chiral SFC: R _t =1.30 min): 1.18 g, the only stereoisomer 4 (chiral SFC: R _t =1.34 min): 1.15 g.

Separation method 1. SFC: column: Daicel Chiralpak AD 20 µm, 450 mmx50 mm; eluent: 75% carbon dioxide/25% 2-propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.

- 26 044932

Separation Method 2. Single stereoisomer 3 and single stereoisomer 4 eluted as a mixture during the first separation. This mixture was then separated according to the following conditions:

SFC: column: Daicel Chiralpak AD 20 µm, 450 mmx50 mm; eluent: 20% carbon dioxide/80% 2propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.

Method of analysis: SFC. Column: Daicel Chiralpak AD-H 5 µm, 250 mm x 4.6 mm; eluent: 80% carbon dioxide/20% methanol; flow rate: 3.0 ml/min; UV detection: 210 nm.

LC-MS (method 1): R _t =0.82 min; MS (ESIpos): m/z=373 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.71 (s, 1H), 1.12-1.66 (m, 1H), 7.65-7.59 (m, 1H), 7.57-7.46 (m, 2H ), 7.43-7.26 (m, 1H), 4.80-4.66 (m, 1H), 3.88 (d, 1H), 3.54-3.41 (m, 1H), 3.40-3.33 (m, 1H), 2.11-1.95 (m , 2H), 1.88-1.69 (m, 1H), 1.61 (d, 1H), 1.53-1.38 (m, 3H), 1.31-1.21 (m, 1H).

Example 1.8A.

4-( {(2R)-2-Bromo-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl} amino)benzamide (single stereoisomer)

General method 11 was performed with 4-aminobenzamide (5.95 g, 43.7 mmol, 1.0 eq.), 2-bromo-3(tetrahydro-2H-pyran-2-yl)propanoic acid (mixture of stereoisomers) (11.4 g, 48.1 mmol, 1.1 eq.), pyridine (3.9 ml, 48.1 mmol, 1.1 eq.) and T3P (39 ml, 50% solution in ethyl acetate, 66 mmol, 1.5 eq.) in tetrahydrofuran (79 ml), including the following variations of the procedure: After stirring at room temperature overnight, the reaction mixture was worked up by adding water, extracted with ethyl acetate, washed with brine, dried and concentrated under reduced pressure. Separation of the stereoisomers of the crude mixture gave:

single stereoisomer 1 (title compound 1.8A) (chiral SFC: R _t =1.52 min, 99% de): 2.71 g (17% of theoretical yield), single stereoisomer 2 (chiral SFC: R _t =1.66 min): 3.29 g, single stereoisomer 3 (chiral SFC: R _t =1.30 min): 1.43 g, single stereoisomer 4 (chiral SFC: R _t =1.34 min): 1.45 g.

Separation method 1. SFC. Column: Daicel Chiralpak AD 20 µm, 450 mmx50 mm; eluent: 75% carbon dioxide/25% 2-propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.

Separation Method 2. Single stereoisomer 3 and single stereoisomer 4 eluted as a mixture during the first separation. This mixture was then separated according to the following conditions: SFC: column: Daicel Chiralpak AD 20 µm, 450 mm x 50 mm; eluent: 20% carbon dioxide/80% 2-propanol; temperature: 40°C; flow rate: 400 ml/min; UV detection: 210 nm.

Method of analysis: SFC. Column: Daicel Chiralpak AD-H 5 µm, 250 mm x 4.6 mm; eluent: 80% carbon dioxide/20% methanol; flow rate: 3.0 ml/min; UV detection: 210 nm.

LC-MS (method 1): R _t =0.75 min; MS (ESIpos): m/z=355 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.58 (s, 1H), 7.95-7.82 (m, 3H), 7.71-7.63 (m, 2H), 7.29 (br s, 1H) , 4.81 (dd, 1H), 3.92 (d, 1H), 3.58-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.12-1.99 (m, 2H), 1.80 (d, 1H), 1.64 (d, 1H), 1.57-1.41 (m, 4H), 1.37-1.22 (m, 1H).

Example 1.9A.

tert-Butyl (4R)-4-hydroxypentanoate (single stereoisomer)

To a stirred solution of lithium diisopropylamide (86 ml, 2.0 M in tetrahydrofuran/hexane, 170 mmol, 2.0 eq.) in tetrahydrofuran (250 ml) was added tert-butyl acetate (20.0 g, 172 mmol, 2.0 eq.) dropwise at -78 °C. After stirring for 0.5 h, the mixture was warmed to -40°C, diethylaluminum chloride (170 ml, 1.0 M in hexane, 170 mmol, 2.0 eq.) was added over a period of 20 min and stirring was continued for another 15 min. Then, (2R)-2-methyloxirane (single stereoisomer) (5.00 g, 86.1 mmol, 1.0 eq.) was added and the mixture was stirred at -40°C for 5 hours, followed by the addition of saturated aqueous ammonium chloride and ice in aqueous hydrochloric acid (6H) at -20°C. The mixture was extracted with diethyl ether, and the combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: ngexane/ethyl acetate 4:1). Yield: 8.0 g (90% purity, 48% theoretical yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=4.43 (d, 1H), 3.62-3.49 (m, 1H), 2.33-2.14 (m, 2H), 1.61-1.46 (m, 2H), 1.39 (s, 9H), 1.03 (d, 3H).

Example 1.9V.

tert-Butyl (4R)-4-methoxypentanoate (sole stereoisomer) <у ^СНз ςΟΗ ₃

O^CH ₃ G^cHo O CH ₃ ³

Into a suspension of tert-butyl (4R)-4-hydroxypentanoate (single stereoisomer) (9.00 g, 95% purity, 49.1 mmol, 1.0 eq.) and freshly prepared silver(I) oxide (34.1 g, 147 mmol, 3.0 eq.) in 1,2dichloropentane (150 ml), iodomethane (31 ml, 490 mmol, 10.0 eq.) was added at 0°C. After stirring at 40°C for 72 hours, the reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: n-hexane/ethyl acetate 8:1 - 1:1). Yield: 1.90 g (20% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.28-3.21 (m, 1H), 3.18 (s, 3H), 2.20 (t, 2H), 1.71-1.50 (m, 2H), 1.39 (s, 9H), 1.04 (d, 3H).

Example 1.9C.

tert-Butyl (4R)-2-bromo-4-methoxypentanoate (mixture of two diastereomers)

To a solution of tert-butyl (4R)-4-MemoKcuneHTaHoaT (single stereoisomer) (1.70 g, 8.58 mmol, 1.0 eq.) in tetrahydrofuran (70 ml) was added lithium diisopropylamide (6.4 ml, 2.0 M in tetrahydrofuran, 13 mmol, 1.5 eq. .) at -78°C. After stirring at -78°C for 15 min, a solution of 1,2-dibromo1,1,2,2-tetrachloroethane (6.98 g, 21.4 mmol, 2.5 eq.) in tetrahydrofuran (10 ml) was added dropwise. The resulting mixture was allowed to slowly warm to room temperature over a period of 1 hour and stirred for a further 2 hours before adding water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, eluent: petroleum ether/ethyl acetate 8:1). Yield: 0.95 g (90% purity, 37% theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=4.40-4.28 (m, 1H), 3.47-3.36/3.34-3.26 (2m, 1H), 3.21/3.18 (2s, 3H), 2.21 -1.86 (m, 2H), 1.43/1.42 (2s, 9H), 1.15-1.05 (m, 3H).

Example 1.10A.

tert-Butyl (4S)-4-hydroxypentanoate (sole stereoisomer)

tert-Butyl acetate (4.00 g, 34.4 mmol, 2.0 eq.) was added dropwise at -78°C to a stirred solution of lithium diisopropylamide (17.2 mL, 34.4 mmol, 2M in tetrahydrofuran/n-hexane, 2.0 eq.) in tetrahydrofuran ( 50 ml). After stirring for 0.5 h, the mixture was heated to -40°C. Diethylaluminum chloride (34.4 mL, 34.4 mmol, 1 M in n-hexane, 2.0 eq.) was added over a period of 5 minutes and stirring was continued for an additional 15 minutes. Then, (2S)-2-methyloxyrane (single stereoisomer) (1.00 g, 17.2 mmol, 1.0 eq.) was added and the mixture was stirred at -40°C for 5 h, followed by the addition of a saturated aqueous solution of ammonium chloride and ice in aqueous hydrochloric acid (6H) at -20°C. The mixture was extracted with diethyl ether. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: n-hexane/ethyl acetate 4:1). Yield: 1.50 g (90% purity, 45% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=4.45 (d, 1H), 3.64-3.46 (m, 1H), 2.34-2.12 (m, 2H), 1.61-1.45 (m, 2H ), 1.40 (s, 9H), 1.04 (d, 3H).

- 28 044932

Example 1.10V.

tert-Butyl (4S)-4-methoxypentanoate (single stereoisomer) ₀ , ^sn ςΟΗ ₃

O^CH3 O CH ₃ ³

Iodomethane (61.3 g, 432 mmol, 10.0 eq.) was added at 0°C to a suspension of tert-butyl (4S)-4hydroxypentanoate (single stereoisomer) (8.00 g, 43.2 mmol, 1.0 eq.) and freshly prepared silver(I) oxide. (30.0 g, 130 mmol, 3.0 eq.) in 1,2-dichloroethane (150 ml). After stirring at 40°C for 72 hours, the reaction mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: n-hexane/ethyl acetate 8:1 - 1:1). Yield: 2.20 g (26% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.28-3.21 (m, 1H), 3.18 (s, 3H), 2.20 (t, 2H), 1.68-1.54 (m, 2H), 1.39 (s, 9H), 1.04 (d, 3H).

Alternative synthesis route.

N,N,N',N'-Tetramethylnaphthalene-1,8-diamine (14.36 g, 66.99 mmol, 1.1 equiv., weighed in a glove box!) was added under an argon atmosphere at 0-4°C to a solution of tert-butyl ( 4S)-4-hydroxypentanoate (single stereoisomer) (13.10 g, 60.90 mmol) in dichloromethane (260 ml). The reaction mixture was stirred at room temperature for 30 min, cooled again to 0-4°C, mixed with trimethyloxonium tetrafluoroborate (19.91 g, 127.89 mmol, 2.1 eq., weighed in a glove box!), stirred for 30 min at 0- 4°C and then for 60 minutes, allowing it to warm to room temperature. The reaction mixture was quenched with water (250 ml) and diluted with dichloromethane (150 ml). The precipitate was filtered off and discarded. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (>100 mbar and <25°C). The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient, evaporation of eluent at >80 mbar and <30°C). Yield: 10.13 g (88% of theoretical yield).

1H-NMR (600 MHz, DMSO-d6): δ [ppm]=3.28-3.22 (m, 1H), 3.19 (s, 3H), 2.20 (t, 2H), 1.64-1.57 (m, 2H), 1.39 (s, 9H), 1.05 (d, 3H).

Example 1.10C.

tert-Butyl (4S)-2-bromo-4-methoxypentanoate (mixture of two diastereomers)

Lithium diisopropylamide (5.7 ml, 11.4 mmol, 2.0 M in tetrahydrofuran, 1.5 eq.) was added at 78°C to a solution of tert-butyl (4S)-4-methoxypentanoate (single stereoisomer) (1.50 g, 7.6 mmol, 1.0 eq.) in tetrahydrofuran (60 ml). After stirring at -78°C for 15 min, a solution of 1,2-dibromo1,1,2,2-tetrachloroethane (6.16 g, 18.9 mmol, 2.5 eq.) in tetrahydrofuran (8 ml) was added dropwise. The resulting mixture was allowed to slowly warm to room temperature over a period of 1 hour and stirred for a further 2 hours before adding water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, eluent: petroleum ether/ethyl acetate 8:1). Yield: 0.94 g (85% purity, 40% theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=4.41-4.28 (m, 1H), 3.47-3.36/3.35-3.25 (2m, 1H), 3.21/3.18 (2s, 3H), 2.21 -1.85 (m, 2H), 1.43/1.42 (2s, 9H), 1.15-1.05 (m, 3H).

Example 1.10D.

(4S)-2-Bromo-4-methoxypentanoic acid (mixture of two diastereomers)

Trifluoroacetic acid (13.3 mL, 172.6 mmol, 20 eq.) was added dropwise under argon to an ice-cold solution of tert-butyl (4S)-2-bromo-4-methoxypentanoate (a mixture of two diastereomers)

- 29 044932 (2.7 g, 85% purity, 8.6 mmol) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of more trifluoroacetic acid (3.3 mL, 43.2 mmol, 5.0 eq.). After stirring for another 1 hour, the reaction mixture was concentrated in vacuo and co-evaporated with dichloromethane. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: 1.37 g (75% of theoretical yield).

1H-NMR (600 MHz, DMSO-d6): δ [ppm]=4.41-4.36 (m, 1H), 3.48-3.40/3.35-3.28 (2m, 1H), 3.23/3.19 (2s, 3H), 2.17- 2.02/1.96-1.89 (2m, 2H), 1.12/1.10 (2d, 3H).

Alternative synthesis route.

Lithium hydroxide monohydrate (233 g, 5.55 mol, 2.1 eq.) was added at room temperature to a solution of methyl (4S)-2-bromo-4-methoxypentanoate (a mixture of two diastereomers) (625 g, 94% purity, 2.61 mol) in the mixture tetrahydrofuran/water (3:1, 6.1 L). The reaction mixture was stirred at room temperature overnight and mixed with 1N aqueous hydrochloric acid (5 L). The aqueous phase was extracted with 2methyltetrahydrofuran. The organic phase was dried and evaporated under reduced pressure. The crude material was used without further purification. Yield: 595 g (94% purity, quantitative theoretical yield).

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=12.9 (br s, 1H, two diastereomers), 4.44-4.30 (m, 1H, two diastereomers), 3.47-3.40 (m, 1H, major diastereomer), 3.37-3.27 (m, 1H, minor diastereomer), 3.22 (s, 3H, major diastereomer), 3.18 (s, 3H, minor diastereomer), 2.17-2.00 (m, 2H, two diastereomers), 1.11 ( d, 3H, major diastereomer), 1.09 (d, 3H, minor diastereomer).

Example 1.10E.

4-{ [(2R,4S)-2-Bromo-4-methoxypentanoyl] amino } benzamide (single stereoisomer)

(4S)-2-Bromo-4-methoxypentαnoic acid (mixture of two diastereomers) (1.37 g, 6.5 mmol), pyridine (579 μl, 7.2 mmol, 1.1 eq.) and T3P (5.7 ml, 50% solution in ethyl acetate, 9.8 mmol, 1.5 eq.) was added under argon at room temperature to a solution of 4-aminobenzamide (975 mg, 7.2 mmol, 1.1 eq.) in tetrahydrofuran (25 ml). The reaction mixture was stirred at room temperature for 2 hours, quenched with water and diluted with ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane/methanol gradient). Yield: 1.91 g (86% of theoretical yield).

LC-MS (method 4): R _t =1.18 min; MS (ESIpos): m/z=329 [M+H]+.

Separation of diastereomers of 1910 mg of 4-{[(4S)-2-bromo-4-methoxypentanoyl]amino}benzamide (a mixture of two diastereomers) gave a single stereoisomer 1 (titled compound Example 1.10E) (chiral HPLC: R _t =11.7 min , >99% de): 901 mg, single stereoisomer 2 (chiral HPLC: R _t =14.0 min, 89% de): 576 mg.

Separation method: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 80% nheptane/20% ethanol; temperature: 40°C; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx4.6 mm; eluent: 80% isohexane/20% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.56 (s, 1H), 7.92-7.81 (m, 3H), 7.65 (d, 2H), 7.25 (br s, 1H), 4.75 (t, 1H), 3.54-3.44 (m, 1H), 3.26 (s, 3H), 2.10-2.02 (m, 2H), 1.15 (d, 3H).

Alternative synthesis route.

Under nitrogen, 4-aminobenzamide (419 g, 3.08 mol, 1.17 eq.) in tetrahydrofuran (6.1 L) was treated at room temperature with (4S)-2-bromo-4-methoxypentanoic acid (a mixture of two diastereoisomers) (591 g, 94 % purity, 2.63 mol), pyridine (249 ml, 3.08 mol, 1.17 eq.) and T3P (50% in ethyl acetate, 2.51 1, 4.21 mol). After 4 hours of stirring at room temperature, the reaction mixture was diluted with ethyl acetate (7.0 L) and then with water (8.0 L). After extraction and phase separation, the aqueous phase was re-extracted with ethyl acetate (7.0 L). The combined organic phases were washed with saturated aqueous sodium chloride (6.0 L). The residue was suspended in diisopropyl ether (7.5 L) and ethyl acetate (550 ml) and stirred for 2.5 hours at room temperature. The mixture was filtered under reduced pressure. Methanol was added with stirring to ensure good filtration. The resulting solid was washed with diisopropyl ether and dried under air. This substance was triturated with acetonitrile at 80°C for 20 minutes. The suspension was allowed to slowly reach room temperature and then cooled to 0°C. After mixing

- 30 044932 for 1 hour, the suspension was filtered under reduced pressure, the residue was washed with cold acetonitrile and then dried in air (yield: 81 g). The filtrate from the first filtration was concentrated under reduced pressure and the resulting residue was triturated with acetonitrile (5.0 L) at 80°C for 20 min. The suspension was allowed to slowly reach room temperature and then cooled to 0°C. After stirring for 1 hour, the suspension was filtered under reduced pressure, the residue was washed with cold acetonitrile and then dried under air (yield: 451 g). The combined filtrates were concentrated under reduced pressure and the resulting residue was dissolved with acetonitrile (1.0 L) at 60°C. The suspension was allowed to slowly reach room temperature and then cooled to 0°C. After stirring for 1 hour, the suspension was filtered under reduced pressure, the residue was washed with cold acetonitrile and then dried in air. This substance was dissolved in dichloromethane and methanol and loaded onto Isolute. This substance was purified by column chromatography (Biotage Isolera LS, 1.5 kg SNAP-Ultra cartridge, eluent: dichloromethane/20% acetone (1 cv), 20-60% acetone gradient (10 cv), 60% acetone (2 cv), yield 63 d. Separation of the diastereomers of all crude products (81 g, 451 g and 63 g) by SFC gave the product as a single stereoisomer.Combined yield: 266 g (31% theoretical yield, >99% de).

Separation method: SFC: column: Chiralpak AY, 20 µm, 250 mmx50 mm, eluent: isocratic 82% carbon dioxide/18% methanol, 5 min, temperature: 30°C; flow rate: 350 ml/min; UV detection: 210 nm; back pressure 100 ba and SFC: column: Chiralpak AZ 20 µm, 350 mmx50 mm, eluent: isocratic 65% carbon dioxide/35% methanol; 5 min, temperature: 30°C; flow rate: 350 ml/min; UV detection: 210 nm; back pressure: 100 bar.

Chiral SFC: R _t =1.56 min, >99% de.

Method of analysis: SFC. Column: Chiralcel AY-3, 3 µm, 100 mm x 4.6 mm, eluent: isocratic 80% carbon dioxide/20% methanol; 10 min, temperature: 40°C; flow rate: 3.0 ml/min; UV detection: 210 nm; back pressure: 130 bar.

LC-MS (method 4): R _t =1.16 min; MS (ESIpos): m/z=329, 331 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.5 (br s, 1H), 7.85 (br d, 3H), 7.65 (br d, 2H), 7.23 (br s, 1H) , 4.75 (br t, 1H), 3.57-3.43 (m, 1H), 3.26 (s, 3H), 2.07 (br t, 2H), 1.15 (brd, 3H).

Example 1.11A.

tert-Butyl 4-oxobutanoate

3,3,3-Triacetoxy-3-iodophthalide (123.7 g, 291.6 mmol, 2.0 eq.) was added portionwise at 0°C to a mixture of tert-butyl 4-hydroxybutanoate (23.4 g, 145.8 mmol, 1.0 eq.) and bicarbonate sodium (24.5 g, 291.6 mmol, 2.0 eq.) in dichloromethane (500 ml). After stirring at room temperature for 2 hours, the reaction mixture was quenched by adding a mixture of saturated aqueous sodium carbonate and sodium trisulfate (1:1), stirred for another 30 minutes and extracted with dichloromethane. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 95:5). Yield: 15.4 g (63% of theoretical yield).

¹ H-NMR (300 MHz, CDCl ₃ ): δ [ppm]=9.79 (s, 1H), 2.76-2.68 (m, 2H), 2.59-2.50 (m, 2H), 1.43 (s, 9H).

Example 1.11B.

tert-Butyl 4-cyclopropyl-4-hydroxybutanoate (racemate)

HE

Cyclopropylmagnesium bromide (185.0 mL, 1.0 M in tetrahydrofuran, 185.0 mmol, 2.0 eq.) was added under argon at -10°C to a stirred solution of tert-butyl 4-oxobutanoate (15.4 g, 92.5 mmol) in tetrahydrofuran (300 mL). The reaction mixture was allowed to warm to room temperature over a period of 1 hour, stirred for an additional 1 hour, quenched with aqueous hydrochloric acid (2N), diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 90:10). Yield: 5.88 g (85% purity, 27% theoretical yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=4.55-4.30 (m, 1H), 2.89-2.72 (m, 1H), 2.39-2.13 (m, 2H), 1.821.52 ( m, 2H), 1.39 (s, 9H), 0.88-0.67 (m, 1H), 0.45-0.05 (m, 4H).

- 31 044932

Example 1.11C.

tert-Butyl 4-cyclopropyl-4-methoxybutanoate (racemate)

Iodomethane (34.82 g, 245.3 mmol, 10.0 eq.) was added under argon at room temperature to a mixture of tert-butyl 4-cyclopropyl-4-hydroxybutanoate (racemate) (5.78 g, 85% purity, 24.5 mmol) and freshly prepared silver oxide (I) (17.05 g, 73.6 mmol, 3.0 eq.) in 1,2-dichloroethane (100 ml). After stirring at 45°C for 24 hours, the resulting mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was redissolved in 1,2-dichloroethane (100 ml), followed by the addition of silver(I) oxide (8.53 g, 36.8 mmol, 1.5 eq.) and sweep (17.41 g, 122.7 mmol, 5.0 eq.) under argon at room temperature. The resulting mixture was stirred at 45°C for 48 hours and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 99:1 to 80:20). Yield: 1.44 g (27% of theoretical yield).

¹ H-NMR (300 MHz, CDCl ₃ ): δ [ppm]=3.38 (s, 3H), 2.53-2.42 (m, 1H), 2.42-2.28 (m, 2H), 1.97-1.77 (m, 2H) , 1.44 (s, 9H), 0.84-0.69 (m, 1H), 0.68-0.54 (m, 1H), 0.53-0.31 (m, 2H), 0.14-0.02 (m, 1H).

Example 1.11D.

tert-Butyl 2-bromo-4-cyclopropyl-4-methoxybutanoate (mixture of stereoisomers)

Lithium diisopropylamide (4.9 mL, 2.0 M in tetrahydrofuran, 9.9 mmol, 1.5 eq.) was added under argon at -78°C to a solution of tert-butyl 4-cyclopropyl-4-methoxybutanoate (racemate) (1.44 g, 6.6 mmol) in tetrahydrofuran (20 ml). The resulting mixture was stirred at -78°C for 1 hour, followed by the dropwise addition of a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (2.57 g, 7.9 mmol, 1.2 eq.) in tetrahydrofuran (10 ml ) at -78°C. The resulting mixture was allowed to warm to room temperature, stirred for an additional 2 hours, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluent: petroleum ether/ethyl acetate 80:20). Yield: 1.52 g (80% purity, 63% theoretical yield).

¹ H-NMR (400 MHz, CDC^): δ [ppm]=4.42-4.33 (m, 1H), 3.43/3.36 (2s, 3H), 2.74-2.61 (m, 1H), 2.572.49/2.44- 2.34 (2m, 1H), 2.29-2.19 (m, 1H), 1.47 (s, 9H), 0.87-0.72 (m, 1H), 0.71-0.60 (m, 1H), 0.53-0.36 (m, 2H), 0.19-0.03 (m, 1H).

Example 1.11E.

2-Bromo-4-cyclopropyl-4-methoxybutanoic acid (mixture of stereoisomers)

Trifluoroacetic acid (6.2 mL, 80.2 mmol, 20 eq.) was added dropwise under argon to an ice-cooled solution of tert-butyl 2-bromo-4-cyclopropyl-4-methoxybutanoate (stereoisomer mixture) (1.47 g, 80% purity, 4.01 mmol) in dichloromethane (40 ml). The reaction mixture was stirred at room temperature for 1.5 h, concentrated in vacuo and co-evaporated twice with dichloromethane. The residue was purified by column chromatography (silica gel, eluent: dichloromethane/methanol gradient). Yield: 641 mg (67% of theoretical yield).

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=13.15 (br s, 1H), 4.44-4.34 (m, 1H), 3.32/3.27 (2s, 3H), 3.042.97/2.85 -2.79/2.72-2.62 (3m, 1H), 2.35-2.28/2.28-2.21 (2m, 1H), 2.19-2.11/2.07-2.00 (2m, 1H), 0.88-0.73 (m, 1H), 0.64-0.53 (m, 1H), 0.50-0.36 (m, 2H), 0.12-0.0 (m, 1H).

Example 1.11F.

4-{[(2R,4R)-2-Bromo-4-cyclopropyl-4-methoxybutanoyl]amino}benzamide (single stereoisomer)

- 32 044932

2-Bromo-4-cyclopropyl-4-methoxybutanoic acid (mixture of stereoisomers) (641 mg, 2.70 mmol), pyridine (241 μl, 2.97 mmol, 1.1 eq.) and T3P (2.37 ml, 50% solution in ethyl acetate, 4.06 mmol , 1.5 eq.) was added under argon at room temperature to a solution of 4-aminobenzamide (368 mg, 2.70 mmol, 1.0 eq.) in tetrahydrofuran (15 ml). The reaction mixture was stirred at room temperature for 1.5 h before adding more 4-aminobenzamide (110 mg, 0.81 mmol, 0.3 eq.) and T3P (316 μl, 50% solution in ethyl acetate, 0.54 mmol, 0.2 eq.) and stirring for another 1 hour. The reaction mixture was quenched with water and diluted with ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Yield: 941 mg.

Separation of stereoisomers of 941 mg of 4-(2-bromo-4-cyclopropyl-4-methoxybutane-amido)benzamide (mixture of stereoisomers) gave a mixture of two stereoisomers 1+2 (chiral SFC: Rt=2.81 min): 197 mg, single stereoisomer 3 ( chiral SFC: Rt=3.25 min, 98% ee): 134 mg, single stereoisomer 4 (titled compound example 1.11F) (chiral SFC: Rt=3.58 min, 98% ee): 123 mg.

Method of separation. SFC: column: Daicel OJ-H, 250 mmx20 mm; eluent: 89% carbon dioxide/11% ethanol; temperature: 40°C; flow rate: 80 ml/min; UV detection: 210 nm.

Method of analysis. SFC. Column: Daicel OJ-3, 50 mmx4.6 mm; eluent: 90% carbon dioxide/10% methanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

LC-MS (method 4): Rt=1.38 min; MS (ESIneg): m/z=353 [M-N]-.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.55 (s, 1H), 7.89-7.81 (m, 3H), 7.65 (d, 2H), 7.23 (br s, 1H), 4.74 (dd, 1H), 3.36 (s, 3H), 2.70 (dt, 1H), 2.26-2.13 (m, 2H), 0.84-0.76 (m, 1H), 0.65-0.57 (m, 1H), 0.49- 0.41 (m, 2H), 0.06-0.0 (m, 1H).

Example 1.12A.

tert-Butyl 4-(difluoromethoxy)butanoate

Gn O^F

L/° _> / ^CH 3 P Ъсн, о сн ₃ ³

[Bromo(difluoro)methyl](trimethyl)silane (5.28 ml, 29.6 mmol, 2.0 eq.) was added dropwise under argon at room temperature to a solution of tert-butyl 4-hydroxybutanoate (2.50 g, 14.8 mmol) and potassium acetate ( 5.82 g, 59.3 mmol, 4.0 eq.) in a mixture of dichloromethane (8.7 ml) and water (8.7 ml). The reaction mixture was stirred overnight and diluted with dichloromethane and water. After phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Unrefined product without further purification. Yield: 3.82 g.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=6.63 (t, 1H), 3.82 (t, 2H), 2.27 (t, 2H), 1.83-1.75 (m, 2H), 1.40 (s, 9H).

Example 1.12V.

tert-Butyl 2-bromo-4-(difluoromethoxy)butanoate (racemate)

A solution of n-butyllithium (12.2 ml, 1.6 M in hexane, 19.5 mmol, 1.2 eq.) was added dropwise under argon at 0°C to a solution of diisopropylamine (3.2 ml, 22.8 mmol, 1.4 eq.) in tetrahydrofuran (25 ml) . The reaction mixture was stirred at 0°C for 30 minutes and cooled to -78°C. A solution of tert-butyl 4-(difluoromethoxy)butanoate (3.8 g, 90% purity, 16.3 mmol) in tetrahydrofuran (12.5 ml) was added dropwise and stirred at -78°C for 30 min. A solution of 1,2-dibromo-1,1,2,2-tetrafluoroethane (5.1 g, 19.5 mmol, 1.2 eq.) was added dropwise and stirred at -78°C for 10 min. The reaction mixture was allowed to warm to room temperature, stirred for another 1 hour and quenched

- 33 044932 with a saturated aqueous solution of ammonium chloride. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Exit:

1.7 g (36% of theoretical yield).

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=6.59 (t, 1H), 4.35-4.30 (m, 1H), 3.90-3.80 (m, 2H), 2.30-2.22 (m, 1H), 2.10-2.02 (m, 1H).

Example 1.13A.

tert-Butyl (4R)-4-(difluoromethoxy)pentanoate (sole stereoisomer)

[Bromo(difluoro)methyl](trimethyl)silane (6.64 g, 32.7 mmol, 3.0 eq.) and potassium bifluoride (5.11 g, 65.4 mmol, 6.0 eq.) were added at room temperature to the tert-butyl (4R)-4hydroxypentanoate mixture (single stereoisomer) (2.00 g, 10.9 mmol) in dichloromethane (7 ml) and water (7 ml) in a plastic container. After stirring at room temperature for 10 hours, the reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Yield: 2.17 g (85% of theoretical yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=6.22 (t, 1H), 4.37-4.26 (m, 1H), 2.41-2.31 (m, 2H), 1.89-1.77 (m, 2H) , 1.46 (s, 9H), 1.31 (d, 3H).

¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ [ppm]=-80.81 (q, 2F).

Example 1.13V.

tert-Butyl (4R)-2-bromo-4-(difluoromethoxy)pentanoate (mixture of two diastereomers)

Lithium diisopropylamide (3.9 mL, 2.0 M in tetrahydrofuran, 7.7 mmol, 1.2 eq.) was added at 78°C under argon to a solution of tert-butyl (4R)-4-(difluoromethoxy) pentanoate (single stereoisomer) (1.50 g, 6.4 mmol) in tetrahydrofuran (20 ml). The resulting mixture was stirred at -78°C for 1 hour, followed by the dropwise addition of a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (2.30 g, 7.1 mmol, 1.1 equiv.) in tetrahydrofuran (8 ml ) at -78°C. The resulting mixture was allowed to warm to room temperature, stirred for an additional 4 hours, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The crude product was purified by preparative thin layer chromatography (silica gel, eluent: petroleum ether/ethyl acetate 83:17). Yield: 0.85 g (85% purity, 37% theoretical yield).

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=6.44-5.96 (m, 1H), 4.59-4.40 (m, 1H), 4.38-4.21 (m, 1H), 2.39-2.01 (m, 2H ), 1.51/1.44 (2s, 9H), 1.36/1.32 (2d, 3H).

¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ [ppm]=-84.64 - -79.29 (m, 2F).

Example 1.14A.

tert-Butyl (4S)-4-(difluoromethoxy)pentanoate (sole stereoisomer)

A mixture of tert-butyl (4S)-4-hydroxypentanoate (single stereoisomer) (3.00 g, 16.2 mmol, 1.0 eq.) in dichloromethane (10 ml) and water (10 ml) was added to a plastic vessel, followed by the addition of [bromo(difluoro) )methyl](trimethyl)silane (9.86 g, 48.6 mmol, 3.0 eq.) and potassium hydrodifluoride (7.58 g, 97.1 mmol, 6.0 eq.) at room temperature. After stirring at room temperature in

- 34 044932 for 10 hours, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and used in the subsequent reaction without further purification. Yield: 3.50 g (92% of theoretical yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=6.47-5.97 (m, 1H), 4.39-4.18 (m, 1H), 2.39-2.25 (m, 2H), 1.90-1.72 (m, 2H), 1.45 (s, 9H), 1.30 (d, 3H).

Example 1.14V.

tert-Butyl (48)-2-bromo-4-(difluoromethoxy)pentanoate (mixture of two diastereomers)

Lithium diisopropylamide (8.9 ml, 2.0 M in tetrahydrofuran, 17.8 mmol, 1.2 eq.) was added at 78°C to a solution of tert-butyl (4S)-4-(difluoromethoxy)pentanoate (single stereoisomer) (3.50 g, 14.8 mmol, 1.0 eq.) in tetrahydrofuran (40 ml). After stirring at -78°C for 1 hour, 1,2-dibromo1,1,2,2-tetrachloroethane (5.79 g, 17.8 mmol, 1.2 eq.) in tetrahydrofuran (15 ml) was added. The resulting mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (silica gel, eluent: petroleum ether/ethyl acetate 91:9). Yield: 2.09 g (45% of theoretical yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=6.48-5.92 (m, 1H), 4.52-4.44 (m, 1H), 4.36-4.22 (m, 1H), 2.44-1.98 (m, 2H), 1.49/1.49 (2s, 9H), 1.36/1.32 (2d, 3H).

Example 1.15A.

Cyclobutyl 4-methylbenzene-1-sulfonate

A solution of cyclobutanol (13 ml, 170 mmol, 1.0 eq.) in pyridine (86 ml) was cooled to 0°C, then 4methylbenzene-1-sulfonyl chloride (34.9 g, 183 mmol, 1.1 eq.) was added in parts and stirring was continued in for 80 min. Then, the reaction mixture was poured into a mixture of ice and water, extracted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was then dissolved in n-heptane and concentrated again three times. The crude product was used in the next step without further purification. Yield: 33.9 g (90% of theoretical yield).

GC-MS (method 6): Rt=6.65 min; MS (APCIpos): m/z=227 [M+H]+.

Example 1.15V.

4-(Cyclobutyloxy)butan-1-ol

A solution of butane-1,4-diol (39.8 g, 442 mmol, 10.0 eq.) and potassium hydroxide (4.96 g, 88.4 mmol, 2.0 eq.) in 1,4-dioxane (220 ml) was heated to 105°C before adding a solution of cyclobutyl 4-methylbenzene 1-sulfonate (10.0 g, 44.2 mmol, 1.0 eq.) in 1,4-dioxane (46 ml). The mixture was stirred at 105°C for 4 hours, then diatomaceous earth was added and the suspension was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 1:1 - 3:7 - 1:9). Yield: 7.1 g (71% purity, 79% theoretical yield).

GC-MS (method 6): Rt=3.61 min; MS (APCIpos): m/z=145 [M+H] ⁺ .

Example 1.15C.

4-(Cyclobutyloxy)butanoic acid

- 35 044932

Sulfuric acid (9.7 ml) and water (60 ml) were added to a solution of chromium trioxide (11.1 g, 111 mmol, 8.0 eq.) in water (30 ml) at 0°C. The resulting mixture was stirred at 0°C for 15 min and then transferred to a solution of 4-(cyclobutyloxy)butan-1-ol (2.00 g, 13.9 mmol, 1.0 eq.) in acetone (40 ml) at room temperature. Stirring was continued at room temperature for 16 hours, followed by the addition of water and extraction with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 1.30 g of crude product.

GC-MS (method 6): R _t =4.05 min; MS (APCIpos): m/z=159 [M+H]+.

Example 1.15D.

Ethyl 4-(cyclobutyloxy)butanoate

Thionyl chloride (1.2 mL, 16 mmol, 2.0 eq.) was added dropwise to a crude mixture of 4-(cyclobutyloxy)butanoic acid (1.30 g, 8.22 mmol, 1.0 eq.) in ethanol (29 mL) at 0°C. The resulting mixture was allowed to warm to room temperature and stirring was continued for 4 hours before the mixture was concentrated under reduced pressure and co-evaporated with toluene. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 9:1 - 4:1 - 7:3 3:1 - 1:1). Yield: 100 mg (76% purity, 5% theoretical yield) and 270 mg (86% purity, 15% theoretical yield).

GC-MS (method 6): R _t =4.15 min; MS (APCIpos): m/z=187 [M+H]+.

Example 1.15E.

Ethyl 2-bromo-4-(cyclobutyloxy)butanoate (racemate)

To a solution of diisopropylamine (280 μL, 2.0 mmol, 1.4 equiv.) in tetrahydrofuran (4.6 ml) was added a solution of n-butyllithium (700 μL, 2.5 M in hexane, 1.7 mmol, 1.2 equiv.) at 0°C. After stirring at this temperature for 30 min, the mixture was cooled to -78°C and a solution of 1,2-dibromo-1,1,2,2tetrachloroethane (566 mg, 1.74 mmol, 1.2 eq.) in tetrahydrofuran (4.6 ml) was added drop by drop. The mixture was stirred at -78°C for 45 min, followed by the addition of more 1,2-dibromo-1,1,2,2tetrachloroethane (566 mg, 1.74 mmol, 1.2 eq.) portionwise. The resulting mixture was allowed to warm to room temperature over a period of 1 hour, quenched by adding saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 98:2 - 96:4 - 94:6 - 92:8 - 9:1). Yield: 120 mg (75% purity, 23% theoretical yield).

GC-MS (method 6): R _t =5.13 min; MS (APCIpos): m/z=266 [M+H]+.

Example 1.16A.

Ethyl 5,5,5-trifluoro-4-hydroxypentanoate (racemate)

To a solution of ethyl 5,5,5-trifluoro-4-oxopentanoate (4.00 g, 20.2 mmol, 1.0 eq.) in ethanol (40 ml), sodium borohydride (3.82 g, 100.9 mmol, 5.0 eq.) was added in parts at 0° WITH. After stirring at

- 36 044932 room temperature for 5 hours, the reaction mixture was poured into a mixture of aqueous hydrochloric acid (0.5 N) and ethyl acetate and stirred for 10 minutes. The aqueous solution was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 92:8). Yield: 1.65 g (39% of theoretical yield).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=6.22 (d, 1H), 4.06 (q, 2H), 4.01-3.89 (m, 1H), 2.48-2.41 (m, 2H), 1.90-1.79 (m, 1H), 1.73-1.60 (m, 1H), 1.18 (t, 3H).

Example 1.16V.

Ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoropentanoate (racemate)

To a solution of ethyl 5,5,5-trifluoro-4-hydroxypentanoate (racemate) (1.10 g, 5.3 mmol, 1.0 eq.) in acetonitrile (15 ml), add imidazole (1.40 g, 21.1 mmol, 4.0 eq.) and butyldimethylsilyl chloride (2.40 g, 15.8 mmol, 3.0 eq.) at room temperature. The mixture was then heated to reflux and stirred at this temperature for 7 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether). Yield: 1.30 g (75% of theoretical yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=4.16 (q, 2H), 4.11-4.01 (m, 1H), 2.55-2.37 (m, 2H), 2.09-1.84 (m, 2H) , 1.27 (t, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H).

Example 1.16C.

Ethyl 2-bromo-4-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoropentanoate (mixture of stereoisomers) H ₃ CI CH ₃ ³ CH ₃

A solution of lithium diisopropylamide ( 2.0 ml, 2.0 M in tetrahydrofuran, 4.0 mmol, 1.0 eq.) at -78°C. After stirring at -78°C for 1 hour, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (1.42 g, 4.4 mmol, 1.1 eq.) in tetrahydrofuran (6 ml) was added. The resulting mixture was allowed to warm to room temperature and stirred for an additional 4 hours. Water was then added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 98:2). Yield: 1.10 g (69% purity, 49% of theoretical yield).

¹ H-NMR (300 MHz, CDCl ₃ ): δ [ppm]=4.39-4.04 (m, 3H), 2.72-2.41 (m, 1H), 2.37-2.21 (m, 1H), 2.13-1.79 (m, 1H), 1.45-1.17 (m, 3H), 0.94-0.88 (m, 9H), 0.23-0.00 (m, 6H).

Example 1.17A.

Ethyl 5,5,5-trifluoro-4-methoxypentanoate (racemate)

Freshly prepared silver(I) oxide (10.0 g, 43.2 mmol, 3.0 equiv.) and iodomethane (9.0 ml, 140 mmol, 10.0 equiv.) at room temperature and the mixture was heated to 35°C. After stirring for 54 hours at this temperature, the reaction mixture was cooled to room temperature, filtered through Celite® and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 96:4). Yield: 600 mg (20% of theoretical yield).

- 37 044932 ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=4.07 (q, 2H), 3.97-3.80 (m, 1H), 3.45 (s, 3H), 2.48-2.40 (m , 2H),

1.96-1.82 (m, 1H), 1.81-1.62 (m, 1H), 1.19 (t, 3H).

Example 1.17V.

Ethyl 2-bromo-5,5,5-trifluoro-4-methoxypentanoate (mixture of stereoisomers)

A solution of lithium diisopropylamide (6.0 mL, 2.0 M in tetrahydrofuran, 12.1 mmol, 1.0 equiv.) at -78°C. After stirring at -78°C for 1 hour, 1,2-dibromo-1,1,2,2tetrachloroethane (3.93 g, 12.1 mmol, 1.2 eq.) in tetrahydrofuran (15 ml) was added, the resulting mixture was allowed to warm to room temperature and stirring were continued for 2 hours. The reaction mixture was treated with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (silica gel, eluent: petroleum ether/ethyl acetate 91:9). Yield: 1.46 g (84% purity, 42% theoretical yield).

1H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=4.55-4.42 (m, 1H), 4.34-4.21 (m, 2H), 4.00-3.74 (m, 1H), 3.63 (d, 2H), 3.51 (s, 1H), 2.38 (s, 1H), 2.34-2.22 (m, 1H), 1.41-1.24 (m, 3H). Additional signals from the minor diastereomer are visible.

Example 1.17C.

2-Bromo-5,5,5-trifluoro-4-methoxypentanoic acid (mixture of stereoisomers)

General method 10 was performed with ethyl 2-bromo-5,5,5-trifluoro-4-methoxypentanoate (mixture of stereoisomers) (1.26 g, 84% purity, 3.61 mmol, 1.0 eq.) and lithium hydroxide (432 mg, 18.1 mmol, 5.0 eq.) in tetrahydrofuran/water (3.6:1, 115 ml). The crude mixture was used in the subsequent reaction without further purification. Yield: 1.10 g (85% purity, 99% theoretical yield).

GC-MS (method 6): Rt=3.51/3.56 min; MS (APCIpos): m/z=265 [M+H]+.

Example 1.17D.

4-{[(2R,4R)-2-Bromo-5,5,5-trifluoro-4-methoxypentanoyl]amino}benzamide (single stereoisomer)

General method 11 was performed with 4-aminobenzamide (518 mg, 3.81 mmol, 1.0 eq.), 2-bromo-5,5,5-trifluoro-4-methoxypentanoic acid (mixture of stereoisomers) (1.13 g, 85% purity, 4.19 mmol, 0.95 eq.), T3P (3.4 ml, 50% solution in ethyl acetate, 5.71 mmol, 1.5 eq.) and pyridine (339 μl, 4.19 mmol, 1.1 eq.) in tetrahydrofuran (15 ml) for 1 h, including the following variations of the procedure : Ice water was added to the reaction mixture, which was then extracted with dichloromethane and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica gel, eluent: dichloromethane/methanol 98:2 - 80:20). Yield: 910 mg (91% purity, 57% theoretical yield).

Separation of stereoisomers of 910 mg of 4-[(2-bromo-5,5,5-trifluoro-4-methoxypentanoyl)amino]-benzamide (mixture of stereoisomers) gave:

single stereoisomer 1 (title compound 1.17D) (chiral SFC: R _t =2.44 min, 99% de): 53.1 mg (4% of theoretical yield), single stereoisomer 2 (chiral SFC: R _t =2.72 min): 46.6 mg, single stereoisomer 3 (chiral SFC: R _t =3.46 min): 215 mg, single stereoisomer 4 (chiral SFC: R _t =7.83 min): 259 mg.

Separation method 1. SFC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 80% carbon dioxide/20% methanol; temperature: 35°C; flow rate: 80 ml/min; UV detection: 210 nm.

Separation Method 2. Single stereoisomer 1 and single stereoisomer 2 eluted as a mixture in the first separation, this mixture was then separated according to the following conditions: SFC:

- 38 044932 column: Daicel Chiralpak IF 5 µm, 250 mmx20 mm; eluent: 88% carbon dioxide/12% methanol; temperature: 35°C; flow rate: 80 ml/min; UV detection: 210 nm.

Method of analysis: SFC. Column: Daicel Chiralpak IE-3 3 µm, 250 mm x 4.6 mm; eluent: 90% carbon dioxide/10% methanol; flow rate: 3.0 ml/min; UV detection: 210 nm.

LC-MS (method 5): R _t =1.04 min; MS (ESIpos): m/z=383 [M+H]+.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.73 (s, 1H), 7.92-7.83 (m, 3H), 7.67 (d, 2H), 7.27 (br s, 1H), 4.72 (dd, 1H), 3.90-3.82 (m, 1H), 3.44 (s, 3H), 2.64-2.56 (m, 1H), 2.22-2.14 (m, 1H).

Example 1.18A.

Ethyl 5,5-difluoro-4-oxopentanoate

[Bromo(difluoro)methyl](trimethyl)silane (74.04 g, 364.5 mmol, 1.5 eq.), triphenylphosphine (70.12 g, 267.3 mmol, 1.1 eq.) and 1,3-dimethyl-3,4,5,6- tetrahydro-2(1H)-pyrimidinone (62.30 g, 486.1 mmol, 2.0 eq.) was added under argon at room temperature to a solution of ethyl 4-chloro-4-oxobutanoate (40.0 g, 243.0 mmol, 1.0 eq.) in acetonitrile ( 240 ml). After stirring for 5 hours at room temperature, the resulting mixture was quenched with water (200 ml) and pyridine (76.90 g, 972.1 mmol, 4.0 eq.). After stirring for another 1.5 h at 80°C, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and extracted with methyl tert-butyl ether. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 95:5). Yield: 15.20 g (70% purity, 22% theoretical yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=5.94-5.60 (m, 1H), 4.23-4.07 (m, 2H), 2.98-2.94 (m, 1H), 2.71-2.64 (m, 2H), 2.14-2.06 (m, 1H), 1.30-1.22 (m, 3H).

¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ [ppm]=-127.60 (s, 2F).

Example 1.18V.

Ethyl 5,5-difluoro-4-hydroxypentanoate (racemate) he f A L°xz ^CH 3

ABOUT

Sodium borohydride (2.23 g, 59.1 mmol, 1.0 eq.) was added at 0°C to a solution of ethyl 5,5-difluoro-4oxopentanoate (15.20 g, 70% purity, 59.1 mmol) in tetrahydrofuran (140 ml) and ethanol (20 ml ). After stirring at 0°C for 2 hours, the reaction mixture was quenched with aqueous hydrochloric acid (3H) at 0°C and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 90:10). Yield: 5.40 g (48% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=5.96-5.67 (m, 1H), 5.53 (d, 1H), 4.08-4.00 (m, 2H), 3.69-3.53 (m, 1H), 2.48-2.32 (m, 2H), 1.82-1.69 (m, 1H), 1.64-1.51 (m, 1H), 1.18 (t, 3H).

¹⁹ F-NMR (376 MHz, DMSO-d6): δ [ppm]=-128.80 (q, 2F).

Example 1.18C.

Ethyl 5,5-difluoro-4-methoxypentanoate (racemate)

N ₃ s ³ O F A ⁿ

I O^CHS o

Iodomethane (40.39 g, 284.6 mmol, 10.0 eq.) was added under argon at room temperature to a mixture of ethyl 5,5-difluoro-4-hydroxypentanoate (racemate) (5.40 g, 28.5 mmol, 1.0 eq.) and freshly prepared silver oxide (I) (19.78 g, 85.4 mmol, 3.0 eq.) in dichloroethane (80 ml). After stirring at 45°C for 72 hours, the resulting mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 95:5). Yield: 2.40 g (90% purity, 39% of theoretical yield).

- 39 044932 ‘H-NMR (300 MHz, CDCI3): δ [ppm]=5.84-5.45 (m, 1H), 4.17-4.09 (m, 2H), 3.47 (s, 3H), 3.42-3.36 (m,

1H), 2.54-2.40 (m, 2H), 2.03-1.89 (m, 1H), 1.88-1.74 (m, 1H), 1.28 (t, 3H).

¹⁹ F-NMR (282 MHz, CDCI3): δ [ppm]=-126.70 (d, 2F).

Example '.18D.

Ethyl 2-bromo-5,5-difluoro-4-methoxypentanoate (mixture of stereoisomers)

A ^ ^sn z ³ o

A solution of lithium diisopropylamide (8.0 ml, 2.0 M in tetrahydrofuran, '6.0 mmol, 1.2 eq.) was added under argon at -78°C to a solution of ethyl 5,5-difluoro-4-methoxypentanoate (racemate) (2.90 g, 90% purity, 13.3 mmol, 1.0 eq.) in tetrahydrofuran (70 ml). The resulting mixture was stirred at -78°C for 1 hour, followed by the addition of a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.20 g, 16.0 mmol, 1.2 eq.) in tetrahydrofuran (20 ml) at drops at the same temperature. After warming to room temperature and stirring for an additional 2 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, eluent: petroleum ether/ethyl acetate 80:20). Yield: 1.85 g (85% purity, 43% theoretical yield).

'H-NMR (400 MHz, CDCI3): δ [ppm]=5.87-5.70 (m, 1H), 4.50-4.22 (m, 3H), 3.66-3.42 (m, 4H), 2.23-2.16 (m, 2H ), 1.35-1.26 (m, 3H).

¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ [ppm]=-126.60 (s, 2F).

Example 1.18E.

2-Bromo-5,5-difluoro-4-methoxypentanoic acid (mixture of stereoisomers) n ₃ cr ³ 9 F

Lithium hydroxide (255 mg, 10.6 mmol, 2.0 eq.) was added at room temperature to a solution of ethyl 2-bromo-5,5-difluoro-4-methoxypentanoate (stereoisomer mixture) (1.72 g, 85% purity, 5.3 mmol) in the mixture tetrahydrofuran and water (3:1, 20 ml). The reaction mixture was stirred at room temperature for 100 min and then acidified with an aqueous solution of hydrochloric acid (1H). After removing all volatile compounds under reduced pressure, the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (<30°C and >100 mbar). The crude product was used without further purification. Yield: 1.65 g.

Example 1.18F.

4-{ [(2R,4R)-2-Bromo-5,5-difluoro-4-methoxypentanoyl] amino} benzamide (single stereoisomer)

2-Bromo-5,5-difluoro-4-methoxypentanoic acid (mixture of stereoisomers) (1.65 g, 90% accepted crude purity, 6.0 mmol), pyridine (0.53 ml, 6.6 mmol, 1.1 eq.) and T3P (5.3 ml , 50% solution in ethyl acetate, 9.0 mmol, 1.5 eq.) was added under argon at room temperature to a mixture of 4-aminobenzamide (817 mg, 6.0 mmol, 1.0 eq.) in tetrahydrofuran (20 ml). The reaction mixture was stirred at room temperature for 1 hour, mixed with water, stirred for another 15 minutes, and mixed with additional water. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized with dichloromethane, filtered and dried in vacuum. Yield: 993 mg (94% purity, 43% theoretical yield). The combined mother liquors were concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane/methanol gradient). Yield: 297 mg (13% of theoretical yield).

LC-MS (method 4): Rt=1.26 min; MS (ESIpos): m/z=365 [M+H]+.

- 40 044932

Separation of stereoisomers 1410 mg 4-[(2-bromo-5,5-difluoro-4-methoxypentanoyl)amino]-benzamide (mixture of stereoisomers) gave a mixture of two stereoisomers 1+2 (chiral SFC 1: R _t =1.34/1.45 min ): 290 mg, single stereoisomer 3 (titled compound example 1.18F) (chiral SFC 1:

R _t =1.18 min, >98% ee): 330 mg, single stereoisomer: (chiral SFC 2: R _t =1.40 min): 410 mg.

Separation method: SFC. Column: Chiralpak AD-H 5 µm, 250 mmx20 mm; eluent: carbon dioxide/ethanol, gradient: 0 min 80% carbon dioxide, 5.00-8.43 min 70% carbon dioxide, 8.53-11.31 min 80% carbon dioxide; temperature: 40°C; flow rate: 100 ml/min; UV detection: 210 nm.

Analysis method: SFC 1. Column: Chiralpak AD-H, 50 mmx4.6 mm; eluent: 80% carbon dioxide/20% ethanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm. SFC 2: column: Chiralpak AD-H, 50 mmx4.6 mm; eluent: 60% carbon dioxide/40% ethanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.61 (s, 1H), 7.90-7.81 (m, 3H), 7.65 (d, 2H), 7.24 (br s, 1H), 6.17 (dt, 1H), 4.76 (dd, 1H), 3.71-3.62 (m, 1H), 3.49 (s, 3H), 2.21-2.11 (m, 2H).

Example 1.19A.

4-{[(2R)-2-Bromopropanoyl]amino}-2-fluorobenzamide (sole stereoisomer)

(2R)-2-Bromopropanoic acid (sole stereoisomer) (4.0 g, 26.1 mmol), pyridine (2.3 ml, 28.8 mmol, 1.1 eq.) and T3P (22.9 ml, 50% solution in ethyl acetate, 39.2 mmol, 1.5 eq. ) was added under argon at room temperature to a mixture of 4-amino-2-fluorobenzamide (4.0 g, 26.1 mmol, 1.0 eq.) in tetrahydrofuran (60 ml). The reaction mixture was stirred at room temperature for 1 hour, mixed with water and stirred for another 1 hour. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 5.7 g (75% of theoretical yield). The combined filtrates were extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from water and the precipitate was dried in vacuum. Yield: 1.5 g (20% of theoretical yield).

Main batch: LC-MS (method 1): R _t =0.61 min; MS (ESIpos): m/z=289 [M+H]+.

Main batch: 1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.68 (s, 1H), 7.70 (t, 1H), 7.64 (dd, 1H), 7.57-7.46 (m, 2H) , 7.36 (dd, 1H), 4.69 (q, 1H), 1.76 (d, 3H).

Example 1.20A.

4-{ [(2R)-2-Bromopropanoyl] amino} benzamide (single stereoisomer)

(2R)-2-Bromopropanoic acid (sole stereoisomer) (1.00 g, 6.54 mmol), pyridine (0.58 ml, 7.19 mmol, 1.1 eq.) and T3P (5.73 ml, 50% solution in ethyl acetate, 9.81 mmol, 1.5 eq. ) was added under argon at room temperature to a mixture of 4-aminobenzamide (890 mg, 6.54 mmol, 1.0 eq.) in tetrahydrofuran (15 ml). The reaction mixture was stirred at room temperature for 30 minutes. After removing all volatile compounds under reduced pressure, the residue was mixed with additional water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 1.77 g (quantitative theoretical yield).

LC-MS (method 15): R _t =0.97 min; MS (ESIpos): m/z=271 [M+H]+.

1H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.52 (s, 1H), 7.87 (br s, 1H), 7.86 (d, 2H), 7.66 (d, 2H), 7.26 (br s , 1H), 4.71 (q, 1H), 1.76 (d, 3H).

Example 1.21A.

Trimethyl {[(5K)-5-methyl-4,5-dihydrofuran-2-yl]oxy}silane (sole stereoisomer)

CH ₃

Under argon, a solution of n-butyllithium (3.34 1, 1.6 M in hexanes, 5.35 mol, 1.1 eq.) was added at 0°C for 1.5 h to a solution of diisopropylethylamine (818 ml, 5.84 mol, 1.2 eq.) in tetrahydrofuran ( 5.0 l) and stirred for 30 min at 0°C before cooling to -78°C. A solution of (5R)-5-41 044932 methyldihydrofuran-2(3H)-one (single stereoisomer) (487 g, 4.86 mol) in tetrahydrofuran (500 ml) was added at -78°C over 1 hour and the reaction mixture was stirred at -78°C for 90 min, followed by dropwise addition of chloro(trimethyl)silane (803 ml, 6.32 mol, 1.3 eq.). The reaction mixture was stirred at -78°C for 1 hour and allowed to warm to room temperature overnight while stirring was continued. The suspension was discarded and the filtrate was evaporated under reduced pressure and resuspended in n-pentane. The mixture was stirred for 30 minutes at 10°C and filtered. The filtrate was evaporated under reduced pressure. The crude material was used without further purification. Yield: 759 g (85% purity, 79% theoretical yield).

1H-NMR (600 MHz, CDCl ₃ ): δ [ppm]=4.53-4.46 (m, 1H), 3.45 (t, 1H), 2.63 (ddd, 1H), 2.10 (ddd, 1H), 1.20 (d, 3H), 0.12 (s, 9H).

Example 1.21B.

(5R)-3-Bromo-5-methyldihydrofuran-2(3H)-one (mixture of two diastereomers)

Bromine (197 ml, 3.83 mol, 1.0 eq.) was added slowly at -78°C to a solution of trimethyl {[(5R)-5methyl-4,5-dihydrofuran-2-yl]oxy}silane (single stereoisomer) (759 g , 87% purity, 3.83 mol) in dichloromethane (7.6 L). The reaction mixture was allowed to warm to room temperature overnight while stirring was continued and then concentrated under reduced pressure. The residue was purified with a thin film vacuum evaporator (crude dose: 50 ml/min, 107°C, 0.5 mbar). Yield: 563 g (trans/cis: about 2:1, about 80% purity, about 66% of theoretical yield).

1H-NMR (600 MHz, CDCl ₃ ): δ [ppm]=4.80-4.67 (m, 1H, trans-diastereomer), 4.59-4.47 (m, 2H, cis-diastereomer), 4.35 (dd, 1H, trans-diastereomer) , 2.93 (ddd, 1H, cis-diastereomer), 2.46 (ddd, 1H, trans-diastereomer), 2.42-2.35 (m, 1H, cis-diastereomer), 2.30-2.20 (m, 1H, trans-diastereomer), 2.15-2.04 (m, 1H, cis-diastereomer), 1.38 (d, 3H, cis-diastereomer), 1.34 (d, 3H, trans-diastereomer).

Example 1.21C.

Methyl (4S)-2-bromo-4-methoxypentanoate (mixture of two diastereomers).CH ₃ o ³ |^CH ₃ Br-^Y°'CH ₃ o

Trimethoxymethane (688 ml, 6.28 mol, 2.5 eq.) and then sulfuric acid (16.7 ml, 314 mmol, 0.125 eq.) were added at room temperature to a solution of (5R)-3-bromo-5-methyldihydrofuran-2(3H) -ona (mixture of two diastereomers) (563 g, about 80% purity, 2.51 mol) in methanol (5.1 L). The reaction mixture was stirred at 50°C for 24 h and concentrated under reduced pressure, then trimethoxymethane (688 ml, 6.28 mol, 2.5 eq.) and then sulfuric acid (16.7 ml, 314 mmol, 0.125 eq.) were added again at at room temperature into a solution of the crude substance in methanol (5.1 l). The reaction mixture was stirred at 50°C for 24 hours and concentrated under reduced pressure. This procedure was repeated one more time to ensure complete conversion of the reaction. The resulting residue was mixed with ethyl acetate, and the mixture was washed with 0.5 N aqueous sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was used without further purification. Yield: 625 g (94% purity, quantitative theoretical yield).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=4.55-4.43 (m, 1H, two diastereomers), 3.68 (s, 3H, minor diastereomer), 3.67 (s, 3H, major diastereomer), 3.46-3.37 (m, 1H, major diastereomer), 3.34-3.25 (m, 1H, minor diastereomer), 3.19 (s, 3H, major diastereomer), 3.15 (s, 3H, minor diastereomer), 2.22-2.05 (m, 1H, major diastereomer), 1.99-1.90 (m, 1H, minor diastereomer), 1.11-1.05 (m, 3H, two diastereomers).

Example 2.1A.

3-(2-Bromo-4-chlorophenyl)-2-methylprop-2-enal (E/Z mixture)

Propionaldehyde (3.6 ml, 50.1 mmol, 1.1 eq.) was added dropwise at room temperature to a mixture of 2-bromo-4-chlorobenzaldehyde (10.0 g, 45.6 mmol) and sodium hydroxide (0.18 g, 4.6 mmol, 0.1 eq.) in methanol (100 ml). The mixture was stirred at room temperature for 1 hour, followed by the addition of acetic acid to achieve a pH of 6. The resulting mixture was stirred for another 16 hours

- 42 044932 and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate

10:1). Yield: 6.0 g (50% of theoretical yield).

LC-MS (method 10): R=1.28 min; MS (ESIpos): m/z=259 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=9.70 (s, 1H), 7.93-7.91 (m, 1H), 7.59-7.56 (m, 2H), 7.52-7.50 (m, 1H ), 1.81/1.81 (2s, 3H).

Example 2.1B.

3-(2-Bromo-4-chlorophenyl)-2-methylprop-2-en-1-ol (E/Z mixture)

A mixture of 3-(2-bromo-4-chlorophenyl)-2-methylprop-2-enal (E/Z mixture) (10.0 g, 38.5 mmol, 1.0 eq.) in tetrahydrofuran (90 ml) was added at 0°C to the suspension sodium borohydride (7.29 g, 192.7 mmol, 5.0 eq.) in tetrahydrofuran (10 ml) and methanol (10 ml). The reaction mixture was stirred at room temperature for 3 hours, followed by the addition of aqueous hydrochloric acid to achieve a pH of 6. Volatile compounds were removed under reduced pressure and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 10:1). Yield: 5.7 g (55% of theoretical yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=7.78 (d, 1H), 7.47 (dd, 1H), 7.37 (d, 1H), 6.44 (br s, 1H), 5.12 ( t, 1H), 4.05-3.98 (m, 2H), 1.67 (s, 3H).

Example 2.1C.

3-(2-Bromo-4-chlorophenyl)-2-methylpropan-1-ol (racemate)

Tris(triphenylphosphine)rhodium(!) chloride (3.2 g, 3.4 mmol, 0.3 eq.) was added at room temperature under a nitrogen atmosphere to the mixture of 3-(2-bromo-4-chlorophenyl)-2-methylprop-2-en-1 -ol (E/Z mixture) (3.0 g, 11.5 mmol, 1.0 eq.) in ethanol (30 ml). The resulting mixture was purged with hydrogen gas and stirred at room temperature for 48 hours under a hydrogen gas atmosphere (2 bar). The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 20:1). Yield: 1.90 g (59% of theoretical yield).

¹ H-NMR (300 MHz, DMSO-d6): δ [ppm]=7.71 (d, 1H), 7.41 (dd, 1H), 7.33 (d, 1H), 4.57 (t, 1H), 3.32-3.26 ( m, 2H, partially hidden), 2.85-2.76 (m, 1H), 2.49-2.39 (m, 1H), 1.93-1.79 (m, 1H), 0.82 (d, 3H).

Example 2.2A.

(2-Bromo-4-chloro-3-fluorophenyl)methanol

2-Bromo-4-chloro-3-fluorobenzoic acid (5.00 g, 19.7 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (150 ml), cooled to 0°C and a solution of borane-tetrahydrofuran complex (59 ml, 1.0 M in tetrahydrofuran , 59 mmol, 3.0 eq.) was added dropwise. The mixture was stirred at 0°C for 1 hour and at room temperature for 2 days. Additional amounts of borane-tetrahydrofuran complex solution (30 mL, 1.0 M in tetrahydrofuran, 30 mmol, 1.5 eq.) were added at 0° C. and stirring was continued at room temperature overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was used in the next step without further purification. Yield: 4.49 g (95% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.71-7.58 (m, 1H), 7.44-7.32 (m, 1H), 5.67-5.56 (t, 1H), 4.584.44 (d , 2H).

Example 2.2V.

2-Bromo-1-(bromomethyl)-4-chloro-3-fluorobenzene

- 43 044932

Br Br

1JCl'^^

A solution of phosphorus tribromide ( 3.6 ml, 38 mmol, 1.5 equiv.) in diethyl ether (40 ml). The mixture was stirred at room temperature for 4 days, followed by the addition of additional phosphorus tribromide (12 mL, 130 mmol, 5.0 eq.) at 0°C. Stirring was continued at room temperature for 0.5 h, followed by the addition of saturated aqueous sodium bicarbonate at 0°C. The mixture was extracted with dichloromethane and ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was used in the next step without further purification. Yield: 10.26 g (quantitative theoretical yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.74-7.59 (m, 1H), 7.57-7.47 (m, 1H), 4.81-4.73 (s, 2H).

Example 2.2C.

Diethyl [(2-bromo-4-chloro-3-fluorophenyl)methyl](methyl)propanedioate ^{n 3} c n ₃

2-Bromo-1-(bromomethyl)-4-chloro-3-fluorobenzene (10.3 g, 33.9 mmol, 1.0 eq.), diethyl methyl malonate (6.21 g, 35.6 mmol, 1.1 eq.) and cesium carbonate (13.3 g, 40.7 mmol , 1.2 eq.) was dissolved in N,Ndimethylformamide (30 ml) and stirred at 70°C overnight. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was used in the next step without further purification. Yield: 11.81 g (54% purity, 48% theoretical yield).

GC-MS (method 6): Rt=7.41 min; MS (APCIpos): m/z=397 [M+H]+.

Example 2.2D.

[(2-Bromo-4-chloro-3-fluorophenyl)methyl](methyl)propanedioic acid

Vg

O^Q o

Diethyl [(2-bromo-4-chloro-3-fluorophenyl)methyl](methyl)propanedioate (11.8 g, 54% purity, 16.1 mmol, 1.0 eq.) was dissolved in ethanol (100 ml), aqueous sodium hydroxide (97 ml, 1.0 M, 97 mmol, 6.0 eq.) was added and the mixture was stirred at room temperature overnight and at 80°C for 3 days. The mixture was concentrated under reduced pressure, the residue was treated with aqueous hydrochloride (1H) and extracted with dichloromethane and ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 7.01 g (50% purity, 64% theoretical yield).

LC-MS (method 1): Rt=0.85 min; MS (ESIneg): m/z=339 [M-N]-.

Example 2.2E.

3-(2-Bromo-4-chloro-3-fluorophenyl)-2-methylpropanoic acid (racemate)

[(2-Bromo-4-chloro-3-fluorophenyl)methyl](methyl)propanedioic acid (7.00 g, 50% purity, 10.3 mmol, 1.0 eq.) was dissolved in acetic acid (100 ml) and stirred at 120°C all night long. The mixture was then concentrated under reduced pressure, dissolved in acetonitrile and water, filtered and the filtrate was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 2.52 g (77% purity, 64% theoretical yield).

LC-MS (method 1): Rt=1.03 min; MS (ESIneg): m/z=293 [M-N]-.

Example 2.2F.

3-(2-Bromo-4-chloro-3-fluorophenyl)-2-methylpropan-1-ol (racemate)

- 44 044932

Br

3-(2-Bromo-4-chloro-3-fluorophenyl)-2-methylpropanoic acid (racemate) (2.40 g, 77% purity, 6.25 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (60 ml), cooled to 0° C and a solution of borane-tetrahydrofuran complex (19 mL, 1.0 M in tetrahydrofuran, 19 mmol, 3.0 eq.) were added dropwise. The mixture was stirred at 0°C for 1 hour and at room temperature overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 99:1 to 40:60). Yield: 1.65 g (87% purity, 82% theoretical yield).

^-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=7.59-7.47 (m, IH), 7.24-7.11 (m, IH), 4.58 (t, IH), 3.31-3.21 (m, 2H ), 2.90-2.82 (m, IH), 2.49-2.46 (m, IH), 1.96-1.79 (m, IH), 0.82 (d, 3H).

Example 2.FOR.

2-[(2-Bromo-4-chlorophenyl)methylidene]butanal (E/Z mixture)

To a solution of 2-bromo-4-chlorobenzaldehyde (10.0 g, 45.6 mmol, 1.0 eq.) and sodium hydroxide (182 mg, 4.56 mmol, 0.1 eq.) in methanol (40 ml) was added butanal (4.5 ml, 50 mmol, 1.1 eq.) drop by drop at room temperature. The mixture was stirred at room temperature overnight, followed by the addition of water. The mixture was partially concentrated under reduced pressure, dried over anhydrous sodium sulfate, filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude mixture was used in the next step without further purification. Yield: 12.8 g (86% purity, 78% theoretical yield).

^-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=9.67 (s, IH), 7.93 (d, IH), 7.59 (dd, IH), 7.54-7.42 (m, 2H), 2.26 ( q, 2H), 0.96 (t, 3H).

Example 2.ZV.

2-[(2-Bromo-4-chlorophenyl)methylidene]butan-1-ol (E/Z mixture) / ^CH3

A solution of 2-[(2-bromo-4-chlorophenyl)methylidene]butanal (E/Z mixture) was added to a suspension of sodium borohydride (2.68 g, 70.9 mmol, 2.0 eq.) in tetrahydrofuran (10 ml) and methanol (10 ml). (11.3 g, 86% purity, 35.5 mmol, 1.0 eq.) in tetrahydrofuran (90 ml) dropwise at 0°C. The resulting mixture was stirred at room temperature for 3 hours and cooled to 0°C, followed by the addition of aqueous hydrochloride (1H) to achieve a pH of 6. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered . The filtrate was concentrated under reduced pressure and the crude product was used in the next step without further purification. Yield: 10.58 g (86% purity, 93% theoretical yield).

^-NMR (500 MHz, DMSO-d ₆ ): δ [ppm>7.73 (d, IH), 7.43 (dd, IH), 7.28 (d, IH), 6.38 (s, IH), 4.09-3.94 (m , 2H), 2.06 (q, 2H), 1.98 (s, IH), 0.96 (t, 3H).

Example 2.3C.

2-(2-Bromo-4-chlorobenzyl)butan-1-ol (racemate) ^ ^CH 3

Tris was added to a solution of 2-[(2-bromo-4-chlorophenyl)methylidene]butan-1-ol (E/Z mixture) (10.6 g, 86% purity, 33.0 mmol, 1.0 eq.) in dichloromethane (200 ml). (triphenylphosphine)rhodium(1) chloride (1.53 g, 1.65 mmol, 0.1 equiv.) in an argon atmosphere. The resulting mixture was purged with hydrogen gas and stirred at 22°C for 48 hours under a hydrogen atmosphere at 50 bar. The reaction mixture was filtered through Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 100:0 - 65:35). Yield: 8.84 g (77% purity, 74% theoretical yield).

^-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=7.68 (d, IH), 7.39 (dd, IH), 7.35-7.28 (m, IH), 4.46 (t, IH), 3.32- 3.24 (m, 2H), 2.70-2.65 (m, IH), 2.63-2.57 (m, IH), 1.69-1.56 (m, IH), 1.44-1.35 (m, IH), 1.24 (s, IH), 0.86 (t, 3H).

Example 2.4A.

3-(2-Bromo-4-chlorophenyl)-2-methylpropanal (racemate)

-45 044932

Br Η

3,3,3-triacetoxy- 3-iodophthalide (19.5 g, 46.0 mmol, 2.5 eq.) and sodium bicarbonate (11.6 g, 138.0 mmol, 7.5 eq.) at 0°C. After stirring at room temperature for 3 hours, the reaction mixture was quenched with a 1:1 mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium carbonate and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 97:3). Yield: 3.90 g (85% purity, 68% theoretical yield).

^-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=9.66 (s, 1H), 7.74 (d, 1H), 7.44-7.37 (m, 2H), 3.16-3.11 (m, 1H), 2.78-2.64 (m, 2H), 1.01 (d, 3H).

Example 2.4B.

4-(2-Bromo-4-chlorophenyl)-3-methylbutan-2-ol (mixture of stereoisomers)

Vg he

To a solution of 3-(2-bromo-4-chlorophenyl)-2-methylpropanal (racemate) (4.2 g, 90% purity, 14.4 mmol, 1.0 eq.) in tetrahydrofuran (80 ml) was added methylmagnesium bromide (14.5 ml, 3.0 M in 2methyltetrahydrofuran, 43.3 mmol, 3.0 equiv.) at 0°C in a nitrogen atmosphere. After stirring at 0°C for 2 hours, the reaction mixture was quenched with water and stirred for 10 minutes. The mixture was then extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 87:13) to obtain 2.8 g of 4-(2-bromo-4-chlorophenyl)-3-methylbutan-2-ol (mixture of stereoisomers) at 63% purity . To remove solids, the crude product was dissolved in dichloromethane (15 ml), treated with imidazole (0.66 g, 9.7 mmol, 0.7 eq.) and tert-butyldimethylsilyl chloride (0.73 g, 4.8 mmol, 0.35 eq.), stirred at room temperature for 2 hours and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: n-hexane/ethyl acetate 94:6). Yield: 1.47 g (83% purity, 30% theoretical yield).

^-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.71-7.68 (m, 1H), 7.41-7.37 (m, 1H), 7.35-7.28 (m, 1H), 4.514.45 (m , 1H), 3.57-3.50 (m, 1H), 2.93-2.79 (m, 1H), 2.49-2.34 (m, 1H), 1.77-1.68 (m, 1H), 1.16-1.05 (m, 3H), 0.75 -0.67 (m, 3H).

Example 2.5A.

2-Cyclobutylidene-1,1-dimethylhydrazine

V ^H 3

CH ₃

A solution of cyclobutanone (1.00 g, 14.3 mmol) and 1,1-dimethylhydrazine (1.1 ml, 14 mmol, 1.0 eq.) in tetrahydrofuran (6.0 ml) was stirred at 60°C for 2.5 h under microwave irradiation. All volatile compounds were removed at 30°C in vacuum (>50 mbar). The residue was purified by ball distillation (75° C., 20 mbar). Yield: 1.08 g (67% of theoretical yield).

GC-MS (method 2): R _t =1.79 min; m/z=l 12 [M] ⁺ .

^-NMR (400 MHz, CDC1 ₃ ): δ [ppm]=3.02-2.87 (m, 4H), 2.58 (s, 6H), 1.98 (quin, 2H).

Example 2.5V.

2-[(2-Bromo-4-chlorophenyl)methyl]cyclobutan-1-one (racemate)

VG u--o ° CI

A solution of n-butyllithium (6.1 ml, 1.6 M in hexane, 9.8 mmol, 1.1 equiv.) was added under argon at -10°C to a solution of 2-cyclobutylidene-1,1-dimethylhydrazine (1.00 g, 8.92 mmol) in tetrahydrofuran ( 40 ml). The reaction mixture was stirred at -10°C for 1 hour, followed by the addition of a solution of 2-bromo-1-(bromomethyl)-4-chlorobenzene (3.13 g, 81% purity, 8.92 mmol, 1.0 eq.) in tetrahydrofuran (10 ml ). The reaction mixture was stirred at room temperature for 20 hours, diluted with aqueous

-46044932 hydrochloric acid (2H) and stirred at room temperature for 1 hour. After adding ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate mixtures). Yield: 1.89 g (77% of theoretical yield).

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.72 (d, 1H), 7.43 (dd, 1H), 7.38 (d, 1H), 3.73-3.61 (m, 1H), 3.15 -2.97 (m, 2H), 2.95-2.81 (m, 2H), 2.06 (qd, 1H), 1.77-1.64 (m, 1H).

Example 2.5C.

trans-2-[(2-Bromo-4-chlorophenyl)methyl]cyclobutan-1-ol (racemate)

Br y— ^he

C.I.

Sodium borohydride (505 mg, 13.3 mmol, 1.0 eq.) was added at 0°C to a solution of 2-[(2-bromo-4chlorophenyl)methyl]cyclobutan-1-one (racemate) (3.65 g, 13.3 mmol) in a mixture of dichloromethane /methanol (2:1, 67 ml). The reaction mixture was stirred at 5°C for 1 hour and diluted with water. After phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate mixtures). Yield: 1.03 g (27% of theoretical yield) of the cis product and 2.67 g (72% of theoretical yield) of the target trans product (compound 2.5C indicated in the title).

LC-MS (method 4): Rt=2.00 min; MS (ESIpos): m/z=299 [M+Na]+.

'H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.68 (d, 1H), 7.39 (dd, 1H), 7.36 (d, 1H), 5.03 (d, 1H), 3.71 (quin, 1H), 2.91 (dd, 1H), 2.69 (dd, 1H), 2.35-2.20 (m, 1H), 2.08-1.99 (m, 1H), 1.65-1.51 (m, 2H), 1.15-1.01 (m, 1H).

Example 2.6A.

Ethyl 3-(2-bromo-4-chlorophenyl)prop-2-enoate (E/Z mixture)

While cooling in an ice bath, ethoxycarbonylmethylenetriphenylphosphorane (47.6 g, 136.7 mmol, 1.5 eq.) was added dropwise to a solution of 2-bromo-4-chlorobenzaldehyde (20.0 g, 91.1 mmol) in dichloromethane (200 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 6:1). Yield: 26.0 g (98% of theoretical yield).

'H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.94 (d, 0.8H), 7.84 (d, 0.8 H), 7.80 (d, 1H), 7.50 (dd, 0.8H), 7.45 (dd, 0.2H), 7.42 (d, 0.2H), 7.06 (d, 0.2H), 6.68 (d, 0.8H), 6.18 (d, 0.2H), 4.21 (q, 1.6H), 4.04 (q , 0.4H), 1.26 (t, 2.4H), 1.10 (t, 0.6H).

Example 2.6V.

Ethyl 3 -(2-bromo-4-chlorophenyl)propanoate

Chlortris(triphenylphosphine)rhodium(1) (12.3 g, 13.3 mmol, 0.15 eq.) was added under nitrogen atmosphere to a solution of ethyl 3-(2-bromo-4-chlorophenyl)prop-2-enoate (E/Z mixture) (26.0 g, 88.9 mmol) in ethanol (250 ml). The resulting mixture was purged with hydrogen for 5 minutes and stirred at room temperature for 12 hours under a hydrogen atmosphere (2 bar). The mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was redissolved in ethanol (100 mL), followed by the addition of chlorotris(triphenylphosphine)rhodium(1) (6.2 g, 6.7 mmol, 0.075 eq.) under nitrogen. The resulting mixture was purged with hydrogen for 5 minutes and stirred at room temperature for 15 hours under a hydrogen atmosphere (2 bar). The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: 100% petroleum ether). Yield: 25.6 g (97% of theoretical yield).

'H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.73 (d, 1H), 7.43 (dd, 1H), 7.38 (d, 1H), 4.06 (m, 2H), 2.95 (t, 2H), 2.62 (t, 2H), 1.17 (t, 3H).

Example 2.6C.

3-(2-Bromo-4-chlorophenyl)propanoic acid

- 47 044932

A solution of sodium hydroxide (31.9 g, 798.4 mmol, 4.0 eq.) in water (250 ml) was added to a stirred solution of ethyl 3-(2-bromo-4-chlorophenyl) propanoate (60.0 g, 199.6 mmol) in ethanol (400 ml) . After stirring at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure. The mixture was adjusted to pH 3 with aqueous hydrochloric acid (4 N) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Yield: 54.0 g (98% of theoretical yield).

1H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=12.25 (s, 1H), 7.71 (s, 1H), 7.45-7.34 (m, 2H), 2.91 (t, 2H), 2.53 ( t, 2H).

Example 2.6D.

(4R)-3-[3-(2-Bromo-4-chlorophenyl)propanoyl]-4-phenyl-1,3-oxazolidin-2-one (single stereoisomer) “ “O

N,N-Dimethylformamide (0.62 g, 8.5 mmol, 0.1 eq.) was added to a suspension of 3-(2-bromo-4chlorophenyl)propanoic acid (22.5 g, 85.4 mmol) in thionyl chloride (60 ml). After stirring at 80°C for 4 hours, the reaction mixture was evaporated to dryness to obtain 24.0 g of 3-(2-bromo-4chlorophenyl)propanoyl chloride.

A solution of n-butyllithium (35.7 mL, 2.5 M in hexane, 89.4 mmol, 1.05 eq.) was added at -78°C under nitrogen to a stirred solution of (4R)-4-phenyl-1,3-oxazolidin-2-one ( single stereoisomer) (13.9 g, 85.1 mmol, 1.0 eq.) in tetrahydrofuran (300 ml). The resulting mixture was stirred at -78°C for 30 minutes, followed by the addition of a solution of 3-(2-bromo-4chlorophenyl)propanoyl chloride (24.0 g, 85.1 mmol) in tetrahydrofuran (200 ml) at -78°C. After stirring at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 10:1). Yield: 29.5 g (85% of theoretical yield).

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.71 (d, 1H), 7.44-7.25 (m, 7H), 5.46 (dd, 1H), 4.74 (t, 1H), 4.17 ( dd, 1H), 3.28-3.11 (m, 2H), 2.99-2.85 (m, 2H).

Example 2.6E.

(4R)-3-{(2R)-2-[(2-Bromo-4-chlorophenyl)methyl]-3,3,3-trifluoropropanoyl}-4-phenyl-1,3-oxazolidin-2one (single stereoisomer)

A solution of lithium bis(trimethylsilyl)amide (75.8 mL, 1.0 M in tetrahydrofuran, 75.8 mmol, 1.05 eq.) was added at -78°C under nitrogen to a stirred solution of (4R)-3-[3-(2-bromo-4chlorophenyl )propanoyl]-4-phenyl-1,3-oxazolidin-2-one (single stereoisomer) (29.5 g, 72.2 mmol) in tetrahydrofuran (300 ml). After stirring at -78°C for 30 minutes, 1-trifluoromethyl-1,2benziodoxol-3(1H)-one (24.0 g, 75.8 mmol, 1.05 eq.) was added to the mixture at -78°C. The resulting mixture was allowed to warm to room temperature over 1 hour and stirred for an additional 4 hours. The reaction mixture was quenched with saturated aqueous sodium carbonate and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 22.5 g of crude product, which was triturated with methanol and stirred for 30 minutes. The solid was collected by filtration, washed with methanol and dried under air. Yield: 16.0 g (46% of theoretical yield).

LC-MS (method 10): Rt=1.26 min; MS (ESIpos): m/z=478 [M+H]+.

1H-NMR (400 MHz, DMSO4): δ [ppm]=7.80 (d, 1H), 7.48 (dd, 1H), 7.44-7.37 (m, 2H), 7.37-7.31 (m, 2H), 7.30-7.24 (m, 2H), 5.50-5.37 (m, 2H), 4.66 (t, 1H), 4.20 (dd, 1H), 3.34-3.16 (m, 2H).

- 48 044932 ¹⁹ P-NMR (376 MHz, DMSO-d ₆ ): δ [ppm]=-65.71 (s, 3F).

Example 2.6F.

(2B)-2-[(2-Bromo-4-chlorophenyl)methyl]-3,3,3-trifluoropropan-1-ol (sole stereoisomer)

Cl

He

Br

Sodium borohydride (3.4 g, 90.4 mmol, 5.0 eq.) was added at 0°C to a stirred solution of (4K)-3-[(2K)-2-(2-bromo-4-chlorobenzyl)-3,3,3- trifluoropropanoyl]-4-phenyl-1,3-oxazolidin-2-one (single stereoisomer) (8.9 g, 18.1 mmol) in tetrahydrofuran (60 ml) and water (20 ml). After stirring at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 5:1). Yield: 4.5 g (75% of theoretical yield).

Chiral SFC: R _t =l. 11 min, >99% ee.

Analysis method: SFC: column: Chiralpak AD-3 3 µm, 100 mmx3 mm, eluent: carbon dioxide (A), methanol with 0.1% DEA (B), gradient: 5% - 20% B in 2 min, maintained for 1 min at 20% B; temperature: 35°C; flow rate: 2.0 ml/min; UV detection: 254 nm.

^-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.75 (d, 1H), 7.50-7.40 (m, 2H), 5.02 (t, 1H), 3.64-3.44 (m, 2H), 3.03-2.93 (m, 2H), 2.75-2.59 (m, 1H).

¹⁹ P-NMR (376 MHz, DMSO-d ₆ ): δ [ppm]=-67.19 (s, 3F).

Example 2.7A.

tert-Butyl (4-chloro-3-fluorophenyl)carbamate

Cl

II I^CH3 N^O^CH, n ³

To a mixture of 4-chloro-3-fluoroaniline (15.0 g, 103 mmol, 1.0 eq.) in water (150 ml) was added di-tert-butyl dicarbonate (26 ml, 110 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 24 hours, extracted with diethyl ether, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the subsequent reaction without further purification. Yield: 21.6 g (85% of theoretical yield).

LC-MS (method 1): R _t =1.12 min; MS (ESIneg): m/z=244 [M-N]'.

Example 2.7V.

tert-Butyl (2-bromo-4-chloro-3-fluorophenyl)carbamate.

A solution of tert-butyllithium (88 ml, 1.7 M in pentane, 150 mmol, 1.5 eq.) in tetrahydrofuran (350 ml) was cooled to -78°C, a solution of tert-butyl (4-chloro-3-fluorophenyl)carbamate (24.4 g , 99.4 mmol, 1.0 eq.) in tetrahydrofuran (150 ml)

Cl

O n ₃ s Ji J Ϊ > ^сн з

1g ^N was added dropwise over a period of 90 minutes. Stirring was continued at this temperature for 60 min before 1,2-dibromethane (10 mL, 120 mmol, 1.2 eq.) was added dropwise. The resulting mixture was stirred at -78°C for 1.5 hours at room temperature overnight and then treated with saturated aqueous ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 20:1 - 10:1). Yield: 15.9 g (49% of theoretical yield).

LC-MS (method 3): R _t =4.20 min; MS (ESIneg): m/z=323 [M-N]'.

Example 2.7C.

2-Bromo-4-chloro-3-fluoroaniline trifluoroacetate

XI xTFA

Br

To a solution of tert-butyl (2-bromo-4-chloro-3-fluorophenyl)carbamate (15.9 g, 49.0 mmol, 1.0 eq.) in dichloromethane (200 ml) was added trifluoroacetic acid (19 ml, 240 mmol, 5.0 eq.) and the resulting mixture was stirred at room temperature overnight. The mixture was then concentrated under reduced pressure and the remaining residue was dissolved twice in dichloromethane, followed by evaporation.

-49044932

The crude product was used in the subsequent reaction without further purification. Yield: 15.1 g (87% of theoretical yield).

LC-MS (method 15): Rt=1.62 min; MS (ESIneg): m/z=222 [MH-TFA] ^- .

Example 2.7D.

2-Bromo-4-chloro-3-fluoro-1-iodobenzene

Br

A solution of 2-bromo-4-chloro-3-fluoroaniline trifluoroacetate in water (320 ml) was cooled to 0°C, followed by the addition of sulfuric acid (60 ml) dropwise. A solution of sodium nitrite (3.27 g, 47.4 mmol, 1.1 eq.) in water (30 ml) was added to the mixture and the resulting suspension was stirred for 1 hour while the temperature was maintained at 5-10°C. Then, a solution of potassium iodide (9.38 g, 56.5 mmol, 1.3 eq.) in water (50 ml) was added with vigorous stirring. The reaction mixture was allowed to warm to room temperature and extracted with ethyl acetate. The combined organic phases were washed with aqueous solutions of sodium hydroxide (1H), sodium thiosulfate (1H), hydrochloride (1H) and saturated aqueous sodium bicarbonate. The washed organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 50:1). Yield: 12.1 g (82% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.81 (dd, 1H), 7.43 (dd, 1H).

Example 2.7E.

-(2-Bromo-4-chloro-3-fluorophenyl)propanal

C.L.

Br Η

2-Bromo-4-chloro-3-fluoro-1-iodobenzene (9.00 g, 26.3 mmol, 1.0 eq.), palladium(P) acetate (118 mg, 526 µmol, 0.02 eq.), tetra-N-butylammonium chloride (7.31 g, 26.3 mmol, 1.0 eq.) and sodium bicarbonate (5.52 g, 65.8 mmol, 2.5 eq.) were dissolved in N,N-dimethylformamide (60 ml) and argon was purged through the resulting suspension for 10 min. After adding prop-2-en-1-ol (2.7 ml, 39 mmol, 1.5 eq.), the mixture was heated to 40°C and stirred at this temperature overnight, followed by the addition of diethyl ether and water. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was used in the next step without further purification. Yield: 6.29 g (82% purity, 74% theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=9.72 (s, 1H), 7.56 (dd, 1H), 7.25 (dd, 1H), 2.98 (t, 2H), 2.81 (t, 2H).

Example 2.7F.

(2R)-2-(2-Bromo-4-chloro-3-fluorobenzyl)-3,3,3-trifluoropropan-1-ol (single stereoisomer)

Argon was passed through a mixture of 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (3.53 g, 10.7 mmol, 1.0 eq.), (5R)-5-benzyl-2,2,3-trimethyl-4 -oxoimidazolidin-1-ium trifluoroacetate (single stereoisomer) (711 mg, 2.14 mmol, 0.2 eq.) and copper (I) chloride (52.9 mg, 535 µmol, 0.05 eq.) for 10 min. The mixture was cooled to -20°C before a solution of 3-(2-bromo-4-chloro-3-fluorophenyl)propanal (4.50 g, 82% purity, 13.9 mmol, 1.3 eq.) in chloroform (30 ml) was added. The resulting mixture was stirred at 20°C for 5 hours and stored in a freezer at -18°C overnight. Additional amounts of 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (2.12 g, 6.41 mmol, 0.6 eq.), (5R)-5-benzyl-2,2,3trimethyl-4-oxoimidazolidine-1 -ium trifluoroacetate (single stereoisomer) (355 mg, 1.07 mmol, 0.1 eq.) and copper(I) chloride (265 mg, 2.67 mmol, 0.25 eq.) were added and the mixture was stirred at -20°C for another 5.5 h. After cooling to -78°C, pre-cooled dichloromethane (45 ml, -78°C) was added and the mixture was treated with sodium borohydride (4.04 g, 107 mmol, 10.0 eq.) and pre-cooled methanol (21 ml, -78°C) . Stirring was continued at -78°C for 1 hour, followed by the addition of saturated aqueous ammonium chloride and warming the reaction mixture to room temperature. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 3.68 g (76% of theoretical yield).

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.61 (dd, 1H), 7.33 (dd, 1H), 5.03 (t, 1H), 3.62-3.46 (m, 2H), 3.10-2.99 pigcho (m, 2H), 2.76-2.64 (m, 1H).

Example 2.8A.

3-(4-Chloro-3-fluorophenyl)propanal

1-Chloro-2-fluoro-4-iodobenzene (10.0 g, 39.0 mmol, 1.0 eq.), tetra-N-butylammonium chloride (10.8 g, 39.0 mmol, 1.0 eq.) and sodium bicarbonate (8.19 g, 97.5 mmol, 2.5 equiv.) was dissolved in N,N-dimethylformamide (80 ml) and argon was passed through the resulting suspension for 10 min. After adding palladium(II) acetate (175 mg, 780 µmol, 0.02 eq.) and prop-2-en-1-ol (4.0 ml, 58 mmol, 1.5 eq.), the mixture was heated to 50°C and stirred at this temperature for 4 hours, followed by the addition of methyl tert-butyl ether and water. After phase separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was used in the next step without further purification. Yield: 6.55 g (90% of theoretical yield).

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=9.70 (t, 1H), 7.51-7.40 (m, 1H), 7.31-7.27 (m, 1H), 7.10 (dd, 1H), 2.89-2.84 (m, 2H), 2.83-2.77 (m, 2H).

Example 2.8V.

(2R)-2-(4-Chloro-3-fluorobenzyl)-3,3,3-trifluoropropanal (sole stereoisomer)

ABOUT

Argon was passed through a mixture of 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (10.6 g, 32.2 mmol, 1.0 eq.), (5R)-5-benzyl-2,2,3-trimethyl-4 -oxoimidazolidin-1-ium trifluoroacetate (single stereoisomer) (2.14 g, 6.43 mmol, 0.2 eq.) and copper (I) chloride (239 mg, 2.41 mmol, 0.075 eq.) for 10 min. The mixture was cooled to -20°C before a solution of 3-(4-chloro-3-fluorophenyl)propanal (6.00 g, 32.2 mmol, 1.0 eq.) in chloroform (70 ml) was added. The resulting mixture was stored in a freezer at -18°C for 72 hours and stirred at -20°C for a further 4 hours. The mixture was then immediately purified by column chromatography (silica gel, eluent: dichloromethane/methanol 98:2 -80:20 ). Yield: 5.94 g (73% of theoretical yield).

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=9.69 (t, 1H), 7.52 (dd, 1H), 7.42 (dd, 1H), 7.19 (dd, 1H), 4.214.12 (m, 1H), 3.26 (dd, 1H), 3.04 (dd, 1H).

Example 2.8C.

(2R)-2-(4-Chloro-3-fluorobenzyl)-3,3,3-trifluoropropan-1-ol (single stereoisomer)

(2R)-2-(4-Chloro-3-fluorobenzyl)-3,3,3-trifluoropropanal (single stereoisomer) (3.00 g, 11.8 mmol, 1.0 eq.) was dissolved in dichloromethane (21 ml) and cooled to -78 °C. The mixture was then treated with sodium borohydride (5.83 g, 58.9 mmol, 5.0 eq.) and pre-cooled methanol (10 ml, 78°C). Stirring was continued at -78°C for 1 hour, followed by the addition of saturated aqueous ammonium chloride and warming to room temperature. The aqueous phase was then extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 5:95). Yield: 1.86 g (60% of theoretical yield).

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=7.51 (dd, 1H), 7.37 (dd, 1H), 7.17 (dd, 1H), 4.96 (t, 1H), 3.573.52 ( m, 1H), 3.50-3.40 (m, 1H), 2.92-2.84 (m, 2H), 2.77-2.64 (m, 1H).

Example 2.9A.

3-(3,4-Dichlorophenyl)propanal

ABOUT

1,2-Dichloro-4-iodobenzene (5.00 g, 18.0 mmol, 1.0 eq.), theta-N-butylammonium chloride (4.99 g, 18.0 mmol, 1.0 eq.) and sodium bicarbonate (3.77 g, 44.9 mmol, 2.5 eq. .) dissolved in N,N-dimethylformamide

- 51 044932 (30 ml) and argon was passed through the resulting suspension for 10 minutes. After adding palladium(II) acetate (80.6 mg, 359 µmol, 0.02 eq.) and prop-2-en-1-ol (1.8 ml, 27 mmol, 1.5 eq.), the mixture was heated to 50°C and stirred at this temperature for 5 hours, followed by the addition of methyl tert-butyl ether and water. After phase separation, the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 80:20). Yield: 2.56 g (69% of theoretical yield).

^-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=9.69 (t, 1H), 7.53-7.50 (m, 2H), 7.23 (dd, 1H), 2.86-2.79 (m, 4H).

Example 2.9B.

(2R)-2-(3,4-Dichlorobenzyl)-3,3,3-τpiφτopπpoπanal (single stereoisomer)

ABOUT

Argon was passed through a mixture of 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (4.06 g, 12.3 mmol, 1.0 equiv.), (5R)-5-benzyl-2,2,3-trimethyl-4 -oxoimidazolidin-1-ium trifluoroacetate (single stereoisomer) (818 mg, 2.46 mmol, 0.2 eq.) and copper (I) chloride (239 mg, 2.41 mmol, 0.075 eq.) for 10 min. The mixture was cooled to -20°C before a solution of 3-(3,4-dichlorophenyl)propanal (2.55 g, 12.3 mmol, 1.0 eq.) in chloroform (35 ml) was added. The resulting mixture was stirred at -20°C for 5 hours, stored in a freezer at -18°C overnight and stirred at -20°C for a further 3 hours. The mixture was then immediately purified by column chromatography (silica gel, eluent: dichloromethane /methanol 98:2 - 80:20). Yield: 2.20 g (68% of theoretical yield).

Example 2.9C.

(2R)-2-(3,4-Dichlorobenzyl)-3,3,3-τpiφτopπpopan-l-ol (single stereoisomer)

(2R)-2-(3,4-Dichlorobenzyl)-3,3,3-trifluoropropanal (single stereoisomer) (2.20 g, 8.12 mmol, 1.0 eq.) was dissolved in dichloromethane (20 ml) and cooled to -78°C . The mixture was then treated with sodium borohydride (4.02 g, 40.6 mmol, 5.0 eq.) and pre-cooled methanol (5.0 ml, 78°C). Stirring was continued at -78°C for 1.5 hours, followed by the addition of saturated aqueous ammonium chloride and heating to room temperature.

The aqueous phase was then extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was used in the next step without further purification. Yield: 1.82 g (62% purity, 51% theoretical yield).

^-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.62-7.55 (m, 2H), 7.33-7.26 (m, 1H), 4.98 (t, 1H), 3.58-3.43 (m, 2H ), 2.91-2.84 (m, 2H), 2.78-2.66 (m, 1H).

Example 2.10A.

(22)-3-(4-Chlorophenyl)-2-(trifluoromethyl)prop-2-enoic acid

Under a nitrogen atmosphere, titanium tetrachloride (470 g, 2.48 mol) in dichloromethane (200 ml) was added dropwise at 0°C to a stirred mixture of 3,3,3-trifluoropropanoic acid (210 g, 1.64 mol) and 4chlorobenzaldehyde (251 g, 1.79 mol) in tetrahydrofuran (1 l). The resulting mixture was stirred for 1 hour at 0°C under a nitrogen atmosphere, followed by the addition of triethylamine (684 mL, 4.92 mol) dropwise over 1 hour. The resulting mixture was stirred for an additional 12 hours at room temperature. The reaction was repeated in parallel for 4 more batches. The reaction mixtures were separately quenched with ice/water (5 L) and the resulting mixtures were combined and extracted three times with dichloromethane (5 L). The combined organic layers were washed twice with saturated aqueous ammonium chloride (5 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was suspended with petroleum ether (500 ml). The precipitated solids were collected by filtration, washed with petroleum ether (500 ml) and dried in vacuo. Yield: 1070 g (52% of theoretical yield).

LC-MS (method 19): R _t =l .01 min; MS (ES): m/z=249 [M-H] ⁺ .

-52044932 'H-NMR (400 MHz, CDC1 ₃ ): δ [ppm]=l 1.92 (br s, 1H), 8.22 (s, 1H), 7.47-7.39 (m, 4H).

¹⁹ G-NMR (376 MHz, CDC1 ₃ ): δ [ppm]= -58.2 (s, 3F).

Example 2.10V.

(2C)-2-(4-Chlorobenzyl)-3,3,3-trifluoropropanoic acid (sole stereoisomer)

(8)-2,6-diethyldinaphtho[2,1-b:G,2'-1][1,3,2]dioxaphosphepine 4-oxide (20.9 g, 53.9 mmol, 0.010 eq.) [Y. Li et al., Angew. Chem. Int. Ed. 2013, 101, 6748-6752] in 2-propanol/water (4:1, 4.5 l) were treated at room temperature with bis(1,5-cyclooctadiene)rhodium(1) tetrafluoroborate (10.9 g, 26.9 mmol, 0.015 eq.) and stirred for 2 minutes. Then, triphenylphosphine (4.71 g, 18.0 mmol, 0.010 eq.) was added and stirring was continued for another 10 min. (22)-3-(4-chlorophenyl)-2-(trifluoromethyl)prop-2enoic acid (450 g, 1.80 mol) and morpholine (15.7 ml, 180 mmol, 0.10 eq.) were added and the reaction mixture was transferred to a 7 l. Stirring was continued at a hydrogen pressure of 20 bar for 24 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and 2propanol was largely removed under reduced pressure. The residue was treated with 1N aqueous hydrochloride solution (1.0 L) and water (1.0 L). The mixture was extracted with ethyl acetate (4.5 L) and after phase separation, the aqueous phase was extracted with ethyl acetate (3x2.5 L). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was used in the subsequent reaction without further purification. Yield: 482 g (94% purity, quantitative theoretical yield, >97% ee).

LC-MS (method 17): R _t =6.82 min; MS (ESIpos): m/z=253 [M+H] ⁺ Chiral SFC: R _t =0.87 min, >97% ee.

Method of analysis: SFC. Column: Chiralpak AD-3, 3 µm, 100 mmx4.6 mm, eluent: isocratic 95% carbon dioxide/5% methanol, 10 min, temperature: 40°C; flow rate: 3.0 ml/min; UV detection: 210 nm, back pressure: 130 bar.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=13.34 (br s, 1H), 7.46-7.19 (m, 4H), 3.79 (td, 1H), 3.14-2.97 (m, 2H ).

Example 2.10C.

Methyl (2R)-2-(4-chlorobenzyl)-3,3,3-trifluoropropanoate (sole stereoisomer)

ci

Methanol (3.6 L) was treated dropwise with thionyl chloride (346 ml, 4.75 mol, 2.0 eq.) at -10°C. After stirring for an additional 10 min at 0°C, (2E)-2-(4-chlorobenzyl)-3,3,3-trifluoropropanoic acid (single stereoisomer) (600 g, 2.38 mol) was added and the reaction mixture was stirred for 3 hours with return of phlegm. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate (4.0 L). The organic phase was washed with saturated aqueous sodium bicarbonate (3.0 L) and 10% aqueous sodium chloride (2.5 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was re-diluted in dichloromethane, treated with silica gel (3.0 kg) and the mixture was concentrated under reduced pressure. This material was purified by flash column chromatography (9.0 kg silica gel, eluent: petroleum ether/dichloromethane 8:2). Yield: 493 g (78% of theoretical yield).

GC-MS (method 2): R _t =3.91 min; MS (Elpos): m/z=266 [M] ⁺ .

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=7.40-7.34 (m, 2H), 7.33-7.28 (m, 2H), 4.07-3.96 (m, 1H), 3.61 (s, 3H), 3.18-3.05 (m, 2H).

Example 2.10D.

(2E)-2-(4-Chlorobenzyl)-3,3,3-trifluoropropan-1-ol (sole stereoisomer)

Two experiments of the same scale were carried out in parallel; purification was carried out with the combined reaction mixtures.

Methyl (2E)-2-(4-chlorobenzyl)-3,3,3-trifluoropropanoate (single stereoisomer) (171 g, 641 mmol) in tetrahydrofuran (3.2 L) was treated under argon with lithium aluminum hydride (673 ml,

-53 044932

2.4 M solution in tetrahydrofuran, 673 ml, 1.62 mol, 2.52 eq.) at -10°C for 10 min. The reaction mixture was then stirred while allowing heating to reach room temperature. The reaction mixture was diluted with tert-butyl methyl ether (700 ml), cooled to 0°C and carefully treated dropwise with water (61.4 ml) with stirring. Then, the reaction mixture was carefully treated dropwise with 15% aqueous sodium hydroxide solution (61.4 ml) and finally again with water (184 ml). The reaction mixture was warmed to room temperature, stirred for 15 minutes and then treated with anhydrous magnesium sulfate (1.4 kg). After stirring for an additional 15 minutes, the reaction mixture was filtered under reduced pressure and the filter cake was washed with t-butyl methyl ether (1.7 L). The organic phase was concentrated under reduced pressure to obtain the crude material. The combined crude material of the two batches was subjected to column chromatography (8.0 kg silica gel, eluent: dichloromethane). Yield for two batches combined: 271.4 g (89% theoretical yield, >95% ee).

GC-MS (method 2): Rt=4.23 min; MS (EIpos): m/z=238 [M] ⁺ . Chiral SFC: Rt=0.85 min, >95% ee.

Analysis method: SFC: column: Chiralcel OD-3, 3 µm, 100 mmx4.6 mm, eluent: isocratic 90% carbon dioxide/10% isopropanol, 10 min, temperature: 40°C; flow rate: 3.0 ml/min; UV detection: 210 nm, back pressure: 130 bar.

L-NMR (600 MHz, DMSO-d6): δ [ppm]=7.39-7.34 (m, 2H), 7.33-7.29 (m, 2H), 5.00 (t, 1H), 3.61-3.45 (m, 2H) , 2.93-2.81 (m, 2H), 2.63 (ddt, 1H).

Example 2.11A.

2-(4-Chlorobenzyl)-3-hydroxypropanenitrile (racemate)

Lithium bis(trimethylsilyl)amide (1.41 1, 1.0 M in tetrahydrofuran, 1.41 mol, 2.0 eq.) was added at -78°C to a solution of 3-hydroxypropanenitrile (50.0 g, 704 mmol) in tetrahydrofuran (500 ml) and the reaction mixture was stirred at -78°C for 1 hour, followed by the addition of 1-(bromomethyl)-4chlorobenzene (145 g, 704 mmol, 1.0 eq.) in tetrahydrofuran (200 ml) at -78°C. The reaction mixture was stirred at -78°C for 1 hour and then at 0°C for 1 hour. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 20:1 to 10:1). Yield: 55.0 g (90% purity, 36% of theoretical yield).

Sh-NMR (400 MHz, CDCl3): δ [ppm]=7.16 (d, 2H), 7.07-7.02 (m, 2H), 3.61 (q, 2H), 2.79 (s, 3H), 2.492.42 (m , 1H).

Example 2.11B.

3-{[tert-Butyl(diphenyl)silyl]oxy}-2-(4-chlorobenzyl)propanenitrile (racemate)

tert-Butyl(chloro)diphenylsilane (72.2 mL, 77.3 g, 281 mmol, 1.0 eq.) was added at room temperature to a solution of 2-(4-chlorobenzyl)-3-hydroxypropanenitrile (racemate) (55.0 g, 90% purity, 252 mmol), 4-dimethylaminopyridine (1.72 g, 14.1 mmol, 0.055 eq.) and imidazole (57.4 g, 843.4 mmol, 3.3 eq.) in dichloromethane (750 ml). The reaction mixture was stirred at room temperature for 12 hours. Then, the mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 20:1 to 10:1). Yield: 75.0 g (87% purity, 59% theoretical yield).

'H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=7.60-7.53 (m, 4H), 7.37-7.27 (m, 6H), 7.18 (d, 2H), 7.04 (d, 2H), 3.66 (d, 2H), 2.92-2.83 (m, 2H), 2.83-2.73 (m, 1H), 1.02 (s, 9H).

Example 2.11C.

3-{[tert-Butyl(diphenyl)silyl]oxy}-2-(4-chlorobenzyl)propanal (racemate)

- 54 044932

A solution of diisobutylaluminum hydride (618 ml, 1.0 M in toluene, 4.6 eq.) was added at -70°C to a solution of 3-{[tert-butyl(diphenyl)silyl]oxy}-2-(4-chlorobenzyl)propanenitrile (racemate) (67.0 g, 87% purity, 133 mmol) in toluene (1.0 L) and the reaction mixture was stirred at 0°C for 2 hours. The mixture was diluted with saturated potassium tartrate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the subsequent reaction without further purification. Yield: 80.0 g.

Example 2.11D.

tert-Butyl[2-(4-chlorobenzyl)-3,3-difluoropropoxy]diphenylsilane (racemate) 'Si. CH ₃ CH ^with ₃ ^H 3 (Diethylamino)sulfur trifluoride (72.6 ml, 88.5 g, 549 mmol, 3.0 eq.) was added at -70°C to a solution of crude 3-{[tert-butyl(diphenyl)silyl]oxy}-2 -(4-chlorobenzyl)propanal (racemate) (80.0 g, 183 mmol) in dichloromethane (1.0 L) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 100:0 to 20:1). Yield: 17.0 g (65% purity, 18% of theoretical yield for two steps).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=7.63-7.55 (m, 4H), 7.48-7.37 (m, 6H), 7.22-7.17 (m, 2H), 7.02 (d, 2H) , 6.05 (d, 1H), 3.74-3.67 (m, 1H), 3.64-3.58 (m, 1H), 2.98-2.84 (m, 1H), 2.78-2.69 (m, 1H), 2.32-2.11 (m, 1H), 1.11-1.08 (m, 9H).

Example 2.11E.

2-(4-Chlorobenzyl)-3,3-difluoropropan-1-ol (racemate)

A solution of theta-N-butylammonium fluoride (74.1 ml, 1.0 M in tetrahydrofuran, 74.1 mmol, 3.1 eq.) was added at -30°C to a solution of tert-butyl[2-(4-chlorobenzyl)-3,3-difluoropropoxy]diphenylsilane (racemate) (17.0 g, 65% purity, 24.1 mmol) in tetrahydrofuran (180 ml) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was dissolved in ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC. Yield: 5.50 g (99% of theoretical yield).

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=7.34-7.28 (m, 2H), 7.17 (d, 2H), 6.35-5.56 (m, 1H), 3.89-3.59 (m, 2H) , 3.13-2.56 (m, 2H), 2.45-2.13 (m, 1H), 1.55 (br s, 1H).

Example 3.1A.

2-Methoxy-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

A solution of tert-butyllithium (22.2 ml, 1.6 M in pentane, 35.4 mmol, 2.0 eq.) was added at -78°C under nitrogen atmosphere to a solution of 2-methoxy-5-(methoxymethoxy)pyridine (3.0 g, 17.7 mmol, 1.0 eq. .) in tetrahydrofuran (60 ml). After stirring at -78°C for 0.5 h, 2-isopropoxy-4,4,5,5-tetramethyl1,3,2-dioxaborolane (3.96 g, 21.3 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 2 hours, quenched with methanol at -78°C and then concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 5.25 g.

Example 3.1B.

3-{4-Chloro-2-[2-methoxy-5-(methoxymethoxy)pyridin-4-yl]phenyl}-2-methylpropan-1-ol (racemate)

- 55 044932

2-Methoxy-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (previous crude product, 7.39 g, 25.0 mmol, 2.0 eq .), 1,1'bis(diphenylphosphino)ferrocene-palladium(11) chloride (0.92 g, 1.3 mmol, 0.1 eq.) and sodium carbonate (3.98 g, 37.6 mmol, 3.0 eq.) were added under nitrogen atmosphere to solution 3 -(2-bromo-4-chlorophenyl)-2-methylpropan-1ol (racemate) (3.3 g, 12.5 mmol, 1.0 eq.) in 1,4-dioxane (100 ml) and water (15 ml). The resulting mixture was stirred at 90°C for 2 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:1). Yield: 3.6 g (87% purity, 72% theoretical yield).

LC-MS (method 11): ^=1.14 min; MS (ESIpos): m/z=352 [M+H]+.

Example 3.1C.

4-[5-Chloro-2-(3-hydroxy-2-methylpropyl)phenyl]-6-methoxypyridin-3-ol (racemate)

Aqueous hydrochloric acid (6.0 mL, 3N) was added to a solution of 3-{4-chloro-2-[2-methoxy-5(methoxymethoxy)pyridin-4-yl]phenyl}-2-methylpropan-1-ol (racemate) ( 2.2 g, 87% purity, 5.4 mmol, 1.0 eq.) in tetrahydrofuran (30 ml). The reaction mixture was stirred at 60°C for 3 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:1). Yield: 1.60 g (83% purity, 80% theoretical yield).

LC-MS (method 12): R _t =0.79 min; MS (ESIpos): m/z=308 [M+H] ⁺ .

¹ H-NMR (300 MHz, DMSO-d6): δ [ppm]=9.33 (s, 1H), 7.78 (s, 1H), 7.39-7.35 (m, 1H), 7.30-7.27 (m, 1H), 7.13 (d, 1H), 6.54 (s, 1H), 4.48-4.31 (br s, 1H), 3.77 (s, 3H), 3.15-2.98 (m, 2H), 2.63-2.56 (m, 1H), 2.19 -2.11 (m, 1H), 1.61-1.52 (m, 1H), 0.60 (d, 3H).

Example 3.1D.

5-[3-(2-Bromo-4-chlorophenyl)-2-methylpropoxy]-4-iodo-2-methoxypyridine (racemate)

3-(2-Bromo-4-chlorophenyl)-2-methylpropan-1-ol (racemate) (2.0 g, 7.2 mmol, 1.0 eq.) and (tributylphosphoranilidene)acetonitrile (2.62 g, 10.8 mmol, 1.5 eq.) were added at room temperature into a suspension of 4-iodo-6-methoxypyridin-3-ol (1.82 g, 7.2 mmol, 1.0 eq.) in toluene (10 ml). The reaction mixture was irradiated at 160°C for 2 hours in a microwave reactor and then cooled to room temperature. The above reaction procedure was repeated for three more batches (total 8.02 g (28.9 mmol) of 3-(2-bromo-4-chlorophenyl)-2-methylpropan-1-ol (racemate)). The four batches were combined and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 19:1). Yield: 11.87 g (81% of theoretical yield).

LC-MS (method 13): R _t =1.63 min; MS (ESIpos): m/z=496 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.77-7.70 (m, 2H), 7.42 (dd, 1H), 7.38-7.30 (m, 2H), 3.98-3.86 (m, 2H ), 3.78 (s, 3H), 3.08-2.99 (m, 1H), 2.73-2.63 (m, 1H), 2.35-2.20 (m, 1H), 1.02 (d, 3H).

Example 3.1E.

-Chloro-2-methoxy-7-methyl-7,8-dihydro-6H-[3]benzoxino[2,1-c]pyridine (racemate)

Diisopropyldiazene-1,2-dicarboxylate (2.1 g, 10.4 mmol, 2.4 eq.) was added dropwise at 0°C to

- 56 044932 suspension of 4-[5-chloro-2-(3-hydroxy-2-methylpropyl)phenyl]-6-methoxypyridin-3-ol (racemate) (1.6 g, 83% purity, 4.4 mmol) and triphenylphosphine (2.7 g, 10.4 mmol, 2.4 eq.) in tetrahydrofuran (80 ml). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 10:1). Yield: 0.6 g (91% purity, 43% of theoretical yield).

LC-MS (method 12): R _t ='.27 min; MS (ESIpos): m/z=290 [M+H]+.

'H-NMR (300 MHz, DMSO-d6): δ [ppm]=8.05/8.03 (2s, 1H), 7.47-7.31 (m, 3H), 6.78/6.73 (2s, 1H), 4.494.43 (m , 1H), 3.86 (s, 3H), 3.45-3.38 (m, 1H), 2.70-2.57 (m, 1H), 2.21-2.13 (m, 1H), 2.03-1.96 (m, 1H), 0.900.83 (d, 3H). Additional minor rotamer signals were also detected.

Alternative synthesis route.

Bis(pinacolato)diborone (6.14 g, 24.2 mmol, 2.0 eq.), palladium(P) acetate (0.27 g, 1.2 mmol, 0.1 eq.), tricyclohexylphosphine (0.51 g, 1.8 mmol, 0.15 eq.) and potassium acetate ( 3.56 g, 36.2 mmol, 3.0 eq.) was added to a solution of 4-[3-(2-bromo-4-chlorophenyl)-2-methylpropoxy]-5-iodo-2-methoxypyridine (racemate) (6.00 g, 12.1 mmol, 1.0 eq.) in N,N-dimethylformamide (60 ml). The resulting mixture was purged with nitrogen for 5 minutes, stirred at 80°C for 15 hours under a nitrogen atmosphere, treated with 5 ml of saturated aqueous sodium bicarbonate solution and stirred at 80°C for another 2 hours. After cooling to room temperature, the reaction mixture diluted with ethyl acetate and filtered through Celite®. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 19:1). Yield: 1.2 g (34% of theoretical yield).

LC-MS (method 13): R _t =1.38 min; MS (ESIpos): m/z=290 [M+H] ⁺ .

Example 3.1F.

11-Chloro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (racemate)

4-Toluenesulfonic acid monohydrate (2.72 g, 14.3 mmol, 1.8 eq.) and lithium iodide (5.32 g, 39.7 mmol, 5.0 eq.) were added at room temperature to a solution of 11-chloro-2-methoxy-7-methyl-7, 8dihydro-6H-[3]benzoxocino[2,1-c]pyridine (racemate) (2.30 g, 7.9 mmol) in 1-butanol (20 ml). After stirring at 85°C for 12 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane/methane 19:1). Yield: 1.78 g (79% of theoretical yield).

LC-MS (method 14): R _t =1.21 min; MS (ESIpos): m/z=276 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=11.56-11.25 (br s, 1H), 7.50-7.36 (m, 3H), 7.34-7.27 (m, 1H), 6.33-6.25 (m, 1H), 4.45-4.35/4.23-4.16 (2m, 1H), 3.86-3.78/3.3-3.25 (2m, 1H, partially hidden), 2.862.78/2.72-2.59 (2m, 1H), 2.29 ( dd, 1H), 2.07-1.90 (m, 1H), 0.94-0.80 (m, 3H). Additional minor rotamer signals were also detected.

Example 3.1G.

(7R)-1'-Chloro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (single stereoisomer)

НзС^/ ^- θγ^ΝΗ \/

C.I.

Enantiomer separation of 1.74 g of 11-chloro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin2(6H)-one (racemate), Example 3.1F, gave a single stereoisomer 1 ( title compound example 3.1G) (chiral HPLC: R _t =3.00 min, >99% ee): 603 mg (86% purity), single stereoisomer 2 (chiral HPLC: R _t =5.79 min): 552 mg.

Method of separation. HPLC: column: Daicel Chiralpak AS-H 5 µm, 250 mmx20 mm; eluent: 15% nheptane/85% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis. HPLC: column: Daicel Chiralpak AS-3 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

LC-MS (method 4): R _t =1.52 min; MS (ESIpos): m/z=276 [M+H] ⁺ .

- 57 044932

Example 3.2A.

5-[3-(2-Bromo-4-chloro-3-fluorophenyl)-2-methylpropoxy]-4-iodo-2-methoxypyridine (racemate)

General method 2 was performed three times with 3-(2-bromo-4-chloro-3-fluorophenyl)-2-methylpropan-1-ol (racemate) (500 mg, 1.78 mmol, 1.0 eq.), 4-iodo-6 -methoxypyridin-3-ol (446 mg, 1.78 mmol, 1.0 eq.) and (tributylphosphoranilidene)acetonitrile (643 mg, 2.66 mmol, 1.5 eq.) in toluene (14 ml) at 120°C, including the following variations of the procedure: Three the reaction mixtures were combined, concentrated under reduced pressure and the crude mixture was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 96:4 - 70:30). Yield: 2.01 g (92% purity, 68% of theoretical yield).

LC-MS (method 3): R _t =5.21 min; MS (ESIpos): m/z=516 [M+H]+.

Example 3.2V.

11-Chloro-12-fluoro-2-methoxy-7-methyl-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (racemate)

C.I.

General method 3a was performed twice with 5-[3-(2-bromo-4-chloro-3-fluorophenyl)-2-methylpropoxy]-4-iodo2-methoxypyridine (racemate) (1.00 g, 92% purity, 1.79 mmol, 1.0 eq.), bis(pinacolato)diborone (636 mg, 2.50 mmol, 1.4 eq.), potassium acetate (526 mg, 5.36 mmol, 3.0 eq.), palladium(P) acetate (20.0 mg, 89.0 µmol, 0.05 eq. .) and tricyclohexylphosphine (50.1 mg, 179 µmol, 0.1 eq.) in N,Ndimethylformamide (26 ml), including the following variations of the procedure: after stirring at 80°C overnight, tetrakis(triphenylphosphine)palladium(0) (103.7 mg, 89.0 µmol, 0.05 eq.) and saturated aqueous sodium bicarbonate (12.5 ml) were added to each of the two reaction mixtures. Stirring was then continued at 85°C for 1 hour, the two reaction mixtures were combined, water was added and the combined mixtures were extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 485 mg (84% purity, 37% theoretical yield).

LC-MS (method 3): R _t =3.89 min; MS (ESIpos): m/z=308 [M+H] ⁺ .

Example 3.2C.

11-Chloro-12-fluoro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (racemate)

General Method 4 was performed with 11-chloro-12-fluoro-2-methoxy-7-methyl-7,8-dihydro-6H[3]benzoxocino[2,1-c]pyridine (racemate) (480 mg, 84% purity , 1.31 mmol, 1.0 eq.) and sodium iodide (393 mg, 2.62 mmol, 2.0 eq.) in acetic acid (15 ml) at 100°C for 4 h, including the following variations of the procedure: The crude mixture was purified by preparative column chromatography (silica gel, eluent: dichloromethane/methanol 100:0 - 90:10), followed by purification by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 5:95). Yield: 200 mg (92% purity, 48% theoretical yield).

LC-MS (method 3): Rt=2.37 min; MS (ESIpos): m/z=294 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-06): δ [ppm]=11.49 (br s, 1H), 7.70-7.47 (m, 2H), 7.30-7.17 (m, 1H), 6.40/6.37 (2d, 1H), 4.44-4.36/3.84-3.79 (2m, 1H), 4.24-4.19/3.33-3.28 (2m, 1H), 2.74-2.66/2.72-2.67 (2m, 1H), 2.31-2.18 (m, 1H) , 2.05-1.88 (m, 1H), 0.88/0.81 (2d, 3H).

Example 3.3A.

5-[2-(2-Bromo-4-chlorobenzyl)butoxy]-4-iodo-2-methoxypyridine (racemate)

General method 2 was performed twice with 2-(2-bromo-4-chlorobenzyl)butan-1-ol (racemate) (500 mg, 77%

- 58 044932 purity, 1.39 mmol, 1.0 eq.), 4-iodo-6-methoxypyridin-3-ol (453 mg, 1.80 mmol, 1.3 eq.) and (tributylphosphoranilidene)acetonitrile (502 mg, 2.08 mmol, 1.5 eq. ) in toluene (15 ml) at 120°C, including the following variations of the procedure: The two reaction mixtures were combined and purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 100:0 -65:35). Yield: 750 mg (63% purity, 33% theoretical yield).

LC-MS (method 1): Rt=1.62 min; MS (ESIpos): m/z=510 [M+H]+.

Example 3.3V.

-Chloro-7-ethyl-2-methoxy-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (racemate)

General method 3a was performed with 5-[2-(2-bromo-4-chlorobenzyl)butoxy]-4-iodo-2-methoxypyridine (racemate) (750 mg, 63% purity, 925 µmol, 1.0 eq), bis( pinacolato)diborone (352 mg, 1.39 mmol, 1.5 equiv.), palladium(P) acetate (10.4 mg, 46.3 µmol, 0.1 equiv.), tricyclohexylphosphine (26.0 mg, 92.5 µmol, 0.1 equiv.) and potassium acetate (272 mg , 2.78 mmol, 3.0 eq.) in N,N-dimethylformamide (14 ml), including the following variations of the procedure: After stirring at 80°C overnight, tetrakis(triphenylphosphine)palladium(0) (53.7 mg, 46.3 μmol, 0.1 eq. .) and saturated aqueous sodium bicarbonate solution (6.5 ml) was added to the reaction mixture. Stirring was then continued at 85°C for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered through silica gel (eluent: ethyl acetate) and used in the next step without further purification. Yield: 600 mg (52% purity).

LC-MS (method 1): Rt=1.31 min; MS (ESIpos): m/z=304 [M+H] ⁺ .

Example 3.3C.

11-Chloro-7-ethyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (racemate)

Ih ₃ c<y

Cl

General Method 4 was performed with 11-chloro-7-ethyl-2-methoxy-7,8-dihydro-6H-[3]benzoxocino[2,1c]pyridine (racemate) (600 mg, 52% purity, 1.03 mmol, 1.0 eq.) and sodium iodide (462 mg, 3.08 mmol, 3.0 eq.) in acetic acid (15 ml) at 100°C for 2 h, including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 57 mg (66% purity, 13% theoretical yield) and 15 mg (86% purity, 4% theoretical yield).

LC-MS (method 1): Rt=0.89 min; MS (ESIpos): m/z=290 [M+H] ⁺ .

Example 3.4A.

5-{[4-(2-Bromo-4-chlorophenyl)-3-methylbutan-2-yl]oxy}-4-iodo-2-methoxypyridine (mixture of stereoisomers)

General Method 2 was performed with 4-(2-bromo-4-chlorophenyl)-3-methylbutan-2-ol (mixture of stereoisomers) (500 mg, 91% purity, 1.64 mmol, 1.0 eq.), 4-iodo-6- methoxypyridin-3-ol (416 mg, 1.64 mmol, 1.0 eq.) and (tributylphosphoranilidene)acetonitrile (475 mg, 1.97 mmol, 1.2 eq.) in toluene (15 ml) at 120°C, including the following variations of the procedure: After stirring for 1 hour, additional amounts of (tributylphosphoranylidene)acetonitrile (198 mg, 820 µmol, 0.5 eq.) were added and stirring was continued at 120°C for 1 hour. The crude mixture was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 98 :2 - 80:20). Yield: 670 mg (78% of theoretical yield).

LC-MS (method 1): Rt=1.61 min; MS (ESIpos): m/z=510 [M+H] ⁺ .

Example 3.4V.

11-Chloro-2-methoxy-6,7-dimethyl-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (mixture of stereoisomers)

- 59 044932

General method 3a was performed with 5-{[4-(2-bromo-4-chlorophenyl)-3-methylbutan-2-yl]oxy}-4-iodo-2methoxypyridine (mixture of stereoisomers) (670 mg, 1.29 mmol, 1.0 eq .), bis(pinacolato)diborone (457 mg, 1.80 mmol, 1.4 eq.), palladium(P) acetate (14.4 mg, 64.3 µmol, 0.05 eq.) and potassium acetate (379 mg, 3.86 mmol, 3.0 eq.) in N,N-dimethylformamide (16 ml), including the following variations of the procedure: After stirring at 80°C overnight, tetrakis(triphenylphosphine)palladium(0) (74.6 mg, 64.3 µmol, 0.05 eq.) and saturated aqueous sodium bicarbonate (7.7 ml) was added to the reaction mixture. Stirring was then continued at 85°C overnight. The reaction mixture was filtered through a mixture of silica gel and anhydrous sodium sulfate and eluted with a 1:1 mixture of dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure, water was added and the combined mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and used in the next step without further purification. Yield: 552 mg (63% purity, 89% theoretical yield).

LC-MS (method 1): R _t =1.34 min; MS (ESIpos): m/z=304 [M+H]+.

Example 3.4C.

11-Chloro-6,7-dimethyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (mixture of stereoisomers) n ₃ c ΙΗ ₃ ογ^ ⁰ \ <^pl

Μ ci

General Method 4 was performed with 11-chloro-2-methoxy-6,7-dimethyl-7,8-dihydro-6H-[3]benzoxocino[2,1c]pyridine (mixture of stereoisomers) (550 mg, 63% purity, 1.14 mmol, 1.0 eq.) and sodium iodide (513 mg, 3.42 mmol, 3.0 eq.) in acetic acid (20 ml) at 100°C for 2 h, including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase , eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 157 mg (75% purity, 36% theoretical yield).

LC-MS (method 3): R _t =2.52 min; MS (ESIpos): m/z=290 [M+H] ⁺ .

Example 3.5A.

5-({cis-2-[(2-Bromo-4-chlorophenyl)methyl]cyclobutyl}oxy)-4-iodo-2-methoxypyridine (racemate)

4-Iodo-6-methoxypyridin-3-ol (2.41 g, 9.62 mmol, 1.0 eq.), trans-2-[(2-bromo-4-chlorophenyl)methyl]cyclobutan-1-ol (racemate) (2.65 g , 9.62 mmol) and (tributylphosphoranylidene)-acetonitrile (2.52 ml, 9.62 mmol. 1.0 eq.) were dissolved in toluene (53 ml) and equally distributed into three microwave vessels, which were then sealed. The reaction mixtures were heated at 120°C for 45 min under microwave irradiation. The three mixtures were combined and all volatile compounds were removed in vacuo. The residue was dissolved in ethyl acetate and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate mixtures). Yield: 2.69 g (54% of theoretical yield).

LC-MS (method 4): R _t =2.90/2.98 min; MS (ESIpos): m/z=508 [M+H] ⁺ .

Example 3.5V.

cis-6-Chloro-3-methoxy-9a, 10,11,11 a-tetrahydro-9H-cyclobuta[4,5][3]benzoxocino[2,1-c]pyridine (racemate)

- 60 044932

Bis(pinacolato)diborone (5.17 g, 20.35 mmol, 1.5 eq.), potassium acetate (3.99 g, 40.70 mmol, 3.0 eq.), palladium(P) acetate (305 mg, 1.36 mmol, 0.1 eq.) and tricyclohexylphosphine ( 380 mg, 1.36 mmol, 0.1 eq.) was added to a solution of 5-({cis-2-[(2-bromo-4-chlorophenyl)methyl]cyclobutyl}oxy)-4-iodo-2-methoxypyridine (racemate) (6.90 g, 13.57 mmol) in N,N-dimethylformamide (136 ml, degassed before adding to flame-dried flask). The reaction mixture was stirred at 100°C overnight. Tetrakis(triphenylphosphine)palladium(0) (784 mg, 0.68 mmol, 0.05 eq.), solid sodium bicarbonate (5.70 g, 67.84 mmol, 5.0 eq.) and water (0.93 ml) were added. The reaction mixture was stirred at 100°C overnight, allowed to reach room temperature, diluted with ethyl acetate and filtered through Celite®. The filter cake was washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 8.50 g.

LC-MS (method 4): R _t =2.42 min; MS (ESIpos): m/z=302 [M+H]+.

Example 3.5C.

cis-6-Chloro-9a, 10,11,11 a-tetrahydro-2H-cyclobuta[4,5][3]benzoxocino[2,1-c]pyridin-3(9H)-one (racemate) /H— o γ γ^ΝΗ

C.I.

Sodium iodide (10.3 g, 68.8 mmol) was added to a solution of cis-6-chloro-3-methoxy-9a,10,11,11atetrahydro-9H-cyclobuta[4,5][3]benzoxocino[2,1-c]pyridine (racemate) (crude product from the previous step, calculated purity 50%: 8.3 g, 13.8 mmol) in acetic acid (208 ml). The resulting mixture was stirred at 80°C overnight. All volatile compounds were removed in vacuo. The residue was dissolved in ethyl acetate, washed with phosphate buffer (pH 7) and filtered. After phase separation, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate mixtures). The residue was suspended in acetonitrile, filtered and dried in vacuum. Yield: 1.14 g (91% purity, 26% of theoretical yield).

LC-MS (method 4): Rt=1.58 min; MS (ESIpos): m/z=288 [M+H]+.

Example 3.5D.

(9aR,11aR)-6-Chloro-9a,10,11,11a-tetrahydro-2H-cyclobuta[4,5][3]benzoxocino[2,1-c]pyridin3(9H)-one (single stereoisomer)

Separation of enantiomers of 1.13 g of cis-6-chloro-9a,10,11,11a-tetrahydro-2Hcyclobuta[4,5][3]benzoxocino[2,1-c]pyridin-3(9H)-one (racemate), example 3.5C, gave the only stereoisomer 1 (chiral SFC: R _t =2.08 min, 85% ee): 404 mg, the only stereoisomer 2 (the title compound is example 3.5D) (chiral SFC: R _t =2.23 min, 93% ee ): 406 mg.

Separation method: SFC: column: Daicel Chiralpak OZ-H 5 µm, 250 mmx30 mm; eluent: 60% carbon dioxide/40% methanol; temperature: 40°C; flow rate: 100 ml/min; UV detection: 210 nm.

Method of analysis: SFC: column: Daicel Chiralpak OZ-H 3 µm, 100 mmx4.6 mm; eluent: 70% carbon dioxide/30% methanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

LC-MS (method 4): R _t =1.59 min; MS (ESIpos): m/z=288 [M+H]+.

Example 3.6A1.

5-{(2R)-2-[(2-Bromo-4-chlorophenyl)methyl]-3,3,3-trifluoropropoxy}-4-iodo-2-methoxypyridine (sole stereoisomer)

- 61 044932

(Tributylphosphoranylidene)acetonitrile (3.2 g, 13.3 mmol, 1.5 eq.) and (2R)-2-(2-6pom-4chlorobenzyl)-3,3,3-trifluoropropan-1-ol (single stereoisomer) (3.0 g, 8.8 mmol) was added at room temperature to a solution of 4-iodo-6-methoxypyridin-3-ol (2.2 g, 8.8 mmol, 1.0 eq.) in toluene (15 ml). The resulting mixture was irradiated at 160°C for 2 hours in a microwave reactor and then cooled to room temperature. The above reaction procedure was repeated in a similar manner for the next ten batches. Eleven batches, together 33.0 g (97.3 mmol) of (2R)-2-(2-6pom-4chlorobenzyl)-3,3,3-trifluoropropan-1-ol) (single stereoisomer), were combined, diluted with ethyl acetate and washed with water and saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 9:1). Yield: 23.4 g (43% of theoretical yield).

¹ H-NMR (300 MHz, CDCl ₃ ): δ [ppm]=7.60 (d, 1H), 7.50 (s, 1H), 7.30-7.17 (m, 3H), 4.18 (dd, 1H), 3.943.86 (m, 1H), 3.84 (s, 3H), 3.37-3.23 (m, 2H), 3.07-2.93 (m, 1H).

¹⁹ F-NMR (282 MHz, CDCl ₃ ): δ [ppm]= -68.71 (s, 3F).

Example 3.6A2.

5-[(2R)-2-(4-Chlorobenzyl)-3,3,3-trifluoropropoxy]-4-iodo-2-methoxypyridine (sole stereoisomer)

Under argon, a mixture of (2R)-2-(4-chlorobenzyl)-3,3,3-trifluoropropan-1-ol (single stereoisomer) (558 g, 2.34 mol) and 4-iodo-6-methoxypyridin-3- ol (1.76 kg, 7.01 mol, 3.0 eq.) in toluene (5.6 l) was treated dropwise (addition time: 1 h) with reflux (tributylphosphoranilidene)acetonitrile (847 g, 3.51 mol, 1.5 eq.). The reaction mixture was stirred for 2 hours at reflux, cooled to 0°C and then methanol (366 ml) was added. The reaction mixture was diluted with toluene to a volume of 14.2 L and then washed with 2N aqueous sodium hydroxide solution (3x5.3 L). The organic phase was washed with 10% aqueous sodium chloride solution (7.1 L) and then concentrated under reduced pressure. The crude material was divided into two equal portions, which were purified by column chromatography (12.0 kg silica gel, eluent: dichloromethane/petroleum ether 3:2, then dichloromethane). Yield: 811 g (74% of theoretical yield). Recovery of excess 4-iodo6-methoxypyridin-3-ol: The combined main aqueous phases were washed with toluene (7.0 L). The aqueous phase was neutralized by adding a concentrated aqueous hydrochloride solution and the precipitate was then collected by filtration under reduced pressure. The filter cake was washed with water and then dried over phosphorus pentoxide under reduced pressure. The crude material was further purified by column chromatography (silica gel, eluent: dichloromethane/acetone 4:1) to obtain pure 4-iodo-6-methoxypyridin-3-ol.

LC-MS (method 4): R _t =2.64 min; MS (ESIpos): m/z=471 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=7.70 (s, 1H), 7.39-7.31 (m, 5H), 4.22 (dd, 1H), 3.89 (dd, 1H), 3.77 ( s, 3H), 3.19 (dt, 1H), 3.14-3.04 (m, 2H).

Example 3.6V.

(7R)-11-Chloro-2-methoxy-7-(trifluoromethyl)-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (single stereoisomer)

Cl

Bis(pinacolato)diborone (4.6 g, 18.2 mmol, 2.0 eq.), palladium(P) acetate (0.20 g, 0.9 mmol, 0.1 eq.), tricyclohexylphosphine (0.38 g, 1.4 mmol, 0.15 eq.) and potassium acetate ( 2.67 g, 27.2 mmol, 3.0 equiv.) was added to a solution of 5-{[(2R)-2-(2-bromo-4-chlorobenzyl)-3,3,3-trifluoropropyl]oxy}-4-iodo-2methoxypyridine ( single stereoisomer) (5.0 g, 9.1 mmol) in N,N-dimethylformamide (100 ml). The resulting mixture was purged with nitrogen for 5 minutes and stirred at 80°C for 15 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate

- 62 044932 and filtered through Celite®. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 19:1).

Yield: 0.86 g (28% of theoretical yield).

LC-MS (method 7): R _t =1.79 min; MS (ESIpos): m/z=346 [M+H]+.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm]=8.08 (s, 1H), 7.42-7.39 (m, 1H), 7.33-7.24 (m, 2H), 6.69 (s, 1H), 4.90 -4.75 (m, 1H), 3.98 (s, 3H), 3.96-3.89 (m, 1H), 3.06 (d, 1H), 2.88-2.63 (m, 1H), 2.60-2.51 (m, 1H).

¹⁹ F-NMR (376 MHz, CDCl3): δ [ppm]=-70.92 (s, 3F).

Alternative synthesis route.

Two experiments of the same scale were carried out in parallel; purification was carried out with the combined reaction mixtures.

Under argon, a 10 L round bottom flask was charged with potassium pivalate (44.6 g, 318 mmol, 1.5 eq) in N,N-dimethylacetamide (600 ml) and then the flask was evacuated and refilled with argon three times. The mixture was heated to 150°C (oil bath temperature 180°C). A second 5 L round bottom flask was charged with 5-[(2R)-2-(4-chlorobenzyl)-3,3,3-trifluoropropoxy]-4-iodo-2-methoxypyridine (single stereoisomer) (100 g, 212 mmol) in K,K-dimethylacetamide (3.2 L) and the flask was evacuated and backfilled with argon three times. Tetrakis(triphenylphosphine)palladium(0) (24.5 g, 21.2 mmol, 0.10 eq.) was added and then the mixture was added via an addition pump (flow rate: 60 ml/min) to preheated potassium pivalate in N,N-dimethylacetamide (in During addition, the temperature was always maintained above 140°C). After addition, the reaction mixture was stirred for another 3.5 hours at 150°C. The reaction mixture was diluted with tert-butyl methyl ether (20 L) and 10% aqueous sodium chloride solution (20 L) was added. After mixing, the two phases were filtered through diatomaceous earth. After phase separation, the organic phase was washed with 10% aqueous sodium chloride solution (12 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. The combined crude material of the two batches was dissolved in dichloromethane and purified by column chromatography (8.0 kg silica gel, eluent: petroleum ether/ethyl acetate 19:1). The resulting material (65.5 g) was triturated with methanol (350 ml), the solid was filtered under reduced pressure and washed with cold methanol (2 x 50 ml). The combined mother liquors were concentrated under reduced pressure and the residue was triturated with cold methanol (100 ml). The solid was washed with cold methanol (2x20 ml) and dried. Yield for two batches combined: 41.6 g (29% of theoretical yield). The combined mother liquors were concentrated under reduced pressure and the residue was triturated with cold methanol (100 ml). The solid was washed with cold methanol (2x20 ml) and dried under air. Yield for two batches combined: 2.5 g (94% purity, 2% theoretical yield). Combined total yield for two batches: 44.1 g (31% of theoretical yield).

LC-MS (method 18): R _t =3.96 min; MS (ESIpos): m/z=344 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=8.15 (s, 1H), 7.58-7.30 (m, 3H), 6.81 (s, 1H), 4.68 (br s, 1H), 4.22 -4.03/4.02-3.91 (2m, 1H), 3.88 (s, 3H), 3.25-3.15/3.11-2.82 (2m, 2H), 2.74-2.57/2.48-2.34 (2m, 1H, partially hidden). Additional minor rotamer signals were also detected.

Example 3.6C.

(7R)-11-Chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (single stereoisomer)

4-Toluenesulfonic acid monohydrate (0.75 g, 3.9 mmol, 1.8 eq.) and lithium iodide (1.46 g, 10.9 mmol, 5.0 eq.) were added at room temperature to a solution of (7R)-11-chloro-2-methoxy-7( trifluoromethyl)-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (single stereoisomer) (0.75 g, 2.2 mmol) in 1-butanol (40 ml). After stirring at 85°C for 15 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and saturated aqueous sodium carbonate and stirred for 10 minutes. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate/methanol 5:19:1) to obtain 0.44 g of crude product, which was triturated with methanol and stirred for 30 minutes. The solid was collected by filtration, washed with methanol and dried under air. Yield: 0.35 g (48% of theoretical yield).

LC-MS (method 9): Rt=1.34 min; MS (ESIpos): m/z=330 [M+H]+.

- 63 044932

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.55 (s, 1H), 7.54-7.25 (m, 4H), 6.35 (s, 1H), 4.75-4.55 (m,

1H), 4.11-3.78 (m, 1H), 3.12-2.86 (m, 2H), 2.69-2.55 (m, 1H).

¹⁹ F-NMR (376 MHz, DMSO-d6): δ [ppm]=-69.67 (s, 3F).

Alternative synthesis route.

Under argon, 4-toluenesulfonic acid monohydrate (97.3 g, 511 mmol, 1.85 eq.) and lithium chloride (58.6 g, 42.4 mmol, 5.0 eq.) were added at room temperature to a solution of (7R)-11-chloro-2methoxy- 7-(trifluoromethyl)-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (single stereoisomer) (95.0 g, 276 mmol) in 2-propanol (1.2 L). After stirring and refluxing for 16 hours, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure to a volume of about 250 ml. Water (2.0 L) was added to the mixture and the resulting solution was extracted with ethyl acetate (1.5 L and 500 ml). The precipitate between the two layers was filtered off under reduced pressure, washed with ethyl acetate (200 ml) and dried in air (yield: 53.2 g). After phase separation, the combined organic phases were concentrated under reduced pressure to a residual volume of approximately 100 ml. The precipitate was filtered off under reduced pressure, washed with ethyl acetate and dried in air (yield: 23.5 g). The combined filtrates were washed with saturated aqueous sodium bicarbonate (1.1 L), and the precipitate formed between the two layers was filtered under reduced pressure, washed with ethyl acetate and dried under air (yield: 9.2 g). Combined yield: 85.9 g (94% of theoretical yield).

LC-MS (method 3): Rt=2.54 min; MS (ESIpos): m/z=330 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=11.46 (br s, 1H), 7.59 (br s, 1H), 7.50 (br d, 1H), 7.42-7.26 (m, 2H ), 6.33 (br s, 1H), 4.64 (br d, 1H), 4.09-3.97/3.84 (m/br t, 1H), 3.26-3.14/3.08-2.89 (m, 2H), 2.81-2.69/2.582 .51 (2m, 1H, partially hidden). Additional minor rotamer signals were also detected.

Example 3.7A1.

5-{(2R)-2-[(2-Bromo-4-chloro-3-fluorophenyl)methyl]-3,3,3-trifluoropropoxy}-4-iodo-2-methoxypyridine (single stereoisomer)

General method 2 was performed four times with (2R)-2-[(2-bromo-4-chloro-3-fluorophenyl)methyl]-3,3,3trifluoropropan-1-ol (single stereoisomer) (920 mg, 2.60 mmol, 1.0 eq.), 4-iodo-6methoxypyridin-3-ol (850 mg, 3.39 mmol, 1.3 eq.) and (tributylphosphoranilidene)acetonitrile (1.0 ml, 3.9 mmol, 1.5 eq.) in toluene (15 ml) at 120° C, including the following variations of the procedure: The crude mixtures of the four reactions were combined, concentrated under reduced pressure and purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 100:0 - 75:25). Yield: 2.71 g (46% of theoretical yield).

LC-MS (method 5): Rt=1.78 min; MS (ESIpos): m/z=569 [M+H] ⁺ .

Example 3.7A2.

5-[(2R)-2-(4-Chloro-3-fluorobenzyl)-3,3,3-trifluoropropoxy]-4-iodo-2-methoxypyridine (sole stereoisomer)

General method 2 was performed six times at 120°C for 3.0 h: once with (2R)-2-[(2-bromo-4-chloro3-fluorophenyl)methyl]-3,3,3-trifluoropropan-1-ol (single stereoisomer) (50 mg, 189 µmol, 1.0 eq.), 4-iodo-6-methoxypyridin-3-ol (77 mg, 92% purity, 283 µmol, 1.5 eq.) and (tributylphosphoranilidene)acetonitrile (74 µl , 283 µmol, 1.5 eq.) in toluene (2.5 ml), four times with (2R)-2[(2-bromo-4-chloro-3-fluorophenyl)methyl]-3,3,3-trifluoropropane-1- ol (single stereoisomer) (360 mg, 1.36 mmol, 1.0 eq.), 4-iodo-6-methoxypyridin-3-ol (408 mg, 92% purity, 1.50 mmol, 1.1 eq.) and (tributyl-phosphoranilidene)acetonitrile (530 µl, 2.0 mmol, 1.5 eq.) in toluene (17 ml) and once with (2R)2-[(2-bromo-4-chloro-3-fluorophenyl)methyl]-3,3,3-trifluoropropane -1-ol (single stereoisomer) (360 mg, 1.36 mmol, 1.0 eq.), 4-iodo-6-methoxy-pyridin-3-ol (376 mg, 1.49 mmol, 1.5 eq.) and (tributylphosphoranilidene)-acetonitrile (530 µl, 2.0 mmol, 1.5 eq.) in toluene (17 ml), including the following variations of the procedure: The crude mixtures of the six reactions were combined, concentrated under reduced pressure and purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 100:0 - 80:20). Yield: 1.35 g (40% of theoretical yield).

- 64 044932

LC-MS (method 4): R _t =2.65 min; MS (ESIpos): m/z=490 [M+H]+.

Example 3.7V.

(7R)-11-Chloro-12-fluoro-2-methoxy-7-(trifluoromethyl)-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (single stereoisomer)

F fA

Cl

General method 3a was carried out with 5-{(2R)-2-[(2-bromo-4-chloro-3-fluorophenyl)methyl]-3,3,3 trifluoropropoxy}-4-iodo-2-methoxypyridine (single stereoisomer) (2.71 g, 4.77 mmol, 1.0 eq.), bis(pinacolato)diborone (1.94 g, 7.63 mmol, 1.6 eq.), palladium(P) acetate (107 mg, 477 µmol, 0.1 eq.), potassium acetate (1.40 g, 14.3 mmol, 3.0 eq.) in N,N-dimethylformamide (70 ml), including the following variations of the procedure: After stirring the reaction mixture at 80°C for 3 days, water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 95:0 - 20:80). Yield: 342 mg (99% purity, 20% theoretical yield) and 1.33 g (64% purity, 49% theoretical yield).

LC-MS (method 15): R _t =2.03 min; MS (ESIpos): m/z=362 [M+H] ⁺ .

Alternative synthesis route.

5-[(2R)-2-(4-Chloro-3-fluorobenzyl)-3,3,3-trifluoropropoxy]-4-iodo-2-methoxypyridine (single stereoisomer) (1.25 g, 2.50 mmol, 1.0 eq.) and potassium pivalate (1.40 g, 10.0 mmol, 4.0 eq.) were dissolved in N,N-dimethylacetamide (100 ml) and argon was purged through the mixture for 10 min. Then, tetrakis(triphenylphosphine)palladium(0) (289 mg, 250 μmol, 0.1 eq.) was added and the mixture was stirred at 150°C for 2.5 h. The mixture was concentrated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 95:5 - 60:40). Yield: 420 mg (43% of theoretical yield).

LC-MS (method 5): R _t =1.55 min; MS (ESIpos): m/z=362 [M+H] ⁺ .

Example 3.7C.

(7R)-11-Chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (single stereoisomer)

F

Cl

General method 4 was carried out with (7R)-11-chloro-12-fluoro-2-methoxy-7-(trifluoromethyl)-7,8-dihydro-6H[3]benzoxocino[2,1-c]pyridine (single stereoisomer) (1.62 g, 71% purity, 3.18 mmol) and sodium iodide (954 mg, 6.37 mmol, 2.0 eq.) in acetic acid (70 ml) at 100°C overnight, including the following variations of the procedure: Additional amounts of sodium iodide (954 mg, 6.37 mmol, 2.0 eq.) was added to the reaction mixture and stirring was continued at 100°C for 4 hours. The crude mixture was purified by column chromatography (silica gel, eluent: dichloromethane/methanol 98:2 - 80:20), followed by additional purification by column chromatography (silica gel, eluent: dichloromethane/methanol 98:2 - 80:20). Yield: 1.11 g (76% purity, 76% theoretical yield).

LC-MS (method 5): R _t =1.15 min; MS (ESIpos): m/z=348 [M+H] ⁺ .

Example 3.8A.

5-[(2R)-2-(3,4-dichlorobenzyl)-3,3,3-trifluoropropoxy]-4-iodo-2-methoxypyridine (sole stereoisomer)

General method 2 was performed four times at 120°C for 6.0 h with (2R)-2-(3,4-dichlorobenzyl)3,3,3-trifluoropropan-1-ol (single stereoisomer) (420 mg, 62% purity , 954 µmol, 1.0 eq.), 4iodo-6-methoxypyridin-3-ol (390 mg, 92% purity, 1.43 mmol, 1.5 eq.) and (tributyl-phosphoranilidene) - 65 044932 acetonitrile (500 µl, 1.9 mmol, 2.0 eq.) in toluene (10 ml), including the following variations of the procedure:

The crude mixtures of the four reactions were combined, concentrated under reduced pressure and purified twice by column chromatography (silica gel, first column eluent: cyclohexane/ethyl acetate 100:0 - 85:15, second column eluent: pure dichloromethane). Yield: 0.48 g (25% of theoretical yield).

LC-MS (method 4): Rt=2.72 min; MS (ESIpos): m/z=506 [M+H]+.

Example 3.8V.

(7R)-11,12-Dichloro-2-methoxy-7-(trifluoromethyl)-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (single stereoisomer)

5-[(2R)-2-(3,4-Dichlorobenzyl)-3,3,3-trifluoropropoxy]-4-iodo-2-methoxypyridine (single stereoisomer) (378 mg, 747 µmol, 1.0 eq.) and pivalate potassium (1.05 g, 7.47 mmol, 10.0 eq.) was dissolved in N,N-dimethylacetamide (25 ml) and argon was purged through the mixture for 10 min. Then, tetrakis(triphenylphosphine)palladium(0) (86.3 mg, 74.7 µmol, 0.1 eq.) was added and the mixture was stirred at 120°C overnight. The mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 95:5 - 60:40). Yield: 420 mg (47% purity, 16% theoretical yield).

LC-MS (method 3): Rt=4.22 min; MS (ESIpos): m/z=378 [M+H]+.

Example 3.8C.

(7R)-11,12-Dichloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (single stereoisomer)

General method 4 was carried out with (7R)-11,12-dichloro-2-methoxy-7-(trifluoromethyl)-7,8-dihydro-6H[3]benzoxocino[2,1-c]pyridine (single stereoisomer) (95.0 mg, 47% purity, 118 µmol, 1.0 eq.) and sodium iodide (88.5 mg, 590 µmol, 5.0 eq.) in acetic acid (4.0 ml) at 100°C for 2.0 h, including the following variations of the procedure: Crude mixture purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 21.0 mg (49% of theoretical yield).

LC-MS (method 3): Rt=2.73; MS (ESIpos): m/z=364 [M+H]+.

'H-NMR (600 MHz, DMSO-d6): δ [ppm]=7.75-7.69 (m, 2H), 7.41 (d, 1H), 6.41 (s, 1H), 4.62 (dd, 1H), 3.82 ( t, 1H), 3.07 (d, 2H), 3.02-2.86 (m, 1H).

Example 3.9A.

5-[2-(4-Chlorobenzyl)-3,3-difluoropropoxy]-4-iodo-2-methoxypyridine (racemate)

Under argon, a mixture of 2-(4-chlorobenzyl)-3,3-difluoropropan-1-ol (racemate) (3.50 g, 15.9 mmol) and 4-iodo-6-methoxypyridin-3-ol (3.98 g, 15.9 mmol , 1.0 eq.) in toluene (50 ml) was treated with (tributylphosphoranylidene)acetonitrile (1.50 g, 23.8 mmol, 1.5 eq.). The reaction mixture was stirred for 16 hours under reflux, cooled to room temperature and purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 100:0 -95:5 - 9:1). Yield: 6.74 g (94% of theoretical yield).

LC-MS (method 3): R _t =4.48 min; MS (ESIpos): m/z=454 [M+H]+.

Example 3.9V.

-Chloro-7-(difluoromethyl)-2-methoxy-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (racemate)

- 66 044932

F ^H <

\/

Cl

Under an argon atmosphere, a round bottom flask was loaded with cesium pivalate (3.48 g, 14.9 mmol, 1.5 equiv.)

N,N-dimethylacetamide (150 ml) and then the flask was frozen, evacuated and filled with argon three times. The mixture was then heated to 150°C. The second round bottom flask was charged with 5-[2-(4-chlorobenzyl)3,3-difluoropropoxy]-4-iodo-2-methoxypyridine (racemate) (4.5 g, 9.91 mmol) in N,N-dimethylacetamide (30 ml) and the flask was frozen, evacuated, and backfilled with argon three times.

Tetrakis(triphenylphosphine)palladium(0) (1.15 g, 0.99 mmol, 0.10 eq) was added and the mixture was pumped into the preheated potassium pivalate solution at 150°C for 1.0 h. After addition, the reaction mixture was stirred for another 5.5 h at 150°C. The reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with tert-butyl methyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/toluene 100:0 - 3:1 - 1:1 - 1:3 0:100). Yield: 600 mg (17% of theoretical yield).

LC-MS (method 3): Rt=3.68 min; MS (ESIpos): m/z=326 [M+H]+.

Example 3.9C.

11-Chloro-7-(difluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (racemate)

F γ^ΝΗ \ζ ci

Under argon, 4-toluenesulfonic acid monohydrate (596 mg, 3.13 mmol, 1.85 eq.) and lithium chloride (359 mg, 8.47 mmol, 5.0 eq.) were added at room temperature to a solution of 11-chloro-7(difluoromethyl)-2 -methoxy-7,8-dihydro-6H-[3]benzoxocino[2,1-c]pyridine (racemate) (600 mg, 1.69 mmol) in 2-propanol (7.1 ml). After stirring and refluxing for 16 hours, the reaction mixture was cooled to room temperature and the resulting precipitate was filtered, washed with water and dried. Yield: 515 mg (98% of theoretical yield).

LC-MS (method 3): R _t =2.26 min; MS (ESIpos): m/z=312 [M+H] ⁺ .

Example 4.1A.

2-(Cyclopropyloxy)ethyl trifluoromethanesulfonate

2,6-Dimethylpyridine (171 μl, 1.47 mmol, 1.5 eq.) and trifluoromethanesulfonic acid anhydride (249 μl, 1.47 mmol, 1.5 eq.) were added dropwise in an argon atmosphere at 0°C to a solution of 2(cyclopropyloxy)ethane-1 -ol (100 mg, 0.98 mmol) in dichloromethane (4 ml). The reaction mixture was stirred at 0°C for 45 min, diluted with tert-butyl methyl ether and extracted with a 3:1 mixture of saturated aqueous sodium chloride and aqueous hydrochloric acid (1N). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. Yield: 262 mg.

'H-NMR (600 MHz, DMSO-d6): δ [ppm]=4.44-4.37 (m, 2H), 3.72-3.65 (m, 2H), 3.45-3.38 (m, 1H), 0.550.45 (m , 4H).

Example 4.2A.

2-[(1-Methylcyclopropyl)oxy]ethan-1-ol

- 67 044932

Magnesium turnings (474 mg, 19.5 mmol, 6.5 eq.) were placed in a round bottom flask and heated, followed by the addition of diethyl ether (5 mL) and some iodine. A solution of 1,2-dibromethane (1.1 ml, 13 mmol) in diethyl ether (5 ml) was added dropwise under reflux. After stirring for another 5 min, a solution of 2-(2-bromoethyl)-2-methyl-1,3-dioxolane (585 mg, 3.00 mmol) in diethyl ether (5 ml) was added dropwise. The reaction mixture was stirred under reflux overnight, cooled to room temperature, diluted with diethyl ether, quenched carefully with saturated aqueous ammonium chloride, and diluted with ethyl acetate and water. After phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. Yield: 211 mg (61% of theoretical yield).

¹ H-NMR (500 MHz, CDCI3): δ [ppm]=3.70-3.63 (m, 2H), 3.60-3.54 (m, 2H), 1.40 (s, 3H), 0.81-0.75 (m, 2H), 0.45-0.40 (m, 2H).

Example 4.2V.

2-[(1-Methylcyclopropyl)oxy]ethyl trifluoromethanesulfonate

2,6-Dimethylpyridine (317 μl, 2.73 mmol, 1.5 eq.) and trifluoromethanesulfonic acid anhydride (461 μl, 2.73 mmol, 1.5 eq.) were added dropwise under argon at 0°C to a solution of 2-[(1methylcyclopropyl)oxy ]ethan-1-ol (211 mg, 1.82 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at 0°C for 1.5 h, diluted with tert-butyl methyl ether and extracted with a 3:1 mixture of saturated aqueous sodium chloride and aqueous hydrochloric acid (1H). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. Yield: 509 mg.

¹ H-NMR (600 MHz, CDCI3): δ [ppm]=4.58-4.53 (m, 2H), 3.80-3.75 (m, 2H), 1.39 (s, 3H), 0.84-0.78 (m, 2H), 0.46-0.40 (m, 2H).

Example 4.3A.

[(2S)-5,5-Dimethyloxolan-2-yl]methyl trifluoromethanesulfonate (sole stereoisomer)

2,6-Dimethylpyridine (161 µl, 1.38 mmol, 1.5 eq.) and trifluoromethanesulfonic acid anhydride (234 µl, 1.38 mmol, 1.5 eq.) were added dropwise under argon at 0°C to the solution of [(2S)-5, 5dimethyloxolan-2-yl]methanol (single stereoisomer) (120 mg, 0.92 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at 0°C for 45 min, diluted with tert-butyl methyl ether and extracted with a 3:1 mixture of saturated aqueous sodium chloride and aqueous hydrochloric acid (1N). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. Yield: 265 mg.

1H-NMR (400 MHz, CDCI3): δ [ppm]=4.53-4.46 (m, 1H), 4.44-4.37 (m, 1H), 4.33-4.24 (m, 1H), 2.21-2.10 (m, 1H) , 1.92-1.76 (m, 3H), 1.28 (s, 3H), 1.25 (s, 3H).

Example 5.1A.

tert-Butyl (11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl)acetate (racemate)

- 68 044932 ⁿ 3 ^{Sn 3}

I Chl θ с^ ^Нз \7

C.I.

Potassium carbonate (226 mg, 1.63 mmol, 1.5 eq.) was added to the solution of 11-chloro-7-methyl-7,8-dihydro-3H[3]benzoxocino[2,1-c]pyridin-2(6H)-one (racemate) (300 mg, 1.09 mmol) and tert-butyl bromoacetate (193 μl, 255 mg, 1.31 mmol, 1.2 eq.) in N,N-dimethylformamide (3.0 ml). The reaction mixture was stirred at 50°C overnight and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: 0-95% ethyl acetate/cyclohexane). Yield: 281 mg (66% of theoretical yield).

LC-MS (method 4): Rt=2.10 min; MS (ESIpos): m/z=390 [M+H]+.

Example 5.1B.

tert-Butyl[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzokocino[2,1-c]pyridin-3yl]acetate (single stereoisomer)

Separation of enantiomers 830 mg tert-butyl (11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridin-3-yl) acetate ( racemate), Example 5.1A, gave single stereoisomer 1 (titled compound Example 5.1B) (chiral SFC: R _t =0.74 min, >99% ee): 414 mg, single stereoisomer 2 (chiral SFC: R _t =1.39 min, >99% ee): 413 mg.

Separation method: SFC: column: Daicel Chiralpak AS-H 5 µm, 250 mmx20 mm; eluent: 65% carbon dioxide/35% methanol; temperature: 40°C; flow rate: 80 ml/min; UV detection: 210 nm.

Method of analysis: SFC: column: Daicel Chiralpak AS 5 µm, 100 mmx4.6 mm; eluent: 70% carbon dioxide/30% methanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

LC-MS (method 4): R _t =2.08 min; MS (ESIpos): m/z=390 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=7.74 (s, 1H), 7.47-7.38 (m, 2H), 7.33-7.30 (m, 1H), 6.35 (s, 1H) , 4.65-4.50 (m, 2H), 4.48-4.41 (m, 1H), 3.30-3.25 (m, 1H), 2.70 (d, 1H), 2.33-2.24 (m, 1H), 2.09-1.94 (m, 1H), 1.44 (s, 9H), 0.89 (d, 3H). Additional minor rotamer signals were also detected.

Example 5.2A.

tert-Butyl 2-(11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzokocino[2,1-c]pyridin-3-yl)3-[ (2 S)-tetrahydro-2H-pyran-2-yl] propanoate (mixture of stereoisomers)

A solution of sodium bis(trimethylsilyl)amide (0.8 ml, 1 M b tetrahydrofuran, 0.8 mmol, 1.25 eq.) was added dropwise under argon at -78°C to a solution of tert-butyl (11-chloro-7-methyl-2- oxo-2,6,7,8tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl)acetate (racemate) (250 mg, 0.641 mmol) in tetrahydrofuran (9.3 ml). After stirring at -78°C for 20 min, (2S)-tetrahydro-2H-pyran-2ylmethyl trifluoromethanesulfonate (single stereoisomer) (205 mg, 0.802 mmol, 1.25 eq.) (prepared according to WO 2017/005725, example 3.3D ) added. The resulting reaction mixture was stirred at -78°C for 30 minutes, then slowly warmed to room temperature and stirred for 1 hour. Glacial acetic acid (55 μl, 58 mg, 0.96 mmol, 1.5 eq.) was added and the reaction mixture was concentrated at reduced pressure. The crude product was purified by preparative HPLC (reverse phase, eluent: 10-90% acetonitrile/water with 0.05% formic acid). Yield: 144 mg (46% of theoretical yield).

LC-MS (method 1): R _t =1.27 min; MS (ESIpos): m/z=488 [M+H]+.

Example 5.2V.

2-(11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl)-3-[(2S )tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of stereoisomers)

- 69 044932

V/ci

Trifluoroacetic acid (3.1 ml) was added at room temperature to a solution of tert-butyl 2(11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1- c]pyridin-3-yl)-3-[(2S)-tetrahydro2H-pyran-2-yl]propanoate (mixture of stereoisomers) (140 mg, 0.287 mmol) in dichloromethane (3 ml). The reaction mixture was stirred for 45 minutes and then concentrated under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile and water and lyophilized. The crude product was used without further purification. Yield: 152 mg.

LC-MS (method 1): Rt=1.01 min; MS (ESIpos): m/z=432 [M+H]+.

Example 5.3A.

tert-Butyl 2-[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]- 3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate (mixture of two diastereomers) CH ₃

Ku _o S th; ⁿ s

Cl

A solution of sodium bis(trimethylsilyl)amide (0.51 ml, 1M in tetrahydrofuran, 0.51 mmol, 1.25 eq.) was added dropwise under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-7-methyl -2-oxo2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (158 mg, 0.406 mmol) in tetrahydrofuran (12 ml) . After stirring at -78°C for 20 min, a solution of (2S)-tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulfonate (single stereoisomer) (130 mg, 0.508 mmol, 1.25 eq.) (prepared according to WO 2017/005725, example 3.3D) in tetrahydrofuran (4 ml) was added. The resulting reaction mixture was stirred at -78°C for 30 minutes, then slowly warmed to room temperature and stirred for 1 hour. Glacial acetic acid (35 μl, 37 mg, 0.61 mmol, 1.5 eq.) was added and the reaction mixture was concentrated at low pressure. The crude product was purified by column chromatography (silica gel, eluent: 0100% ethyl acetate/cyclohexane). Yield: 112 mg (87% purity, 49% theoretical yield).

LC-MS (method 4): Rt=2.47 min; MS (ESIpos): m/z=488 [M+H]+.

Example 5.3V.

2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-3 [(2S)-tetrahydro-2H-pyran-2-yl]npronoic acid (mixture of two diastereomers)

Lithium hydroxide (109 mg, 4.58 mmol, 23 equiv.) was added to the solution of tert-butyl 2-[(7R)-11-chloro-7methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3 ]benzoxocino[2,1-c]πpyridin-3-yl]-3-[(2S)-tetrahydro-2H-πpyran2-yl]propanoate (mixture of two diastereomers) (111 mg, 87% purity, 0.197 mmol) in tetrahydrofuran (4.6 ml) and water (2.3 ml). The resulting reaction mixture was shaken at 40°C for 22 hours, then acidified with an aqueous solution of hydrochloric acid (1H) and diluted with ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. Yield: 22 mg (85% purity, 22% theoretical yield).

LC-MS (method 4): Rt=1.86/1.89 min; MS (ESIpos): m/z=432 [M+H]+.

Example 5.4A.

tert-Butyl 2-[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridine-3- 70 044932 yl]-3-[(2R)-1,4-dioxan-2-yl]propanoate (mixture of two diastereomers)

A solution of sodium bis(trimethylsilyl)amide (0.80 ml, 1M in tetrahydrofuran, 0.80 mmol, 1.25 eq.) was added dropwise under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-7-methyl -2-oxo2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (250 mg, 0.641 mmol) in tetrahydrofuran (18 ml) . After stirring at -78°C for 20 min, a solution of (2S)-1,4-dioxan-2-ylmethyltrifluoromethanesulfonate (single stereoisomer) (201 mg, 0.802 mmol, 1.25 eq.) (prepared according to WO 2017/005725, example 3.5A) in tetrahydrofuran (6 ml) was added. The resulting reaction mixture was stirred at -78°C for 30 minutes, then slowly warmed to room temperature and stirred for 1 hour. Glacial acetic acid (55 μl, 58 mg, 0.96 mmol, 1.5 eq.) was added and the reaction mixture was concentrated at low pressure. The crude product was purified by column chromatography (silica gel, eluent: 0-100% ethyl acetate/cyclohexane). Yield: 150 mg (47% of theoretical yield).

LC-MS (method 4): Rt=2.18 min; MS (ESIpos): m/z=490 [M+H]+.

Example 5.4V.

2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-3 [(2R)-1,4-dioxan-2-yl]propanoic acid (mixture of two diastereomers)

JL.o

V/

C.I.

Lithium hydroxide (147 mg, 6.12 mmol, 20 equiv.) was added to the solution of tert-butyl 2-[(7R)-11-chloro-7methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3 ]benzoxocino[2,1-c]pyridin-3-yl]-3-[(2R)-1,4-dioxan-2yl]propanoate (mixture of two diastereomers) (150 mg, 0.306 mmol) in tetrahydrofuran (6.2 ml) and water (3.1 ml). The resulting reaction mixture was shaken at 40°C overnight, then acidified with an aqueous solution of hydrochloric acid (1H) and diluted with ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was dried under vacuum and used in the next step without further purification. Yield: 105 mg (78% of theoretical yield).

LC-MS (method 4): R _t =1.61 min; MS (ESIpos): m/z=434 [M+H] ⁺ .

Example 5.5A.

tert-Butyl 2-[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]- 4-(cyclopropyloxy)butanoate (mixture of two diastereomers)

A solution of lithium bis(trimethylsilyl)amide (0.31 mL, 1M in tetrahydrofuran, 0.31 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-7-methyl-2 -oxo-2,6,7,8tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (101 mg, 0.26 mmol) in tetrahydrofuran (3 ml). After stirring at -78°C for 15 min, 2(cyclopropyloxy)ethyl trifluoromethanesulfonate (91 mg, 0.39 mmol, 1.5 eq.) was added dropwise. The resulting reaction mixture was stirred at -78°C for 15 minutes and then allowed to warm to room temperature. The reaction mixture was quenched with water. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

- 71 044932 pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 12 mg (10% of theoretical yield).

LC-MS (method 4): R _t =2.41 min; MS (ESIpos): m/z=474 [M+H]+.

Example 5.5V.

2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4 (cyclopropyloxy)butanoic acid (mixture of two diastereomers)

Lithium hydroxide (3 mg, 0.12 mmol, 4.5 eq.) was added at room temperature to a solution of tert-butyl 2-[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H -[3]benzoxocino[2,1-c]pyridin-3-yl]-4(cyclopropyloxy)butanoate (a mixture of two diastereomers) (12 mg, 0.03 mmol) in a mixture of tetrahydrofuran and water (3:1, 1 ml). The reaction mixture was stirred at room temperature overnight and then acidified with an aqueous solution of hydrochloric acid (1H). After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. Yield: 9 mg (82% of theoretical yield).

LC-MS (method 1): R _t =1.01 min; MS (ESIpos): m/z=418 [M+H]+.

Example 5.6A.

tert-Butyl 2-[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]- 4-(cyclobutyloxy)butanoate (mixture of two diastereomers)

СНз кАА ₀ О СН ₃ ³

C.I.

A solution of lithium bis(trimethylsilyl)amide (0.31 mL, 1M in tetrahydrofuran, 0.31 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-7-methyl-2 -oxo-2,6,7,8tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (101 mg, 0.26 mmol) in tetrahydrofuran (3 ml). After stirring at -78°C for 15 min, 2(cyclobutyloxy)ethyltrifluoromethanesulfonate (124 mg, 78% assumed crude purity, 0.39 mmol, 1.5 eq.) (prepared according to WO 2016/146606, example 2.2A) was added dropwise . The resulting reaction mixture was stirred at -78°C for 15 minutes, then allowed to warm to room temperature and stirred at room temperature for 3 hours. The reaction mixture was quenched with water. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 80 mg (63% of theoretical yield).

LC-MS (method 3): Rt=4.46 min; MS (ESIpos): m/z=488 [M+H]+.

Example 5.6V.

2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4 (cyclobutyloxy)butanoic acid (mixture of two diastereomers)

- 72 044932

Trifluoroacetic acid (341 μL, 4.43 mmol, 20 equiv.) was added at 0°C to a solution of tert-butyl 2[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro -3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4(cyclobutyloxy)-butanoate (mixture of two diastereomers) (108 mg, 0.22 mmol) in dichloromethane (3 ml). The reaction mixture was stirred for 3.5 h and then concentrated under reduced pressure. The residue was dissolved in toluene and concentrated under reduced pressure. The residue was dissolved in dichloromethane and concentrated under reduced pressure. Yield: 106 mg (83% purity, 92% theoretical yield).

LC-MS (method 4): R=1.96 min; MS (ESIpos): m/z=432 [M+H]+.

Example 5.7A.

tert-Butyl [(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzokocino[2,1c]pyridin-3-yl]acetate (single stereoisomer)

Potassium carbonate (365 mg, 2.64 mmol, 1.5 eq.) and tert-butyl bromoacetate (318 µl, 420 mg, 2.11 mmol, 1.2 eq.) were added to the solution of (7R)-11-chloro-7-(trifluoromethyl)-7 ,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (580 mg, 1.76 mmol) in N,N-dimethylformαmide (8 ml). The reaction mixture was stirred at 100°C for 50 minutes, cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: 635 mg (81% of theoretical yield).

LC-MS (method 1): R _t =1.15 min; MS (ESIpos): m/z=444 [M+H]+.

Example 5.8A.

tert-Butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzokocino[2,1c]pyridin-3-yl ]-3-[(2S)-5,5-dimethyloxolan-2-yl]propanoate (mixture of two diastereomers)

A solution of lithium bis(trimethylsilyl)amide (0.27 mL, 1M in tetrahydrofuran, 0.27 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-2-oxo-7 -(trifluoromethyl)2,6,7,8-tetrahydro-3I-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (100 mg, 0.23 mmol) in tetrahydrofuran (3 ml ). After stirring at -78°C for 15 min, [(2S)-5,5dimethyloxolan-2-yl]methyl trifluoromethanesulfonate (single stereoisomer) (100 mg, 0.36 mmol, 1.6 eq.) was added dropwise.

The reaction mixture was stirred at -78°C for 45 minutes, then allowed to warm to 0°C and stirred at 0°C for an additional 80 minutes. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 65 mg (52% of theoretical yield).

LC-MS (method 4): Rt=2.55/2.58 min; MS (ESIpos): m/z=556 [M+H]+.

Example 5.8V.

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzokocino[2,1-c]pyridin-3yl]-3 -[(2S)-5,5-dimethyloxolan-2-yl]propαnoic acid (mixture of two diastereomers)

- 73 044932

Lithium hydroxide (10 mg, 0.42 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro -3H-[3]benzoxocino[2,1-c]pyridin-3yl]-3-[(2S)-5,5-dimethyloxolan-2-yl]propanoate (mixture of two diastereomers) (117 mg, 0.21 mmol) in a mixture of tetrahydrofuran and water (3:1, 4 ml). The reaction mixture was stirred at room temperature overnight and then acidified with an aqueous solution of hydrochloric acid (1H). After removing all volatile compounds under reduced pressure, the residue was diluted with water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 98 mg (87% purity, 81% theoretical yield).

LC-MS (method 3): Rt=3.56/3.61 min; MS (ESIpos): m/z=500 [M+H]+.

Example 5.9A.

tert-Butyl (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c] pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glycero-pentonate (mixture of two diastereomers)

O' ^SN z |< L ^{SN z} k Aa o

A CI

A solution of lithium bis(trimethylsilyl)amide (0.46 mL, 1M in tetrahydrofuran, 0.46 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-2-oxo-7 -(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (170 mg, 0.38 mmol) in tetrahydrofuran (5 ml ). After stirring at -78°C for 15 min, (2S)-2methoxypropyl trifluoromethanesulfonate (single stereoisomer) (128 mg, 0.58 mmol, 1.5 eq.) (prepared according to WO 2014/154794, example 28.1A) was added dropwise. The reaction mixture was stirred at -78°C for 15 minutes, then allowed to warm to room temperature and stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride.

After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 235 mg.

LC-MS (method 4): R _t =2.36 min; MS (ESIpos): m/z=516 [M+H] ⁺ .

Example 5.9V.

(2ξ)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers)

Trifluoroacetic acid (0.60 mL, 7.74 mmol, 20.0 eq.) was added at room temperature to a solution of tert-butyl (2S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6 ,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonate (mixture of two diastereomers) (235 mg, 85% accepted crude product purity, 0.39 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 4.5 h, concentrated under reduced pressure and co-evaporated twice with dichloromethane. The crude product was used without further purification. Yield: 255 mg (86% purity).

LC-MS (method 4): R _t =1.82/1.84 min; MS (ESIpos): m/z=460 [M+H] ⁺ .

Example 5.10A.

tert-Butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl ]-4-(difluoromethoxy)butanoate (mixture of two diastereomers)

- 74 044932

1,1,3,3-Tetramethylguanidine (149 μL, 1.19 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (132 mg, 0.40 mmol) in 2-propanol/acetone (4:1, 1.75 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of tert-butyl 2-bromo-4-(difluoromethoxy)butanoate (racemate) (157 mg, 80% purity, 0.44 mmol, 1.1 eq.) and more 2-propanol/ acetone (4.1, 1.75 ml). The reaction mixture was stirred at room temperature for 3 days, combined with a previous similar test batch using (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2, 1-c]pyridin-2(6H)-one (single stereoisomer) (28 mg, 0.09 mmol) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: 188 mg (73% of theoretical yield for both batches of reaction).

LC-MS (method 4): R _t =2.43 min; MS (ESIpos): m/z=538 [M+H] ⁺ .

Example 5.10V.

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4 -(difluoromethoxy)butanoic acid (mixture of two diastereomers)

Lithium hydroxide (17 mg, 0.70 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro -3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4-(difluoro-methoxy)butanoate (mixture of two diastereomers) (188 mg, 0.35 mmol) in a mixture of tetrahydrofuran and water (3:1, 7 ml). The reaction mixture was stirred at room temperature overnight and then acidified with an aqueous solution of hydrochloric acid (1H). After removing all volatile compounds under reduced pressure, the residue was diluted with water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 140 mg (83% of theoretical yield).

LC-MS (method 1): R _t =0.96 min; MS (ESIpos): m/z=482 [M+H]+.

Example 5.11A. tert-Butyl (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H

[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-D-glyceropentonate (mixture of two diastereomers)

1,1,3,3-Tetramethylguanidine (205 μL, 1.63 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (181 mg, 0.55 mmol) in 2-propanol/acetone (4:1, 2.5 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of tert-butyl (4R)-2-bromo-4-(difluoromethoxy)-pentanoate (a mixture of two diastereomers) (182 mg, 0.60 mmol, 1.1 eq.) and 2 more -propanol/acetone (4:1, 2.5 ml). The reaction mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: 224 mg (75% of theoretical yield).

- 75 044932

LC-MS (method 1): Rt=1.23 min; MS (ESIpos): m/z=552 [M+H]+.

Example 5.11B.

(2ξ)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-D-glyceropentonic acid (mixture of two diastereomers)

WITH}

C.I.

Lithium hydroxide (19 mg, 0.80 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7 ,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-D-glyceropentonate (mixture of two diastereomers) ( 220 mg, 0.40 mmol) in a mixture of tetrahydrofuran and water (3:1, 5 ml). The reaction mixture was stirred at room temperature overnight and then acidified with an aqueous solution of hydrochloric acid (1H). After removing all volatile compounds under reduced pressure, the residue was diluted with water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 176 mg (89% of theoretical yield).

LC-MS (method 4): Rt=2.04 min; MS (ESIpos): m/z=496 [M+H]+.

Example 5.12A.

tert-Butyl (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c] pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-L-glyceropentonate (mixture of two diastereomers)

1,1,3,3-Tetramethylguanidine (151 μL, 1.20 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (133 mg, 0.40 mmol) in 2-propanol/acetone (4:1, 2.5 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of tert-butyl (4S)-2-bromo-4-(difluoromethoxy)-pentanoate (a mixture of two diastereomers) (138 mg, 0.44 mmol, 1.1 eq.) and 2 more -propanol/acetone (4:1, 2.5 ml). The reaction mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 128 mg (58% of theoretical yield).

LC-MS (method 1): Rt=1.23 min; MS (ESIpos): m/z=552 [M+H]+.

Example 5.12V.

(2ξ)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-b-glyceropentonic acid (mixture of two diastereomers)

Lithium hydroxide (11 mg, 0.46 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7 ,8-tetrahydro-3H-[3]benzoxocino[2,1

- 76 044932

c]pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-L-glycero-pentonate (mixture of two diastereomers) (128 mg, 0.23 mmol) in a mixture of tetrahydrofuran and water (3: 1.5 ml). The reaction mixture was stirred at room temperature overnight and then acidified with an aqueous solution of hydrochloric acid (1H). After removing all volatile compounds under reduced pressure, the residue was diluted with water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 93 mg (89% purity, 72% theoretical yield).

LC-MS (method 4): R _t =1.95 min; MS (ESIpos): m/z=496 [M+H]+.

Example 5.13A.

tert-Butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl ]-4-(2,2-difluoroethoxy)butanoate (mixture of two diastereomers)

A solution of lithium bis(trimethylsilyl)amide (0.41 mL, 1M in tetrahydrofuran, 0.41 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-2-oxo-7 -(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (150 mg, 0.34 mmol) in tetrahydrofuran (5 ml ). After stirring at -78°C for 15 min, 2-(2,2difluoroethoxy)ethyl trifluoromethanesulfonate (131 mg, 0.51 mmol, 1.5 eq.) (prepared according to WO 2016/046164, example 24.1A) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes and then allowed to warm to 0°C. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: 126 mg (66% of theoretical yield).

LC-MS (method 1): Rt=1.21 min; MS (ESIpos): m/z=552 [M+H]+.

Example 5.13V.

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4 -(2,2-difluoroethoxy)butanoic acid (mixture of two diastereomers)

Lithium hydroxide (11 mg, 0.44 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro -3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4-(2,2-difluoroethoxy)butanoate (mixture of two diastereomers) (125 mg, 0.22 mmol) in a mixture of tetrahydrofuran and water (3:1 , 5 ml). The reaction mixture was stirred at room temperature overnight, then acidified with an aqueous solution of hydrochloric acid (1H) and diluted with water. After removing all volatile compounds under reduced pressure, the resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 85 mg (78% of theoretical yield).

LC-MS (method 4): R=1.85 min; MS (ESIpos): m/z=496 [M+H]+.

Example 5.14A.

tert-Butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl ]-4-[(propan-2-yl)oxy]butanoate (mixture of two diastereomers)

- 77 044932 sn ₃

Cl

A solution of lithium bis(trimethylsilyl)amide (0.46 mL, 1 M in tetrahydrofuran, 0.46 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-2-oxo-7 -(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (170 mg, 0.38 mmol) in tetrahydrofuran (5 ml ). After stirring at -78°C for 15 min, 2[(propan-2-yl)oxy]ethyl trifluoromethanesulfonate (136 mg, 0.58 mmol, 1.5 eq.) (prepared according to WO 2016/146606, example 2.1 A) was added at drops. The resulting reaction mixture was stirred at -78°C for 15 minutes, then allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 260 mg.

LC-MS (method 1): R _t =1.29 min; MS (ESIpos): m/z=530 [M+H] ⁺ .

Example 5.14V.

2-[(7E)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4 -[(propan-2-yl)oxy] butanoic acid (mixture of two diastereomers) CH ₃

C.I.

Lithium hydroxide (19 mg, 0.79 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl 2-[(7R)-l 1-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8- tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4-[(propan-2-yl)oxy]butanoate (mixture of two diastereomers) (260 mg, 80% assumed crude purity, 0.39 mmol) in a mixture of tetrahydrofuran and water (3:1, 8 ml). The reaction mixture was stirred at room temperature overnight, then acidified with an aqueous solution of hydrochloric acid (1H) and diluted with water. After removing all volatile compounds under reduced pressure, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. Yield: 166 mg (92% purity, 82% of theoretical yield).

LC-MS (method 4): R _t =1.97 min; MS (ESIpos): m/z=474 [M+H] ⁺ .

Example 5.15A.

tert-Butyl 4-tert-butoxy-2-[(7B)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1- c]pyridin-3-yl]butanoate (mixture of two diastereomers) CH ₃ Lch ₃ o^CH ₃

C.I.

A solution of lithium bis(trimethylsilyl)amide (0.41 mL, 1 M in tetrahydrofuran, 0.41 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-2-oxo-7 -(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (150 mg, 0.34 mmol) in tetrahydrofuran (5 ml ). After stirring at -78°C for 15 min, 2-tert-butoxyethyl trifluoromethanesulfonate (190 mg, 80% assumed crude purity, 0.61 mmol, 1.8 eq.) (prepared according to WO 2016/146606, example 2.3A) was added dropwise . The reaction mixture was stirred at -78°C for 15 minutes, then allowed to warm to room temperature and stirred at room temperature for 20 minutes. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient), the residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient), and both batches were combined. Yield: 81 mg (44% of theoretical yield).

LC-MS (method 4): R _t =2.56 min; MS (ESIpos): m/z=544 [M+H] ⁺ .

Example 5.15V.

4-tert-Butoxy-2-[(7K)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridine -3-yl]butanoic acid (mixture of two diastereomers)

C.I.

Lithium hydroxide (7 mg, 0.29 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl 4-tert-butoxy-2-[(7K)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6 ,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridin-3-yl]butanoate (mixture of two diastereomers) (80 mg, 0.15 mmol) in a mixture of tetrahydrofuran and water (3:1.4 ml ). The reaction mixture was stirred at room temperature overnight, then acidified with an aqueous solution of hydrochloric acid (1H) and diluted with water. After removing all volatile compounds under reduced pressure, the aqueous phase was cooled in an ice bath. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 182 mg (72% of theoretical yield).

LC-MS (method 4): R _t =2.06 min; MS (ESIpos): m/z=488 [M+H] ⁺ .

Example 5.16A.

tert-Butyl 2-[(7R)-l 1-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-(cyclopropyloxy)butanoate (mixture of two diastereomers)

A solution of lithium bis(trimethylsilyl)amide (0.41 mL, 1 M in tetrahydrofuran, 0.41 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-2-oxo-7 -(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) (150 mg, 0.34 mmol) in tetrahydrofuran (5 ml ). After stirring at -78°C for 15 min, 2(cyclopropyloxy)ethyl trifluoromethanesulfonate (127 mg, 0.54 mmol, 1.6 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes and then allowed to warm to room temperature. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: 94 mg (53% of theoretical yield).

LC-MS (method 3): R _t =4.34 min; MS (ESIpos): m/z=528 [M+H] ⁺ .

Example 5.16V.

2-[(7R)-l 1-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]- 4-(cyclopropyloxy)butanoic acid (mixture of two diastereomers)

-79044932

Lithium hydroxide (9 mg, 0.36 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro -3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4-(cyclopropyloxy)butanoate (mixture of two diastereomers) (94 mg, 0.18 mmol) in a mixture of tetrahydrofuran and water (3:1, 5 ml) . The reaction mixture was stirred at room temperature for 2 days, then acidified with an aqueous solution of hydrochloric acid (1H) and diluted with water. After removing all volatile compounds under reduced pressure, the resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 66 mg (79% of theoretical yield).

LC-MS (method 4): Rt=1.91 min; MS (ESIpos): m/z=472 [M+H] ⁺ .

Example 5.17A.

tert-Butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl ]-4-[(1-methylcyclopropyl)oxy]butanoate (mixture of two diastereomers)

A solution of lithium bis(trimethylsilyl)amide (0.84 mL, 1M in tetrahydrofuran, 0.84 mmol, 1.2 eq.) was added under argon at -78°C to a solution of tert-butyl [(7R)-11-chloro-2-oxo-7 -(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (sole stereoisomer) (310 mg, 0.70 mmol) in tetrahydrofuran (10 ml ). After stirring at -78°C for 15 min, 2-[(1methylcyclopropyl)oxy]ethyl trifluoromethanesulfonate (260 mg, 1.05 mmol, 1.5 eq.) was added dropwise. The reaction mixture was stirred at -78°C for 15 minutes, then allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride. After addition of ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was combined with the crude product of a similar previous test using 30 mg (0.07 mmol) tert-butyl [(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H -[3]benzoxocino[2,1-c]pyridin-3-yl]acetate (single stereoisomer) and purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: 260 mg (67% of theoretical yield for both batches).

LC-MS (method 4): R _t =2.51 min; MS (ESIpos): m/z=542 [M+H]+.

Example 5.17V.

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4 -[(1-methylcyclopropyl)oxy]butanoic acid (mixture of two diastereomers)

Lithium hydroxide (23 mg, 0.94 mmol, 2.0 eq.) was added at room temperature to a solution of tert-butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro -3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4-[(1-methylcyclopropyl)oxy]butanoate (mixture of two diastereomers) (260 mg, 0.47 mmol) in a mixture of tetrahydrofuran and water (3: 1.5 ml). The reaction mixture was stirred at room temperature for 26 hours, then acidified with an aqueous solution of hydrochloric acid (1N) and diluted with water. After removing all volatile compounds under reduced pressure, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used

- 80 044932 without further purification. Yield: 182 mg (93% purity, 74% theoretical yield).

LC-MS (method 4): R _t =2.02 min; MS (ESIpos): m/z=486 [M+H]+.

Example 5.18A.

Ethyl

2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl]-4 -(cyclobutyloxy)butanoate (mixture of two diastereomers)

General Method 7 was performed with (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (99.5 mg, 302 µmol, 1.0 eq.), ethyl 2-bromo-4(cyclobutyloxy)butanoate (racemate) (120 mg, 75% purity, 453 µmol, 1.125 eq.) and 1,1,3,3tetramethylguanidine (110 µl, 910 µmol, 3.0 eq.) in 2-propanol/acetone (4:1, 3.75 ml), including the following variations of the procedure: After stirring for 3 days, additional amounts of 1,1,3,3-tetramethylguanidine (100 µl, 800 µmol, 2.65 eq.) was added and the mixture was stirred overnight. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 85 mg (54% of theoretical yield).

LC-MS (method 1): R _t =1.22 min; MS (ESIpos): m/z=514 [M+H] ⁺ .

Example 5.18V.

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4 -(cyclobutyloxy)butanoic acid (mixture of two diastereomers)

General method 10 was carried out with ethyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro

3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4-(cyclobutyloxy)butanoate (a mixture of two diastereomers) (85.0 mg, 165 µmol, 1.0 eq.) and lithium hydroxide (19.8 mg, 827 µmol, 5.0 eq.) in ethanol/tetrahydrofuran (2:1, 3 ml). Yield: 76.2 mg (95% of theoretical yield).

LC-MS (method 1): R _t =1.06 min; MS (ESIpos): m/z=486 [M+H] ⁺ .

Example 5.19A.

tert-Butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl ]-4-[(1-methylcyclobutyl)oxy]butanoate (mixture of two diastereomers)

General Method 9 was carried out with tert-butyl [(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c]pyridin- 3-yl]acetate (single stereoisomer) (150 mg, 338 µmol), 2[(1-methylcyclobutyl)oxy]ethyl trifluoromethanesulfonate (148 mg, 90% purity, 507 µmol, 1.5 eq., prepared according to WO 2017/037051, Example 3.10C) and lithium bis(trimethylsilyl)amide (410 µl, 1.0 M, 410 µmol, 1.2 eq.) in tetrahydrofuran (6.1 ml), including the following variations of the procedure: The reaction mixture was worked up by adding saturated aqueous ammonium chloride, water and ethyl acetate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 49.7 mg (27% of theoretical yield).

LC-MS (method 1): Rt=1.38 min; MS (ESIpos): m/z=556 [M+H] ⁺ .

Example 5.19V.

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridine-3- 81 044932 yl]-4-[(1-methylcyclobutyl)oxy]butanoic acid (mixture of two diastereomers)

C.I.

General Method 10 was carried out with tert-butyl 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzoxocino[2,1-c] pyridin-3-yl]-4-[(1-methylcyclobutyl)oxy]butanoate (a mixture of two diastereomers) (49.5 mg, 89.0 µmol, 1.0 eq.) and lithium hydroxide (10.7 mg, 445 µmol, 5.0 eq.) in a mixture ethanol/tetrahydrofuran (2:1, 3 ml). Yield: 50.0 mg (quantitative theoretical yield).

LC-MS (method 1): R=1.10 min; MS (ESIpos): m/z=500 [M+H]+.

Example 5.20A.

A mixture of ethyl 4-O-[tert-butyl(dimethyl)silyl]-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3] benzoxocin[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-5,5,5-trifluoropentonate (mixture of stereoisomers) and isopropyl 4-O-[tert-butyl(dimethyl)silyl]- 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]- 2,3,5-trideoxy-5,5,5-trifluoropentonate (mixture of stereoisomers)

General Method 7 was carried out with (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (250 mg, 758 µmol, 1.0 eq.), ethyl 2-bromo-4-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoropentanoate (mixture of stereoisomers) (519 mg, 69% purity, 910 µmol, 1.2 eq.) and 1,1,3,3-tetramethylguanidine (270 μl, 2.1 mmol, 2.8 eq.) in a mixture of 2propanol/acetone (4:1, 8.5 ml), including the following variations of the procedure: The mixture was stirred at room temperature in for 3 hours and at 50°C overnight and then used in the subsequent reaction without further purification as a mixture (due to partial transesterification during the reaction) ethyl 4-O[tert-butyl(dimethyl)silyl]-2-[( 7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3, 5-trideoxy-5,5,5-trifluoropentonate (mixture of stereoisomers):

LC-MS (method 1): R=1.65/1.64/1.63 min; MS (ESIpos): m/z=642 [M+H]+ and isopropyl 4-O-[tert-butyl(dimethyl)silyl]-2-[(7R)-11-chloro-2-oxo-7-( trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-5,5,5-trifluoropentonate (mixture of stereoisomers) :

LC-MS (method 1): R=1.53; MS (ESIpos): m/z=656 [M+H]+.

Example 5.20V.

4-O-[tert-butyl(dimethyl)silyl]-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino [2, 1-c]pyridin-3-yl]-2,3,5-trideoxy-5,5,5-trifluoro-D-erythropentonic acid (mixture of stereoisomers)

F

C.I.

General method 10 was carried out with a mixture of ethyl 4-O-[tert-butyl(dimethyl)silyl]-2-[(7R)-11-chloro-2-oxo7-(trifluoromethyl)-2,6,7,8-tetrahydro- 3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-5,5,5trifluoropentonate (mixture of stereoisomers) and isopropyl 4-O-[tert-butyl(dimethyl) silyl]-2-[(7R)-11chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl ]-2,3,5trideoxy-5,5,5-trifluoropentonate (mixture of stereoisomers) (combined 350 mg, 545 µmol, 1.0 eq.) and lithium hydroxide (131 mg, 5.45 mmol, 10.0 eq.), including the following variations of the procedure : The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95), obtaining two separate mixtures of diastereomers.

Diastereomeric mixture 1 (target product): 109 mg (33% of theoretical yield):

- 82 044932

LC-MS (method 3): R _t =4.71/4.73 min; MS (ESIpos): m/z=614 [M+H]+ and Diastereomeric mixture 2: 50.0 mg (15% of theoretical yield):

LC-MS (method 3): R _t =5.24/5.28/5.35 min; MS (ESIpos): m/z=614 [M+H] ⁺ .

Example 5.20C.

4-[(4-{[tert-Butyl(dimethyl)silyl]oxy}-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H- [3]benzoxocino[2,1-c]pyridin-3-yl]-5,5,5-trifluoropentanoyl)amino]benzamide (mixture of stereoisomers)

Into a solution of 4-O-[tert-butyl(dimethyl)silyl]-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3] benzoxocin[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-5,5,5-trifluoropentonic acid (diastereomeric mixture 1) (15.0 mg, 24.4 µmol, 1.0 eq.) in dichloromethane ( 1.0 ml) 1-chloroN,N,2-trimethylprop-1-en-1-amine (4.2 mg, 31.8 µmol, 1.3 eq.) was added and the resulting mixture was stirred for 10 min before 4-aminobenzamide (4.3 mg , 31.8 µmol, 1.3 eq.) was added and stirring was continued at room temperature for 3 hours. The same procedure was repeated with 4-O-[tert-butyl(dimethyl)silyl]-2-[(7R)-11-chloro-2 -oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-5,5, 5-trifluoropentonic acid (diastereomeric mixture 1) (60.0 mg, 97.7 µmol, 1.0 eq.), 1-chloro-N,N,2-trimethylprop-1-en-1-amine (17 µl, 17.0 mg, 130 µmol, 1.3 eq.) and 4-aminobenzamide (20.0 mg, 147 µmol, 1.5 eq.) in dichloromethane (4.0 ml). The two reaction mixtures were then combined, diluted with dichloromethane, then washed with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was used in the next step without further purification. Yield: 88.0 mg (57% purity, 70% theoretical yield).

LC-MS (method 3): Rt=4.70 min; MS (ESIpos): m/z=732 [M+H] ⁺ .

Example 5.21AT.

tert-Butyl (2ξ)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3] benzoxocino [2, 1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-D-glyceropentonate (mixture of two diastereomers)

C.I.

General method 7 was performed twice with (7R)-11-chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro-3H[3]benzoxocino[2,1-c]pyridine-2(6H)- one (single stereoisomer) (130 mg, 76% purity, 284 µmol, 1.0 eq.), tert-butyl (4R)-2-bromo-4-methoxypentanoate (mixture of two diastereomers) (98.2 mg, 85% purity, 313 µmol , 1.1 eq.) and 1,1,3,3-tetramethylguanidine (107 µl, 852 µmol, 3.0 eq.) in a mixture of 2-propanol/acetone (4:1, 4.5 ml) and, in the second batch, (7R) -11-chloro-12-fluoro-7-(trifluoromethyl)-7,8dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (single stereoisomer) (100 mg, 76% purity, 219 µmol, 1.0 eq.), tert-butyl (4R)-2-bromo-4-methoxypentanoate (mixture of two diastereomers) (75.6 mg, 85% purity, 240 µmol, 1.1 eq.) and 1,1,3 ,3-tetramethylguanidine (82 µl, 660 µmol, 3.0 eq.) in 2-propanol/acetone (4:1, 3.5 ml), including the following variations of the procedure: Crude mixtures of the two reactions were combined and purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 196 mg (74% of theoretical yield).

LC-MS (method 1): R _t =1.25 min; MS (ESIpos): m/z=534 [M+H] ⁺ .

Example 5.21B.

(2ξ)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-D-glycero-pentonic acid (mixture of two diastereomers)

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General method 10 was carried out with tert-butyl (2ξ)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3 ]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-D-glyceropentonate (mixture of two diastereomers) (192 mg, 345 µmol, 1.0 eq.) and lithium hydroxide (41.3 mg, 1.73 mmol, 5.0 eq.) in a mixture of tetrahydrofuran/water (2:1, 13 ml) at 40°C. Yield: 152 mg (92% of theoretical yield).

LC-MS (method 3): Rt=3.10/3.13 min; MS (ESIpos): m/z=478 [M+H]+.

Example 5.22A.

tert-Butyl (2ξ)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3] benzoxocino[2, 1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonate (mixture of two diastereomers)

General Method 7 was carried out with (7R)-11-chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro-3H[3]benzoxocino[2,1-c]pyridin-2(6H)-one ( single stereoisomer) (250 mg, 76% purity, 546 µmol, 1.0 eq.), tert-butyl (4S)-2-bromo-4-methoxypentanoate (mixture of two diastereomers) (161 mg, 601 µmol, 1.1 eq.) and 1,1,3,3-tetramethylguanidine (210 µl, 1.6 mmol, 3.0 eq.) in 2propanol/acetone (4:1, 5 ml), including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent : water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 155 mg (53% of theoretical yield).

LC-MS (method 1): R=1.24 min; MS (ESIpos): m/z=534 [M+H] ⁺ .

Example 5.22V.

(2ξ)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers)

General method 10 was carried out with tert-butyl (2ξ)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3 ]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonate (mixture of two diastereomers) (155 mg, 290 µmol, 1.0 eq.) and lithium hydroxide (34.8 mg, 1.45 mmol, 5.0 eq.) in a mixture of tetrahydrofuran/water (2:1, 4.5 ml). Yield: 185 mg (quantitative theoretical yield).

LC-MS (method 1): R _t =0.97 min; MS (ESIpos): m/z=478 [M+H] ⁺ .

Example 5.23A.

tert-Butyl (2ξ)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2, 1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-L-glyceropentonate (mixture of two diastereomers)

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ci

General method 7 was carried out with (7E)-11-chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro-3H[3]benzoxocino[2,1-c]pyridin-2(6H)-one ( single stereoisomer) (120 mg, 76% purity, 262 µmol, 1.0 eq.), tert-butyl (48)-2-bromo-4-(difluoromethoxy)pentanoate (mixture of two diastereomers) (95.4 mg, 315 µmol, 1.2 eq. .) and 1,1,3,3-tetramethylguanidine (99 µl, 790 µmol, 3.0 eq.) in 2 propanol/acetone (4:1, 2.4 ml), including the following variations of the procedure: The reaction mixture was stirred for 4 days and the crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 85.0 mg (53% of theoretical yield).

LC-MS (method 3): R _t =4.29 min; MS (ESIpos): m/z=570 [M+H] ⁺ .

Example 5.23V.

(2ξ)-2-[(7Β)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-E-glyceropentonic acid (mixture of two diastereomers)

General method 10 was carried out with tert-butyl (2ξ)-2-[(7R)-ll-chloro-12-φτop-2-oκco-7-(τpiφτopmethyl)2,6,7,8-tetrahydro-ZH-[3 ]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-E glyceropentonate (mixture of two diastereomers) (83.0 mg, 94% purity, 137 µmol, 1.0 equiv.) and lithium hydroxide (16.4 mg, 684 µmol, 5.0 equiv.) in a mixture of tetrahydrofuran/water (3:1, 4 ml). Yield: 116 mg (99% of theoretical yield).

LC-MS (method 1): R _t =l.01 min; MS (ESIpos): m/z=514 [M+H] ⁺ .

Example 6.1 A.

tert-Butyl [1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate

A mixture of 7-bromo[1,2,4]triazolo[1,5-a]pyridine (18.5 g, 93.4 mmol, 1.0 eq.), tert-butyl carbamate (16.42 g, 140.1 mmol, 1.5 eq.), palladium acetate (P) (2.10 g, 9.3 mmol, 0.1 eq.), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,G-biphenyl (13.36 g, 28.0 mmol, 0.3 eq.) and cesium carbonate ( 60.88 g, 186.8 mmol, 2.0 eq.) in 1,4-dioxane (930 ml) was purged with nitrogen gas for 10 min. The reaction mixture was heated to 100°C for 15 hours, cooled to room temperature and filtered through Celite®. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:3). Yield: 17.0 g (77% of theoretical yield).

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=9.99 (s, 1H), 8.77 (d, 1H), 8.30 (s, 1H), 7.87 (s, 1H), 7.19-7.12 (m, 1H), 1.49 (s, 9H).

Example 6.IB.

[1,2,4]Triazolo[1,5-a]pyridin-7-amine hydrochloride

A solution of hydrochloride (362.8 ml, 4 M in 1,4-dioxane) was added to a stirred solution of tert-butyl [1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (17.00 g, 72.6 mmol) in dichloromethane (1 L ). The reaction mixture was stirred at room temperature for 15 hours and diluted with diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure. Yield: 10.45 g (84% of theoretical yield).

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=8.97-8.90 (m, 1H), 8.67 (d, 1H), 7.40 (br s, 2H), 6.90-6.81 (m,

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1H), 6.73-6.68 (m, 1H).

Example 6.2A.

tert-Butyl (2-methyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate

A mixture of 7-bromo-2-methyl[1,2,4]triazolo[1,5-a]pyridine (8.00 g, 37.7 mmol, 1.0 eq.), tert-butyl carbamate (6.63 g, 56.6 mmol, 1.5 eq. ), palladium(P) acetate (0.85 g, 3.8 mmol, 0.1 eq.), 2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (5.40 g, 11.3 mmol, 0.3 eq.) and Cesium carbonate (24.58 g, 75.4 mmol, 2.0 eq.) in 1,4-dioxane (400 ml) was purged with nitrogen for 5 min. The reaction mixture was stirred at 100°C for 15 hours, cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 2:3). Yield: 5.50 g (58% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=9.92 (s, 1H), 8.63 (d, 1H), 7.74 (s, 1H), 7.12-7.03 (m, 1H), 2.37 (s, 3H), 1.49 (s, 9H).

Example 6.2V.

2-Methyl[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride

A solution of hydrochloride (125 ml, 4 M in 1,4-dioxane) was added to a solution of tert-butyl (2methyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (6.20 g, 25.0 mmol) in dichloromethane (125 ml). The reaction mixture was stirred at room temperature for 15 hours and diluted with diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure. Yield: 3.69 g (78% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=8.58 (d, 1H), 7.45 (br s, 2H), 6.82 (dd, 1H), 6.66 (d, 1H), 2.49 (s , 3H).

Example 6.3A.

1,1-Diphenyl-N-([1,2,4]triazolo[1,5-a]pyridin-6-yl)methanimine

Mixture of 6-bromo[1,2,4]triazolo[1,5-a]pyridine (3.00 g, 15.2 mmol), 1,1-diphenylmethanimine (5.49 g, 30.3 mmol, 2.0 eq.), tris(dibenzylideneacetone)dipalladium (1.11 g, 1.2 mmol, 0.08 eq.), 2,2'bis(diphenylphosphino)-1,1'-binaphthyl (1.89 g, 3.0 mmol, 0.2 eq.) and sodium tert-butoxide (4.37 g, 45.5 mmol, 3.0 eq.) in toluene (100 ml) was heated at 80°C under nitrogen atmosphere overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water and extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 3:1). Yield: 3.00 g (64% of theoretical yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=8.34 (d, 1H), 7.74-7.41 (m, 6H), 7.38-7.13 (m, 6H).

Example 6.3V.

[1,2,4]Triazolo[1,5-a]pyridin-6-amine

Aqueous hydrochloric acid (50 ml, 2 N, 101 mmol, 10 eq.) was added to the solution of 1,1-diphenyl-N([1,2,4]triazolo[1,5-a]pyridin-6-yl)methanimine (3.00 g, 10.1 mmol) in tetrahydrofuran (100 ml). The reaction mixture was stirred at room temperature for 2 hours and washed with ethyl acetate. The aqueous phase was brought to neutral with an aqueous solution of sodium hydroxide (0.1 M) and concentrated under reduced pressure. The residue was purified by column chromatography (reverse phase, eluent: water/acetonitrile: 10% acetonitrile - 35% acetonitrile for 15 min, flow rate: 80 ml/min). Yield: 1.10 g (81% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=8.17 (s, 1H), 8.03 (d, 1H), 7.56 (d, 1H), 7.20 (d, 1H), 5.25 (brs , 2H).

Example 6.4A.

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6-Bromo[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

5-Bromo-2-hydrazinopyridine (15.00 g, 79.78 mmol, 1.0 eq.) was added in several parts over a period of 0.5 h at 0°C to a solution of bis(trichloromethyl) carbonate (71.02 g, 239.3 mmol, 3.0 eq.) in tetrahydrofuran (1 l). After stirring for 15 hours at room temperature, the reaction mixture was diluted with water, adjusted to pH 8 with sodium carbonate and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Yield: 11.30 g (62% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=12.60 (s, 1H), 8.06 (t, 1H), 7.25-7.19 (m, 2H).

Example 6.4V.

6-Bromo-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Iodomethane (5.73 g, 40.4 mmol, 1.2 equiv.) was added dropwise at room temperature to a mixture of 6bromo[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (7.20 g, 33.6 mmol , 1.0 eq.) and cesium carbonate (12.06 g, 37.0 mmol, 1.1 eq.) in N,N-dimethylformamide (144 ml). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure. The remaining mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:1). Yield: 7.10 g (92% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=8.13-8.09 (m, 1H), 7.28 (dd, 1H), 7.22 (dd, 1H), 3.52 (s, 3H).

Example 6.4C.

tert-Butyl (2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6-yl)carbamate

A mixture of 6-bromo-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.00 g, 13.2 mmol, 1.0 eq.), tert-butyl carbamate (2.31 g, 19.7 mmol, 1.5 eq.), complex of tris(dibenzylideneacetone)dipalladium and chloroform (0.68 g, 0.7 mmol, 0.05 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.14 g, 2.0 mmol, 0.15 eq.) and cesium carbonate (8.57 g, 26.3 mmol, 2.0 eq.) in 1,4-dioxane (130 ml) were purged with nitrogen for 5 minutes. The reaction mixture was stirred at 110°C for 4 hours, cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:4). Yield: 3.00 g (82% of theoretical yield).

1H-NMR (300 MHz, DMSO-d6): δ [ppm]=9.43 (br s, 1H), 8.08 (br s, 1H), 7.20 (dd, 1H), 7.13 (dd, 1H), 3.48 (s , 3H), 1.44 (s, 9H).

Example 6.4D.

6-Amino-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride

ABOUT

A solution of hydrochloride (100 ml, 4 M in 1,4-dioxane) was added to a solution of tert-butyl (2-methyl-3oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine- 6-yl)carbamate (6.50 g, 22.4 mmol) in dichloromethane (100 ml). The reaction mixture was stirred for 6 hours at room temperature and diluted with dichloromethane. The precipitate was collected by filtration, washed with acetonitrile and dried in vacuum. Yield: 3.26 g (70% of theoretical yield).

1H-NMR (300 MHz, DMSO-d6): δ [ppm]=9.05 (br s, 3H), 7.71 (s, 1H), 7.27 (dd, 1H), 7.09 (dd, 1H), 3.50 (s, 3H).

Example 6.5A.

4-Bromo-2-hydrazinopyridine

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Hydrazine hydrate (80.0 g, 80% in water, 1.3 mol, 15.0 eq.) was added to a solution of 4-bromo-2fluoropyridine (15.0 g, 85.2 mmol) in ethanol (200 ml). The reaction mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. The remaining mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Yield: 15.0 g (93% of theoretical yield).

D-NMR (400 MHz, DMSO-d6): δ [ppm]=7.85 (d, 1H), 7.72 (s, 1H), 6.93 (d, 1H), 6.72-6.70 (m, 1H), 4.21 (s , 2H).

Example 6.5V.

7-Bromo[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

4-Bromo-2-hydrazinopyridine (10.0 g, 53.2 mmol) was added in several parts over a period of 0.5 h at 0°C to a solution of 1,1'-carbonyldiimidazole (17.25 g, 106.4 mmol, 2.0 eq.) in tetrahydrofuran ( 600 ml). After stirring for 15 hours at room temperature, the reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane/methanol 50:1). Yield: 7.3 g (63% of theoretical yield).

'I-NMR (400 MHz, DMSO-d6): δ [ppm]=12.55 (s, 1H), 7.79-7.76 (m, 1H), 7.63 (d, 1H), 6.68-6.66 (m, 1H).

Example 6.5C.

7-Bromo-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Iodomethane (4.77 g, 33.6 mmol, 1.2 equiv.) was added dropwise at room temperature to a mixture of 7bromo[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (6.00 g, 28.0 mmol ) and cesium carbonate (13.70 g, 42.0 mmol, 1.5 eq.) in N,N-dimethylformamide (100 ml). After stirring for 3 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The remaining mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:1). Yield: 3.60 g (56% of theoretical yield).

D-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=7.83-7.80 (m, 1H), 7.66-7.65 (m, 1H), 6.73-6.70 (m, 1H), 3.52 (s, 3H ).

Example 6.5D.

tert-Butyl (2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl)carbamate

tert-Butyl carbamate (2.77 g, 23.7 mmol, 1.5 eq.), tris(dibenzylideneacetone)dipalladium-chloroform complex (0.82 g, 0.8 mmol, 0.05 eq.), 9,9-dimethyl-4,5-bis(diphenylphosphino) -xanthene (1.37 g, 2.4 mmol, 0.15 eq.) and cesium carbonate (10.29 g, 31.6 mmol, 2.0 eq.) were added to the solution of 7-bromo-2methyl[1,2,4]triazolo[4,3-a] pyridin-3(2H)-one (3.60 g, 15.8 mmol) in 1,4-dioxane (72 ml). The resulting mixture was purged with nitrogen for 5 minutes, stirred at 110°C for 4 hours, cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:4). Yield: 3.10 g (68% of theoretical yield).

D-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=9.82 (m, 1H), 7.79-7.76 (m, 1H), 7.28-7.27 (m, 1H), 6.58-6.55 (m, 1H ), 3.45 (s, 3H), 1.48 (s, 9H).

Example 6.5E.

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-Amino-2-methyl [1,2,4]triazolo[4,3-a]pyridin-3 (2H)-one hydrochloride

A solution of hydrochloride (100 ml, 4 M in 1,4-dioxane) was added to a solution of tert-butyl (2-methyl-3oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridine- 7-yl)carbamate (5.70 g, 19.8 mmol) in dichloromethane (100 ml). The reaction mixture was stirred for 6 hours at room temperature and diluted with dichloromethane. The precipitate was collected by filtration, washed with acetonitrile and dried in vacuum. Yield: 3.06 g (76% of theoretical yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=7.59-7.56 (m, 1H), 6.28-6.25 (m, 2H), 6.20-6.17 (m, 2H), 5.76 (d, 1H), 3.36 (s, 3H).

Example 6.6A.

tert-Butyl[1,2,4]triazolo[4,3-a]pyridin-7-ylcarbamate

Η n ₃ SI Π Τ g 'ν ³ CH ₃ Ο tert-Butylcarbamate (8.87 g, 75.7 mmol, 3.0 eq.), complex of tris(dibenzylideneacetone) dipalladium and chlorophoma (2.61 g, 2.5 mmol, 0.1 eq.), 9, 9-dimethyl-4,5-bis(diphenylphosphino)xanthene (4.38 g, 7.6 mmol, 0.3 eq.) and cesium carbonate (16.4 g, 50.5 mmol, 2.0 eq.) were added to the solution of 7-bromo[1,2,4 ]triazolo[4,3a]pyridine (5.00 g, 25.2 mmol) in 1,4-dioxane (250 ml). The resulting mixture was purged with nitrogen for 5 minutes, stirred at 110°C for 4 hours, cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, eluent: petroleum ether/ethyl acetate 1:9). Yield: 3.50 g (49% of theoretical yield).

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=9.88 (s, 1H), 9.06 (s, 1H), 8.42 (d, 1H), 7.80 (s, 1H), 6.97-6.94 (m, 1H), 1.51 (s, 9H).

Example 6.6V.

[1,2,4]Triazolo[4,3-a]pyridin-7-amine hydrochloride

T 1; ‘n x hci

A solution of hydrochloride (107 mL, 4 M in 1,4-dioxane) was added to a stirred solution of tert-butyl [1,2,4]triazolo[4,3-a]pyridin-7-ylcarbamate (5.00 g, 21.3 mmol) in dichloromethane ( 120 ml). The reaction mixture was stirred for 15 hours at room temperature and diluted with dichloromethane. The precipitate was collected by filtration, washed with dichloromethane and dried in vacuum. The crude product was purified by flash chromatography (330 g C18-linked silica gel, 100% water). Yield: 2.40 g (58% of theoretical yield).

¹ H-NMR (300 MHz, DMSO-d6): δ [ppm]=9.15 (s, 1H), 8.47-8.44 (m, 1H), 7.62 (s, 2H), 6.92-6.70 (m, 1H), 6.58 (d, 1H).

Example 6.7A.

tert-Butyl (3-methyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)carbamate

CH ₃

Mixture of 7-bromo-3-methyl[1,2,4]triazolo[4,3-a]pyridine (210 mg, 0.99 mmol), tert-butyl carbamate (174 mg, 1.49 mmol, 1.5 eq.), palladium acetate (P) (22 mg, 0.1 mmol, 0.1 eq.), 2-dicyclohexylphosphino2',4',6'-triisopropylbiphenyl (142 mg, 0.3 mmol, 0.3 eq.) and cesium carbonate (647 mg, 1.98 mmol, 2.0 eq. .) in 1,4-dioxane (10 ml) was stirred at 100°C overnight.

Tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol, 0.02 eq.) and 9,9-dimethyl-4,5bis(diphenylphosphino)xanthene (46 mg, 0.08 mmol, 0.08 eq.) were added. The reaction mixture was stirred at 100°C for another 3 hours, cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 72 mg (29% of theoretical yield).

LC-MS (method 4): R _t =0.86 min; MS (ESIpos): m/z=249 [M+H]+.

Example 6.7V.

-Methyl [1,2,4]triazolo[4,3-a]pyridin-7-amine hydrochloride

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A solution of tert-butyl(3-methyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)carbamate (72 mg, 0.29 mmol) in a solution of hydrochloride (1.44 ml, 4 M in 1.4 -dioxane, 5.77 mmol, 20 equiv.) was stirred at room temperature overnight. Another hydrochloride solution (1.44 mL, 4 M in 1,4-dioxane, 5.77 mmol, 20 eq.) was added. The reaction mixture was stirred again at room temperature overnight, concentrated in vacuo, co-evaporated twice with dichloromethane and used in the subsequent reaction without further purification. Yield: 59 mg (quantitative theoretical yield).

LC-MS (method 15): R _t =0.43 min; MS (ESIpos): m/z=149 [M+H]+.

1H-NMR (500 MHz, DMSO-d6): δ [ppm]=8.37 (d, 1H), 7.55 (br s, 2H), 6.89 (dd, 1H), 6.53 (d, 1H), 2.61 (s, 3H).

Example 6.8A.

tert-Butyl [1,2,4]triazolo[4,3-a]pyridin-6-ylcarbamate

A mixture of 6-bromo[1,2,4]triazolo[4,3-a]pyridine (1.00 g, 5.05 mmol), tert-butylcarbamate (887 mg, 7.58 mmol, 1.5 eq.), tris(dibenzylideneacetone)dipalladium (93 mg, 0.10 mmol, 0.02 eq.), 9,9-dimethyl-4,5bis(diphenylphosphino)xanthene (234 mg, 0.40 mmol, 0.08 eq.) and cesium carbonate (3.29 g, 10.10 mmol, 2.0 eq.) in 1 ,4-dioxane (20 ml) was stirred at 100°C overnight. Tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol, 0.01 eq.) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (117 mg, 0.20 mmol, 0.04 eq.) were added. The reaction mixture was stirred again at 100°C overnight, cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: dichloromethane/methanol gradient). Yield: 167 mg (14% of theoretical yield).

LC-MS (method 4): R=1.09 min; MS (ESIpos): m/z=235 [M+H]+.

'h-NMR (600 MHz, DMSO-d6): δ [ppm]=9.68 (br s, 1H), 9.23 (d, 1H), 8.97 (br s, 1H), 7.73 (d, 1H), 7.26 ( dd, 1H), 1.50 (s, 9H).

Example 6.8V.

[1,2,4]Triazolo[4,3-a]pyridin-6-amine hydrochloride

A solution of tert-butyl [1,2,4]triazolo[4,3-a]pyridin-6-ylcarbamate (180 mg, 0.75 mmol) in a solution of hydrochloride (3.77 ml, 4 M in 1,4-dioxane, 15.09 mmol, 20 eq.) was stirred at room temperature overnight, concentrated in vacuo, co-evaporated twice with dichloromethane and used in the subsequent reaction without further purification. Yield: 171 mg (80% purity).

'H-NMR (600 MHz, DMSO-d6): δ [ppm]=9.53 (s, 1H), 8.00 (d, 1H), 7.90 (d, 1H), 7.66 (dd, 1H), 6.0 (br s , 3H).

Working examples.

Example 1.

4-{[(2S)-2-(11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl) butanoyl]amino}-2-fluorobenzamide (mixture of two diastereomers)

1,1,3,3-Tetramethylguanidine (52 μL, 0.42 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of 11-chloro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[ 2,1-c]pyridin-2(6H)one (racemate) (40 mg, 0.14 mmol) with 2-propanol/acetone (4:1, 0.5 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R)-2-bromobutanoyl]amino}-2fluorobenzamide (single stereoisomer) (63 mg, 0.21 mmol, 1.5 eq.) and more 2-propanol/ acetone (4:1, 0.6 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Chromatorex C18 10 μm, 125 mm x 30 mm; eluent: acetonitrile/0.05% formic acid; gradient: 0-3 min 10% acetonitrile - 35 min 90% acetonitrile and another 3 min 90% acetonitrile). Yield: 58 mg (83% of theoretical yield).

LC-MS (method 4): Rt=1.88 min; MS (ESIpos): m/z=498 [M+H]+.

1H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.91-10.81 (m, 1H), 7.83-7.75 (m, 1H), 7.73-7.62 (m, 2H), 7.59-7.48 (m, 2H), 7.48-7.30 (m, 4H), 6.42-6.32 (m, 1H), 5.61-5.51 (m, 1H), 4.54-4.44/4.34-4.25/3.913.81/3.39-3.26 (4m, 2H, partially hidden), 2.91-2.80/2.75-2.60 (2m, 1H), 2.35-2.25/2.22-1.95 (2m, 4H), 0.98-0.83 (m, 6H). Additional minor rotamer signals were also detected.

Example 2.

4-({(2S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c] niridin-3yl]butanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

Separation of diastereomers 58 mg 4-{[(2S)-2-(11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1 -c]pyridine -3-yl)butanoyl]amino}-2-fluorobenzamide (mixture of two diastereomers), Example 1, gave single stereoisomer 1 (chiral SFC: R _t =0.97 min, >99% de): 20 mg, single stereoisomer 2 (chiral SFC: R _t =1.98 min, >99% de): 21 mg.

Separation method: SFC: column: Daicel Chiralpak AD, 250 mmx20 mm; eluent: 72% carbon dioxide/28% 2-propanol; temperature: 40°C; flow rate: 80 ml/min; UV detection: 210 nm.

Method of analysis: SFC: column: Daicel Chiralpak AD, 50 mmx4.6 mm; eluent: 70% carbon dioxide/30% 2-propanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

mg of the single stereoisomer 1 was further purified by preparative HPLC (column: Chromatorex C18 10 μm, 125 mm x 30 mm; eluent: acetonitrile/0.05% formic acid; gradient: 0-3 min 10% acetonitrile, up to 35 min 90% acetonitrile and another 3 min 90% acetonitrile) to obtain 18 mg of the title compound Example 2.

LC-MS (method 4): R _t =1.88 min; MS (ESIpos): m/z=498 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.90-10.82 (m, 1H), 7.78 (s, 1H), 7.70 (t, 1H), 7.68-7.61 (m, 1H) , 7.58-7.49 (m, 2H), 7.48-7.36 (m, 3H), 7.36-7.30 (m, 1H), 6.41-6.32 (m, 1H), 5.60-5.52 (m, 1H), 4.544.46/ 4.32-4.25/3.90-3.83/3.3-3.24 (4m, 2H, partially hidden), 2.90-2.81/2.76-2.62 (2m, 1H, partially hidden), 2.34-2.26/2.22-1.96 (2m, 4H), 0.97 -0.83 (m, 6H). Additional minor rotamer signals were also detected.

Example 3.

4-({(2S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c] niridin-3yl]butanoyl}amino)benzamide (sole stereoisomer) /CH ₃ to XX O ^nh ₂ ⁰

C.I.

1,1,3,3-Tetramethylguanidine (38 μL, 0.30 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-methyl-7,8-dihydro-3H-[ 3]benzoxocino[2,1-c]niridin2(6H)-one (single stereoisomer) (32 mg, 86% purity, 0.10 mmol) in 2-propanol/acetone (4:1, 1.25 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R)-2-bromobutanoyl]amino}benzamide (single stereoisomer) (31 mg, 0.11 mmol, 1.1 eq.). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 26 mg (54% of theoretical yield).

LC-MS (method 4): R _t =1.79 min; MS (ESIpos): m/z=480 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.69 (br s, 1H), 7.92-7.77 (m, 4H), 7.73-7.63 (m, 2H), 7.507.30 (m, 3H ), 7.30-7.20 (m, 1H), 6.42-6.32 (m, 1H), 5.66-5.55 (m, 1H), 4.55-4.45/4.33-4.24/3.90-3.82/3.3-3.23 (4m, 2H, partially hidden), 2.91-2.81/2.76-2.63 (2m, 1H), 2.35-2.25/2.22-1.96 (2m, 4H), 0.98-0.83 (m, 6H). Additional minor rotamer signals were also detected.

Example 4.

(2S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridine-3- yl]N-(2-methyl-2H-benzotriazol-5-yl)butanamide (sole stereoisomer)

- 91 044932

1,1,3,3-Tetramethylguanidine (38 μL, 0.30 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-methyl-7,8-dihydro-3H-[ 3]benzoxocino[2,1-c]pyridin2(6H)-one (single stereoisomer) (32 mg, 86% purity, 0.10 mmol) in 2-propanol/acetone (4:1, 1.25 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of (2R)-2-bromo-N-(2-methyl-2H-benzotriazol-5-yl)butanamide (single stereoisomer) (31 mg, 0.10 mmol, 1.0 eq .). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 38 mg (77% of theoretical yield).

LC-MS (method 4): Rt=2.06 min; MS (ESIpos): m/z=492 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.76-10.69 (m, 1H), 8.38-8.33 (m, 1H), 7.89 (d, 1H), 7.85-7.80 (m, 1H ), 7.51-7.31 (m, 4H), 6.42-6.33 (m, 1H), 5.68-5.60 (m, 1H), 4.54-4.48/4.32-4.27/3.91-3.84/3.37-3.3 (4m, 2H, partially hidden), 4.45 (s, 3H), 2.89-2.82/2.75-2.64 (2m, 1H), 2.35-2.27/2.23-1.98 (2m, 4H), 0.98-0.84 (m, 6H). Additional minor rotamer signals were also detected.

Example 5.

4-({(2S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c] pyridin-3yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2-fluorobenzamide (single stereoisomer) η |n

I o ks JL .NH ₂ \ Z^^^o tG \/ °

C.I.

1,1,3,3-Tetramethylguanidine (38 μL, 0.30 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-methyl-7,8-dihydro-3H-[ 3]benzoxocino[2,1-c]pyridin2(6H)-one (single stereoisomer) (32 mg, 86% purity, 0.10 mmol) in 2-propanol/acetone (4:1, 1.25 ml). The mixture was stirred at room temperature for 15 minutes, followed by the addition of 4-({(2R)-2-bromo-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2-fluorobenzamide (single stereoisomer) (37 mg, 0.10 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 27 mg (47% of theoretical yield).

LC-MS (method 4): Rt=2.05 min; MS (ESIpos): m/z=568 [M+H] ⁺ .

Ή-NMR (400 MHz, DMSO-d6): δ [ppm]=10.85-10.66 (m, 1H), 7.84-7.76 (m, 1H), 7.72-7.62 (m, 2H), 7.58-7.48 (m, 2H), 7.48-7.37 (m, 3H), 7.36-7.29 (m, 1H), 6.38-6.30 (m, 1H), 5.81-5.65 (m, 1H), 4.54-4.44/4.314.23/3.92-3.79 /3.3-3.16 (4m, 5H, partially hidden), 2.90-2.80/2.75-2.65 (2m, 1H), 2.35-2.19/2.17-1.95 (2m, 4H), 1.82-1.70 (m, 1H), 1.67- 1.57 (m, 1H), 1.49-1.34 (m, 3H), 1.33-1.20 (m, 1H), 0.96-0.82 (m, 3H). Additional minor rotamer signals were also detected.

Example 6.

4-({(2S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c] pyridin-3yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (single stereoisomer) n

³ 1 Ίτ ^ν ϊι Ίτ π

I Λχ Ο Λ ^ΝΗ ₂ ο θ

C.I.

General Method 7 was performed with (7R)-11-chloro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (50.0 mg, 181 µmol, 1.0 eq.), 4-({(2R)-2-6pom-3[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (single stereoisomer) (96.6 mg, 272 µmol, 1.5 equiv.) and 1,1,3,3-tetramethylguanidine (68 µl, 540 µmol, 3.0 equiv.) in a mixture of 2propanol/acetone (4:1, 2.6 ml). The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 1:99). Yield: 50.0 mg (50% of theoretical yield).

- 92 044932

LC-MS (method 1): Rt=1.04 min; MS (ESIpos): m/z=550 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.70/10.63 (2s, 1H), 7.90 (br s, 1H), 7.87-7.80 (m, 3H), 7.737.66 (m, 2H), 7.49-7.38 (m, 2H), 7.35-7.31 (m, 1H), 7.29 (br s, 1H), 6.37/6.32 (2s, 1H), 5.81/5.75 (2t, 1H), 4.544.44 (m, 1H), 3.91-3.80 (m, 1H), 3.31-3.18 (m, 3H), 2.70 (d, 1H), 2.36-2.17 (m, 2H), 2.17-2.07 (m, 1H), 2.061 .95 (m, 1H), 1.80-1.71 (m, 1H), 1.67-1.56 (m, 1H), 1.46-1.34 (m, 3H), 1.32-1.17 (m, 1H), 0.91/0.86 (2d, 3H). Additional minor rotamer signals were also detected.

Example 7.

4-{2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl ]-3[(2R)-1,4-dioxan-2-yl]propanamido}benzamide (mixture of two diastereomers) °^Ί Λ .°

Cl

2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-3 [(2R)-1,4-dioxan-2-yl]propanoic acid (a mixture of two diastereomers) (51 mg, 0.12 mmol) and 4-aminobenzamide (24 mg, 0.18 mmol, 1.5 eq.) were reacted according to General Method 11. Yield: 57 mg (86% of theoretical yield).

LC-MS (method 4): R _t =1.65/1.68 min; MS (ESIpos): m/z=552 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.73-10.56 (m, 1H), 7.91-7.77 (m, 4H), 7.73-7.64 (m, 2H), 7.48-7.30 ( m, 3H), 7.29-7.20 (m, 1H), 6.40-6.31 (m, 1H), 5.81-5.66 (m, 1H), 4.53-4.44/4.34-4.24/ 3.923.81/3.40-3.19 (4m, 3H, partially hidden), 3.77-3.57 (m, 3H), 3.55-3.40 (m, 3H), 2.90-2.82/2.76-2.65 (2m, 1H), 2.35-1.95 (m, 4H), 0.96-0.83 ( m, 3H). Additional minor rotamer signals were also detected.

Example 8.

4-({(2S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c] pyridin-3yl]-3-[(2R)-1,4-dioxan-2-yl]propanoyl}amino)benzamide (sole stereoisomer)

Separation of diastereomers 50 mg 4-{2-[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H[3]benzoxocino[2, 1-c]pyridin- 3-yl]-3-[(2R)-1,4-dioxan-2-yl] propanamido} benzamide (a mixture of two diastereomers), example 7, gave a single stereoisomer 1 (chiral HPLC: R _t =3.58 min, 99% de): 18 mg, single stereoisomer 2 (chiral HPLC: R _t =4.60 min, 99% de): 37 mg.

Separation method: HPLC: column: Daicel Chiralcel OX-H 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 15 ml/min; UV detection: 210 nm.

Method of analysis: HPLC: column: Daicel Chiralpak OX-3 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

mg of single stereoisomer 1 was further purified by preparative HPLC (reverse phase, eluent: acetonitrile/0.05% formic acid gradient) to obtain 15 mg of the title compound, Example 8.

LC-MS (method 4): Rt=1.69 min; MS (ESIpos): m/z=552 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.69-10.55 (m, 1H), 7.91-7.76 (m, 4H), 7.72-7.66 (m, 2H), 7.48-7.38/7.36 -7.30 (2m, 3H), 7.29-7.22 (m, 1H), 6.40-6.32 (m, 1H), 5.82-5.66 (m, 1H), 4.53-4.46/4.304.23/3.92-3.86/3.37-3.22 (4m, 3H, partially hidden), 3.77-3.65 (m, 2H), 3.65-3.59 (m, 1H), 3.55-3.42 (m, 3H), 2.90-2.81/2.73-2.65 (2m, 1H), 2.33 -2.26/2.26-2.17 (2m, 2H), 2.15-1.95 (m, 2H), 0.94-0.83 (m, 3H). Additional minor rotamer signals were also detected.

Example 9.

5-{2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl ]-3[(2R)-1,4-dioxan-2-yl]propanamido}pyridine-2-carboxamide (mixture of two diastereomers)

- 93 044932

2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-3 [(2R)-1,4-dioxan-2-yl]propanoic acid (mixture of two diastereomers) (51 mg, 0.12 mmol) and 5-aminopyridine-2-carboxamide (24 mg, 0.18 mmol, 1.5 eq.) (prepared according to WO 2017/005725, example 1.3B) was reacted according to general method 11. Yield: 50 mg (75% of theoretical yield).

LC-MS (method 4): Rt=1.69/1.72 min; MS (ESIpos): m/z=553 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.99-10.75 (m, 1H), 8.89-8.80 (m, 1H), 8.27-8.15 (m, 1H), 8.05-7.97 ( m, 2H), 7.88-7.76 (m, 1H), 7.56-7.49 (m, 1H), 7.49-7.29 (m, 3H), 6.41-6.32 (m, 1H), 5.83-5.62 (m, 1H), 4.53-4.45/4.34-4.24/3.92-3.81/3.39-3.21 (4m, 3H, partially hidden), 3.78-3.57 (m, 3h), 3.55-3.41 (m, 3H), 2.90-2.81/2.76-2.65 ( 2m, 1H), 2.38-1.96 (m, 4H), 0.96-0.83 (m, 3H). Additional minor rotamer signals were also detected.

Example 10.

5-({(2S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzokocino[2,1-с] pyridin-3ul]-3-[(2R)-1,4-dioxane-2-yl]propanol}amino)pyridin-2-carboxamide (single stereoisomer)

Separation of diastereomers 45 mg 3-yl]-3-[(2R)-1,4-dioxan-2-yl]propanamido}pyridine-2-carboxamide (a mixture of two diastereomers), example 9, gave a single stereoisomer 1 (chiral HPLC: R _t =3.36 min, 97% de): 14 mg, single stereoisomer 2 (chiral HPLC: R _t =5.43 min, 93% de): 24 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 25% nheptane/75% ethanol; temperature: 50°C; flow rate: 15 ml/min; UV detection: 210 nm.

Method of analysis: HPLC: column: Daicel Chiralpak OX-3 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

mg of single stereoisomer 1 was further purified by preparative HPLC (reverse phase, eluent: acetonitrile/0.05% formic acid gradient) to obtain 9 mg of the title compound, Example 10.

LC-MS (method 4): R=1.72 min; MS (ESIpos): m/z=553 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.96-10.76 (m, 1H), 8.90-8.80 (m, 1H), 8.27-8.17 (m, 1H), 8.05-7.98 ( m, 2H), 7.86-7.77 (m, 1H), 7.55-7.50 (m, 1H), 7.48-7.30 (m, 3H), 6.40-6.32 (m, 1H), 5.83-5.76/5.685.62 (2m , 1H), 4.53-4.46/4.30-4.23/3.93-3.85/3.39-3.23 (4t, 3H, partially hidden), 3.78-3.65 (m, 2H), 3.653.59 (m, 1H), 3.55-3.42 ( m, 3H), 2.89-2.81/2.74-2.65 (2m, 1H), 2.33-2.22 (m, 2H), 2.17-1.95 (m, 2H), 0.94-0.83 (m, 3H). Additional minor rotamer signals were also detected.

Example 11.

4-({(2S,4S)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1- c]pyridin3-yl]-4-methoxypentanoyl}amino)benzamide (single stereoisomer)

1,1,3,3-Tetramethylguanidine (22 μL, 178 μmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-methyl-7,8-dihydro-3H-[ 3]benzoxocino[2,1-c]pyridin2(6H)-one (single stereoisomer) (17 mg, 59 µmol) in 2-propanol/acetone (4:1, 0.6 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R,4S)-2bromo-4-methoxypentanoyl]amino}benzamide (single stereoisomer) (22 mg, 65 µmol, 1.1 eq.) and 2 more -propanol/acetone (4:1, 0.6 ml). The reaction mixture was stirred at room temperature in

- 94 044932 for 2 days and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 22 mg (69% of theoretical yield).

LC-MS (method 1): R _t =0.97 min; MS (ESIpos): m/z=524 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.66 (br s, 1H), 7.92-7.80 (m, 4H), 7.75-7.66 (m, 2H), 7.497.29 (m, 3H), 7.25 (br s, 1H), 6.40-6.31 (m, 1H), 5.87-5.76 (m, 1H), 4.54.4.44/4.31-4.24/3.90-3.82/3.3-3.20 (4m, 2H, partially hidden), 3.20-3.10 (m, 3H), 2.90-2.80/2.75-2.64 (2m, 2H), 2.34-2.13/2.10-1.96 (2m, 4H), 1.16 (d, 3H), 0.97-0.82 (m , 3H). Additional minor rotamer signals were also detected.

Example 12.

4-({(2S,4R)-2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1- c]pyridin3-yl]-4-cyclopropyl-4-methoxybutanoyl} amino)benzamide (single stereoisomer)

I o JL nh ₂ °

C.I.

1,1,3,3-Tetramethylguanidine (19 μL, 149 μmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-methyl-7,8-dihydro-3H-[ 3]benzoxocino[2,1-c]pyridin2(6H)-one (single stereoisomer) (14 mg, 50 µmol) in 2-propanol/acetone (4:1, 0.5 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R,4R)2-bromo-4-cyclopropyl-4-methoxybutanoyl]-amino}benzamide (single stereoisomer) (19 mg, 55 µmol, 1.1 eq.) and another 2-propanol/acetone (4:1, 0.5 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 16 mg (59% of theoretical yield).

LC-MS (method 4): R _t =1.95 min; MS (ESIpos): m/z=550 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.69-10.54 (m, 1H), 7.90-7.74 (m, 4H), 7.73-7.66 (m, 2H), 7.48-7.28 (m , 3H), 7.22 (br s, 1H), 6.38-6.30 (m, 1H), 5.88-5.75 (m, 1H), 4.54-4.45/4.33-4.26/3.36-3.76/3.3-3.26 (4m, 2H, partially hidden), 3.23/3.21 (2s, 3H), 2.89-2.81/2.79-2.67 (2m, 1H), 2.45-2.21 (m, 4H), 2.11-1.97 (m, 1H), 0.96-0.77 (m, 4H), 0.63-0.51 (m, 1H), 0.45-0.33 (m, 2H), 0.10-0.0 (m, 1H). Additional minor rotamer signals were also detected.

Example 13.

4-{2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl ]-4(cyclopropyloxy)butanamido}benzamide (mixture of two diastereomers)

4-Aminobenzamide (3 mg, 25 µmol, 1.2 eq.), pyridine (2 µl, 25 µmol, 1.2 eq.) and T3P (19 µl, 50% solution in ethyl acetate, 31 µmol, 1.5 eq.) were added under argon. at room temperature into a solution of 2-[(7R)-11-chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl ]-4-(cyclopropyloxy)butanoic acid (mixture of two diastereomers) (9 mg, 21 µmol) in tetrahydrofuran (1 ml). The reaction mixture was stirred at room temperature for 1.5 h before adding water. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 5 mg (44% of theoretical yield).

LC-MS (method 4): R _t =1.90 min; MS (ESIpos): m/z=536 [M+H] ⁺ .

'h-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.73-10.61 (m, 1H), 7.91-7.76 (m, 4H), 7.73-7.64 (m, 2H), 7.49-7.21 ( m, 4H), 6.41-6.31 (m, 1H), 5.78-5.69 (m, 1H), 4.54-4.45/4.32-4.26/3.91-3.84/3.58-3.06 (4m, 4H, partially hidden), 2.91-2.82 /2.77-2.69 (2m, 1H), 2.4-2.26 (m, 4H, partially hidden), 2.11-1.97 (m, 1H), 0.970.85 (m, 3H), 0.45-0.28 (m, 4H). Additional minor rotamer signals were also detected.

Example 14.

4-{[2-[(7R)-11-Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridine-3- yl]-4- 95 044932 (cyclobutyloxy)butanoyl]amino}benzamide (mixture of two diastereomers)

4-Aminobenzamide (42 mg, 0.31 mmol, 1.5 eq.) and Ν,N-diisopropylethylamine (107 μl, 0.61 mmol, 3.0 eq.) were added at room temperature to a solution of 2-[(7R)-11-chloro-7- methyl 2-oxo-2,6,7,8tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4-(cyclobutyloxy)butanoic acid (mixture of two diastereomers) (106 mg, 83% purity, 0.20 mmol) in N,N-dimethylformamide (1 ml). A solution of HATU (116 mg, 0.31 mmol, 1.5 eq.) in N,N-dimethylformamide (2 ml) was added dropwise and the reaction mixture was stirred at room temperature for 2 days. More HATU (39 mg, 0.10 mmol, 0.5 eq.) and N,Ndiisopropylethylamine (36 μl, 0.20 mmol, 1.0 eq.) were added. The reaction mixture was stirred for 3 hours before adding water. After adding ethyl acetate and separating the phases, the aqueous phase was extracted with ethyl acetate.

The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 31 mg (27% of theoretical yield).

LC-MS (method 4): Rt=1.99 min; MS (ESIpos): m/z=550 [M+H]+.

'H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.75-10.60 (m, 1H), 7.93-7.77 (m, 4H), 7.74-7.65 (m, 2H), 7.49-7.20 (m , 4H), 6.41-6.31 (m, 1H), 5.81-5.71 (m, 1H), 4.53-4.44/4.32-4.25/3.89-3.78/3.39-3.17 (4m, 5H, partially hidden), 2.89-2.81/ 2.75-2.68 (2m, 1H), 2.41-2.24 (m, 3H), 2.12-1.96 (m, 3H), 1.30-1.49/1.47-1.35 (2m, 4H), 0.96-0.83 (m, 3H). Additional minor rotamer signals were also detected.

Example 15.

4- {[(2S)-2-( 11 -Chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1 -с] pyridin3-yl)butanoyl]amino}-2-fluorobenzamide (mixture of two diastereomers) .сн ₃

In I ^{n J} 1 Ίτ Ν ΤΙ Ίγ ιΓ

I ο ^νη ₂

F Ο

C.I.

General Method 7 was performed with 11-chloro-12-fluoro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (racemate) (30.0 mg, 92 % purity, 94.0 µmol, 1.0 eq.), 4-{[(2R)-2bromobutanoyl]amino}-2-fluorobenzamide (single stereoisomer) (42.7 mg, 141 µmol, 1.5 eq.) and 1,1,3,3 -tetramethylguanidine (35 µl, 280 µmol, 3.0 eq.) in 2-propanol/acetone (4:1, 1.0 ml), including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 35.0 mg (72% of theoretical yield).

LC-MS (method 3): Rt=3.09/3.16 min; MS (ESIpos): m/z=516 [M+H] ⁺ .

Example 16.

4-({(2S)-2-[(7R)-11-Chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]butanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

Separation of diastereomers 30 mg 4-{[(2S)-2-(11-chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1- c]pyridin-3-yl)butanoyl]amino}-2-fluorobenzamide (a mixture of two diastereomers), example 15, gave a single stereoisomer 1 (titled compound 16) (chiral HPLC: R _t =11.5 min, >98% de ): 11.0 mg (23% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =15.3 min): 11.0 mg.

Separation method: HPLC: column: Daicel Chiralpak IA 5 µm, 250 mmx20 mm; eluent: ethanol; temperature: 20°C; flow rate: 7 ml/min; UV detection: 240 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IA 5 µm, 250 mmx4.6 mm; eluent: ethanol; temperature: 20°C; flow rate: 0.4 ml/min; UV detection: 240 nm.

- 96 044932

LC-MS (method 3): R _t =3.36 min; MS (ESIpos): m/z=516 [M+H]+.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.89/10.86 (2s, 1H), 7.89 (s, 1H), 7.73-7.57 (m, 3H), 7.56-7.51 (m, 2H) , 7.43-7.37 (m, 1H), 7.30/7.22 (2d, 1H), 6.49/6.45 (2d, 1H), 5.66-5.50 (m, 1H), 4.50 (dd, 1H), 3.33-3.27 (m, 1H), 2.77 (d, 1H), 2.32-2.24 (m, 1H), 2.31-1.99 (m, 3H), 0.96-0.82 (m, 6H). Additional minor rotamer signals were also detected.

Example 17.

4-({(2S)-2-(11-Chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c] pyridin3-yl)-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2-fluorobenzamide (mixture of two diastereomers)

C.I.

General Method 7 was performed with 11-chloro-12-fluoro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (racemate) (50.0 mg, 92 % purity, 157 µmol, 1.0 eq.), 4-({(2R)-2-6pom-3-[(2S)tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2-fluorobenzamide (sole stereoisomer ) (87.7 mg, 235 µmol, 1.5 eq.) and 1,1,3,3-tetramethylguanidine (59 µl, 470 µmol, 3.0 eq.) in a mixture of 2propanol/acetone (4:1, 1.5 ml), including the following variations Methods: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 65.0 mg (71% of theoretical yield).

LC-MS (method 4): R _t =2.00 min; MS (ESIpos): m/z=586 [M+H] ⁺ .

Example 18.

4-({(2S)-2-[(7R)-11-Chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

C.I.

Separation of diastereomers 60 mg 4-({(2S)-2-(11-chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1- c]pyridin-3-yl)-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2fluorobenzamide (a mixture of two diastereomers), Example 17, gave a single stereoisomer 1 (the title compound 18) (chiral HPLC: R _t =36.3 min, >98% de): 12.0 mg (13% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =48.6 min): 15.0 mg.

Separation method: HPLC: column: two connected Daicel Chiralpak OD-H 5 µm, 250 mmx20 mm; eluent: 90% n-heptane/5% 2-propanol/5% ethanol; temperature: 20°C; flow rate: 8.0 ml/min; UV detection: 240 nm.

Method of analysis: HPLC: column: two connected Daicel Chiralpak OD-H 5 μm, 250 mmx4.6 mm; eluent: 90% n-heptane/5% methanol/5% ethanol; temperature: 20°C; flow rate: 1.0 ml/min; UV detection: 240 nm.

LC-MS (method 3): R _t =3.71 min; MS (ESIpos): m/z=586 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.84/10.75 (2s, 1H), 7.90/7.87 (2s, 1H), 7.74-7.57 (m, 3H), 7.56-7.50 (m , 2H), 7.47-7.42 (m, 1H), 7.29 (d, 1H), 6.49-6.41 (m, 1H), 5.79/5.72 (2t, 1H), 4.49 (dd, 1H), 3.853.79 (m , 1H), 3.29-3.21 (m, 2H), 2.75 (d, 1H), 2.33-2.21 (m, 2H), 2.20-1.95 (m, 2H), 1.81-1.70 (m, 1H), 1.61 (d , 1H), 1.48-1.39 (m, 3H), 1.32-1.21 (m, 2H), 0.90/0.84 (2t, 3H). Additional minor rotamer signals were also detected.

Example 19.

4-({(2S)-2-( 11 -Chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1 -с] pyridin3-yl)-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (mixture of two diastereomers)

- 97 044932

General Method 7 was performed with 11-chloro-12-fluoro-7-methyl-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (racemate) (50.0 mg, 92 % purity, 157 µmol, 1.0 eq.), 4-({(2R)-2-6pom-3-[(2S)tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (sole stereoisomer) (83.4 mg, 235 µmol, 1.5 eq.) and 1,1,3,3-tetramethylguanidine (59 µl, 470 µmol, 3.0 eq.) in a mixture of 2propanol/acetone (4:1, 1.5 ml), including the following variations of the procedure: Crude the mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 57 mg (64% of theoretical yield).

LC-MS (method 3): Rt=3.36/3.42 min; MS (ESIpos): m/z=568 [M+H]+.

Example 20.

4-({(2S)-2-[(7R)-11-Chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (sole stereoisomer)

Separation of diastereomers 55 mg 4-({(28)-2-(11-chloro-12-fluoro-7-methyl-2-oxo-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1- c]pyridin-3-yl)-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (a mixture of two diastereomers), Example 19, gave a single stereoisomer 1 (the title compound 20 ) (chiral HPLC: R _t =43.7 min, >95% de): 11.0 mg (11% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =62.6 min): 13.0 mg.

Separation method: HPLC: column: two connected Daicel Chiralpak OD-H 5 µm, 250 mmx20 mm; eluent: 90% n-heptane/5% 2-propanol/5% ethanol; temperature: 20°C; flow rate: 15 ml/min; UV detection: 240 nm.

Method of analysis: HPLC: column: two connected Daicel Chiralpak OD-H 5 μm, 250 mmx4.6 mm; eluent: 90% n-heptane/5% 2-propanol/5% ethanol; temperature: 20°C; flow rate: 1.0 ml/min; UV detection: 240 nm.

LC-MS (method 3): Rt=3.50 min; MS (ESIpos): m/z=568 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.68/10.61 (2s, 1H), 7.93-7.80 (m, 4H), 7.74-7.67 (m, 2H), 7.62-7.57 ( m, 1H), 7.33-7.19 (m, 2H), 6.49-6.41 (m, 1H), 5.82/5.77 (2t, 1H), 4.51-4.47 (m, 1H), 3.85-3.79 (m, 1H), 3.29-3.21 (m, 2H), 2.75 (d, 1H), 2.33-2.24 (m, 2H), 2.25-2.17 (m, 1H), 2.14-1.99 (m, 1H), 1.81-1.70 (m, 1H ), 1.62 (d, 1H), 1.49-1.35 (m, 3H), 1.35-1.14 (m, 2H), 0.91/0.84 (2t, 3H). Additional minor rotamer signals were also detected.

Example 21.

4-{[(2S)-2-(11-Chloro-7-ethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl) butanoyl]amino}-2-fluorobenzamide (mixture of two diastereomers)

General Method 7 was performed with 11-chloro-7-ethyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)one (racemate) (25.0 mg, 78% purity, 67.3 µmol, 1.0 eq.), 4-{[(2R)-2-bromobutanoyl]amino}-2fluorobenzamide (sole stereoisomer) (40.8 mg, 135 µmol, 2.0 eq.) and 1,1,3,3tetramethylguanidine (25 µl , 200 µmol, 3.0 eq.) in a mixture of 2-propanol/acetone (4:1, 0.9 ml), including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90 :10 - 5:95). Yield: 42.0 mg (quantitative theoretical yield).

LC-MS (method 1): R _t =1.09 min; MS (ESIpos): m/z=512 [M+H] ⁺ .

- 98 044932

Example 22.

4-({(2S)-2-[(7R)-11-Chloro-7-ethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c] pyridin-3yl]butanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

Separation of diastereomers 37 mg 4-{[(2S)-2-(11-chloro-7-ethyl-2-oxo-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1 -c]pyridine -3-yl)butanoyl]amino}-2-fluorobenzamide (a mixture of two diastereomers), Example 21, gave a single stereoisomer 1 (title compound 22) (chiral HPLC: R _t =1.26 min, 99% de): 10.8 mg (31% of theoretical yield), single stereoisomer 2 (chiral HPLC: Rt=2.70 min): 10.2 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID-3 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% ethanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 3): R _t =3.57 min; MS (ESIpos): m/z=512 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.87/10.84 (2s, 1H), 7.78 (s, 1H), 7.73-7.62 (m, 2H), 7.58-7.50 (m, 2H), 7.49-7.44 (m, 1H), 7.42-7.32 (m, 3H), 6.39/6.34 (2s, 1H), 5.61-5.52 (m, 1H), 4.58-4.47 (m, 1H), 3.453. 35 (m, 1H), 2.77 (br d, 1H), 2.28-2.02 (m, 3H), 1.86-1.68 (m, 1H), 1.36-1.16 (m, 2H), 0.99 (t, 3H), 0.89 (t, 3H). Additional minor rotamer signals were also detected.

Example 23.

4-{[(2S)-2-(11-Chloro-6,7-dimethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin- 3yl)butanoyl]amino}-2-fluorobenzamide (mixture of stereoisomers)

General Method 7 was carried out with 11-chloro-6,7-dimethyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin2(6H)-one (mixture of stereoisomers) (65.0 mg, 224 µmol , 1.0 equiv.), 4-{[(2R)-2-bromobutanoyl]amino}-2fluorobenzamide (single stereoisomer) (68.0 mg, 224 µmol, 1.0 equiv.) and 1,1,3,3tetramethylguanidine (84 µl, 670 µmol, 3.0 eq.) in 2-propanol/acetone (4:1, 3.75 ml), including the following variations of the procedure: After stirring overnight, additional amounts of 4-{[(2R)-2bromobutanoyl]amino}-2-fluorobenzamide (single stereoisomer) (20.4 mg, 67.2 µmol, 0.3 eq.) and 1,1,3,3-tetramethylguanidine (21 µl, 168 µmol, 0.75 eq.) were added and stirring was continued at room temperature for 3 hours. The crude mixture purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 55.0 mg (48% of theoretical yield).

LC-MS (method 1): R _t =1.03/1.05 min; MS (ESIpos): m/z=512 [M+H]+.

Example 24.

4-({(2S)-2-[(6R,7R)-11-Chloro-6,7-dimethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]butanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

Separation of stereoisomers 50 mg 4-{[(2S)-2-(11-chloro-6,7-dimethyl-2-oxo-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c ]pyridin-3-yl)butanoyl]amino}-2-fluorobenzamide (mixture of stereoisomers), example 23, gave a single stereoisomer 1 (title compound 24) (chiral HPLC: Rt=5.25 min, 99% de): 5.60 mg (5% of theoretical yield), single stereoisomer 2 (chiral HPLC: Rt=6.01 min): 1.70 mg, single stereoisomer 3 (chiral HPLC: R _t =7.18 min): 17.3 mg, single stereoisomer 4 (chiral HPLC: R _t =8.65 min): 18.3 mg.

Separation method: HPLC: column: Daicel Chiralpak IF 5 µm, 250 mmx20 mm; eluent: 60% nheptane/40% ethanol; temperature: 40°C; flow rate: 15 ml/min; UV detection: 220 nm.

- 99 044932

Method of analysis: HPLC: column: Daicel Chiralpak IF 5 µm, 250 mmx4.6 mm; eluent: 60% isohexane/

40% ethanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 1): R _t =1.07 min; MS (ESIpos): m/z=512 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.82 (s, 1H), 7.77 (s, 1H), 7.73-7.60 (m, 2H), 7.57-7.47 (m, 2H) , 7.46-7.38 (m, 3H), 7.37-7.30 (m, 1H), 6.40/6.35 (2s, 1H), 5.59 (dd, 1H), 3.58-3.45 (m, 1H), 2.70-2.59 (m, 1H), 2.44-2.33 (m, 1H), 2.23-2.03 (m, 2H), 1.78-1.62 (m, 1H), 1.38/1.32 (2d, 3H), 1.01 (d, 3H), 0.89/0.77 ( 2t, 3H). Additional minor rotamer signals were also detected.

Example 25.

4-({(2S)-2-(11-Chloro-6,7-dimethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin- 3yl)-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (mixture of stereoisomers)

C.I.

General method 7 was carried out with 11-chloro-6,7-dimethyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin2(6H)-one (mixture of stereoisomers) (25.0 mg, 86.3 µmol , 1.0 equiv.), 4-({(2R)-2-bromo-3-[(2S)-tetrahydro2H-pyran-2-yl]propanoyl}amino)benzamide (single stereoisomer) (46.0 mg, 129 µmol, 1.5 eq.) and 1,1,3,3-tetramethylguanidine (32 μl, 260 μmol, 3.0 eq.) in 2-propanol/acetone (4:1, 0.5 ml), and the crude mixture was purified by preparative HPLC (reverse phase , eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 38.7 mg (79% of theoretical yield).

LC-MS (method 4): Rt=2.02 min; MS (ESIpos): m/z=564 [M+H] ⁺ .

Example 26.

4-({(2S)-2-[(6R,7R)-11-Chloro-6,7-dimethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (single stereoisomer) o^>

IA Α Ο A ,NH _?

[G vy °

Cl

Separation of stereoisomers 35 mg 4-({(2S)-2-(11-chloro-6,7-dimethyl-2-oxo-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c ]pyridin-3-yl)-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (mixture of stereoisomers), Example 25, gave a single stereoisomer 1 (titled compound 26) ( chiral HPLC: R _t =6.41 min, 99% de): 6.0 mg (12% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =9.80 min): 7.0 mg, mixture of stereoisomers (chiral HPLC: R _t = 6.43/8.10 min): 3.0 mg.

Separation method: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx4.6 mm; eluent: 50% isohexane/50% ethanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 1): R _t =1.07 min; MS (ESIpos): m/z=564 [M+H] ⁺ .

¹ H-NMR (500 MHz, CDCl ₃ ): δ [ppm]=9.80 (s, 1H), 7.84-7.75 (m, 2H), 7.74-7.65 (m, 2H), 7.36-7.31 (m, 2H) , 7.23-7.17 (m, 2H), 6.56 (s, 1H), 5.93 (dd, 1H), 6.20-5.57 (m, 2H), 4.09-3.94 (m, 1H), 3.60-3.50 (m, 1H) , 3.45-3.36 (m, 2H), 2.63-2.46 (m, 3H), 1.97-1.47 (m, 8H), 1.40 (d, 3H), 1.00 (d, 3H). Additional minor rotamer signals were also detected.

Example 27.

4- {[(2S)-2-(cis-6-Chloro-3-oxo-3,9,9a, 10,11,11 a-hexahydro-2H-cyclobuta[4,5][3]benzoxocino[2 ,1 c]pyridin-2-yl)butanoyl]amino}-2-fluorobenzamide (mixture of two diastereomers)

1,1,3,3-Tetramethylguanidine (46 μL, 0.37 mmol, 3.0 equiv.) was added under argon at compo-

- 100 044932 at room temperature into a solution of cis-6-chloro-9a,10,11,11a-tetrahydro-2Hcyclobuta[4,5][3]benzoxocino[2,1-c]pyridin-3(9H)-one (racemate ) (35 mg, 0.12 mmol) in 2propanol/acetone (4:1, 3.75 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (single stereoisomer) (55 mg, 0.18 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 43 mg (69% of theoretical yield).

LC-MS (method 4): R _t =1.93 min; MS (ESIpos): m/z=510 [M+H]+.

Example 28.

4-({(2S)-2-[(9aR, 11 aR)-6-Chloro-3-oxo-3,9,9a, 10,11,11 a-hexahydro-2Hcyclobuta[4,5][3] benzoxocin[2,1-c]pyridin-2-yl]butanoyl}amino)-2-fluorobenzamide (single stereoisomer)

C.I.

Separation of diastereomers and atropisomers 32 mg 4-{[(2S)-2-(cis-6-chloro-3-oxo-3,9,9a,10,11,11ahexahydro-2H-cyclobuta[4,5][3] benzoxocin[2,1-c]pyridin-2-yl)butanoyl]amino}-2-fluorobenzamide (a mixture of two diastereomers), Example 27, gave a single stereoisomer 1 (titled compound Example 28), (chiral HPLC: R _t =2.81 min, >99% de): 5 mg, single stereoisomer 2 (chiral HPLC: R _t =3.37 min): 4 mg, single stereoisomer 3 (chiral HPLC: R _t =4.57 min): 5 mg, single stereoisomer 4 (chiral HPLC: R _t =5.35 min): 3 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 30°C; flow rate: 20 ml/min; UV detection: 265 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx4.6 mm; eluent: 50% nheptane/50% ethanol; temperature: 50°C; flow rate: 1 ml/min; UV detection: 220 nm.

LC-MS (method 4): R _t =1.91 min; MS (ESIpos): m/z=510 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.93-10.74 (m, 1H), 7.70 (br t, 1H), 7.64 (br d, 1H), 7.53 (br d, 2H) , 7.48-7.38 (m, 4H), 7.36 (br s, 1H), 6.39 (s, 1H), 5.66-5.53 (m, 1H), 4.65-4.56 (m, 1H), 2.78-2.65 (m, 2H ), 2.65-2.54 (m, 2H), 2.21-1.99 (m, 3H), 1.82-1.69 (m, 1H), 1.40-1.20 (m, 1H), 0.92-0.83 (m, 3H).

Example 29.

4-({(2S)-2-[cis-6-Chloro-3-oxo-3,9,9a, 10,11,11 a-hexahydro-2H-cyclobuta[4,5][3]benzoxocino[2 ,1 c]pyridin-2-yl]butanoyl}amino)-benzamide (a mixture of two diastereomers)

C.I.

1,1,3,3-Tetramethylguanidine (66 μL, 0.53 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of cis-6-chloro-9a,10,11,11a-tetrahydro-2H-cyclobuta[4 ,5][3]benzoxocino[2,1-c]pyridin-3(9H)-one (racemate) (51 mg, 0.18 mmol) in 2propanol/acetone (4:1, 5.5 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R)-2-bromobutanoyl]amino}benzamide (single stereoisomer) (76 mg, 0.27 mmol, 1.5 eq). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 39 mg (43% of theoretical yield).

LC-MS (method 4): R _t =1.81 min; MS (ESIpos): m/z=492 [M+H] ⁺ .

Example 30.

4-({(2S)-2-[(9aR, 11 aR)-6-Chloro-3-oxo-3,9,9a, 10,11,11 a-hexahydro-2Hcyclobuta[4,5][3] benzoxocin[2,1-c]pyridin-2-yl]butanoyl} amino)benzamide (single stereoisomer)

- 101 044932

Separation of diastereomers and atropisomers 35 mg 4-({(2S)-2-[cis-6-chloro-3-oxo-3,9,9a,10,11,11ahexahydro-2H-cyclobuta[4,5][3] benzoxocin[2,1-c]pyridin-2-yl]butanoyl}amino)benzamide (a mixture of two diastereomers), example 29, gave a single stereoisomer 1 (the title compound example 30) (chiral HPLC: Rt=7.09 min, > 99% de): 5 mg, single stereoisomer 4 (chiral HPLC: Rt=8.30 min): 3 mg, single stereoisomer 3 (chiral HPLC: Rt=10.81 min): 1 mg, single stereoisomer 2 (chiral HPLC: Rt=12.50 min): 9 mg.

Separation method: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 60°C; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx4.6 mm; eluent: 50% nheptane/50% ethanol; temperature: 50°C; flow rate: 1 ml/min; UV detection: 220 nm.

LC-MS (method 4): Rt=1.83 min; MS (ESIpos): m/z=492 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.72-10.63 (m, 1H), 7.94-7.81 (m, 3H), 7.67 (d, 2H), 7.49-7.33 (m, 4H), 7.26 (br s, 1H), 6.38 (s, 1H), 5.70-5.58 (m, 1H), 4.64-4.57 (m, 1H), 2.79-2.66 (m, 2H), 2.63-2.56 (m , 2H), 2.21-2.01 (m, 3H), 1.81-1.65 (m, 1H), 1.37-1.21 (m, 1H), 0.89 (t, 3H).

Example 31.

4-({(2S)-2-[(9aR,11aR)-6-Chloro-3-oxo-3,9,9a,10,11,11a-hexahydro-2Hcyclobuta[4,5][3]benzoxocino[ 2,1-c]pyridin-2-yl]-3-[(2S)-tetrahydro-2H-pyran-2yl]propanoyl}amino)benzamide (single stereoisomer) ο^ι

1,1,3,3-Tetramethylguanidine (33 μL, 0.26 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (9aR,11aR)-6-chloro-9a,10,11,11a-tetrahydro-2Hcyclobuta [4,5][3]benzoxocino[2,1-c]pyridin-3(9H)-one (single stereoisomer) (25 mg, 0.09 mmol) in 2-propanol/acetone (4:1, 2.7 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-({(2R)-2-bromo-3-[(2S)-tetrahydro-2H-pyran-2yl]propanoyl}amino)benzamide (single stereoisomer) ( 46 mg, 0.13 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature overnight, at 40°C for another 22 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 30 mg (61% of theoretical yield).

LC-MS (method 4): R=1.99 min; MS (ESIpos): m/z=562 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.75-10.57 (m, 1H), 7.92-7.78 (m, 3H), 7.70 (d, 2H), 7.54-7.30 (m, 4H), 7.26 (br s, 1H), 6.37 (s, 1H), 5.81 (br t, 1H), 4.60 (q, 1H), 3.85 (br d, 1H), 3.3-3.16 (m, 2H, partially hidden), 2.82-2.63 (m, 2H), 2.63-2.5 (m, 2H, partially hidden), 2.30-2.01 (m, 3H), 1.94-1.57 (m, 3H), 1.48-1.20 (m, 5H) . Additional minor rotamer signals were also detected.

Example 32.

4-({(2S,4S)-2-[(9aR,11aR)-6-Chloro-3-oxo-3,9,9a,10,11,11a-hexahydro-2Hcyclobuta[4,5][3] benzoxocin[2,1-c]pyridin-2-yl]-4-methoxypentanoyl}amino)benzamide (single stereoisomer) _X CH ₃ o ³ J-CH ₃

I o ^nh ₂

X_Z^^^o - y ^z \/ °

Cl

1,1,3,3-Tetramethylguanidine (21 μL, 0.17 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (9aR,11aR)-6-chloro-9a,10,11,11a-tetrahydro-2Hcyclobuta [4,5][3]benzoxocino[2,1-c]pyridin-3(9H)-one (single stereoisomer) (16 mg, 0.06 mmol) in 2-propanol/acetone (4:1, 0.6 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R,4S)-2-bromo-4-methoxypentanoyl]amino}benzamide (single stereoisomer) (18 mg, 0.06 mmol, 1.0 eq.) and 2-propanol/acetone (4:1, 0.6 ml). The reaction mixture was stirred at room temperature for 3 days, followed by the addition of 1,1,3,3tetramethylguanidine (7 µl, 0.06 mmol, 1.0 eq), stirred at room temperature for 1 additional day and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 19 mg (61% of

- 102 044932 theoretical output).

LC-MS (method 4): R _t =1.86 min; MS (ESIpos): m/z=536 [M+H] ⁺ .

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.74-10.58 (m, 1H), 7.88-7.80 (m, 3H), 7.77-7.66 (m, 2H), 7.56-7.31 (m , 3H), 7.23 (br s, 1H), 6.40-6.35 (m, 1H), 5.84 (br t, 1H), 4.60 (q, 1H), 3.3-3.20 (m, 2H, partially hidden), 3.17/ 3.15 (2s, 3H), 2.79-2.66 (m, 2H), 2.64-2.56 (m, 2H), 2.32-2.04 (m, 3H), 1.82-1.66 (m, 1H), 1.40-1.22 (m, 1H ), 1.19-1.10 (m, 3H). Additional minor rotamer signals were also detected.

Example 33.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]butanoyl} amino)-2-fluorobenzamide (single stereoisomer)

1,1,3,3-Tetramethylguanidine (75 μL, 0.60 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (69 mg, 0.20 mmol) in 2-propanol/acetone (4:1, 1.05 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (single stereoisomer) (79 mg, 0.26 mmol, 1.3 eq) and more 2-propanol /acetone (4:1, 1.05 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was suspended in a mixture of N,Ndimethylformamide/acetonitrile/water. The undissolved substance was filtered and dried in vacuum. Yield: 52 mg (47% of theoretical yield).

The filtrate was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 40 mg (36% of theoretical yield).

mg batch: LC-MS (method 4): R _t =1.93 min; MS (ESIpos): m/z=552 [M+H] ⁺ 40 mg batch: LC-MS (method 1): Rt=1.04 min; MS (ESIpos): m/z=552 [M+H] ⁺ .

mg batch: ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.93-10.77 (m, 1H), 8.00-7.90 (m, 1H), 7.69 (t, 1H), 7.64 ( dd, 1H), 7.59-7.47 (m, 3H), 7.47-7.32 (m, 3H), 6.47-6.35 (m, 1H), 5.56 (dd, 1H), 4.80-4.64 (m, 1H), 4.12- 3.99/3.85-3.72 (2m, 1H), 3.27-3.19/3.15-2.99 (2m, 2H), 2.85-2.75/2.61-2.5 (2m, 1H, partially hidden), 2.25-2.08 (m, 2H), 0.99 -0.84 (m, 3H). Additional minor rotamer signals were also detected.

Example 34.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]butanoyl} amino)benzamide (single stereoisomer)

1,1,3,3-Tetramethylguanidine (38 μL, 0.30 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (34 mg, 0.10 mmol) in 2-propanol/acetone (3:1, 0.8 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R)-2-bromobutanoyl]amino}benzamide (single stereoisomer) (31 mg, 0.11 mmol, 1.1 eq.) and more 2-propanol/acetone ( 3:1, 0.8 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 41 mg (76% of theoretical yield).

LC-MS (method 4): Rt=1.85 min; MS (ESIpos): m/z=534 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.74-10.62 (m, 1H), 8.00-7.92 (m, 1H), 7.91-7.81 (m, 3H), 7.68 (d, 2H) , 7.56-7.32 (m, 3H), 7.30-7.19 (m, 1H), 6.47-6.34 (m, 1H), 5.60 (dd, 1H), 4.82-4.65 (m, 1H), 4.124.00/3.92- 3.72 (2m, 1H), 3.3-3.19/3.16-2.96 (2m, 2H), 2.85-2.75/2.62-2.5 (2m, 1H, partially hidden), 2.252.08 (m, 2H), 0.99-0.83 (m , 3H). Additional minor rotamer signals were also detected.

Example 35.

(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-

c]pyridin-3-yl]-N-(2-methyl-2H-benzotriazol-5-yl)butanamide (sole stereoisomer)

- 103 044932

1,1,3,3-Tetramethylguanidine (38 μL, 0.30 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (34 mg, 0.10 mmol) in 2-propanol/acetone (3:1, 0.8 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of (2R)-2-bromo-N-(2-methyl-2H-benzotriazol-5-yl)butanamide (single stereoisomer) (34 mg, 0.11 mmol, 1.1 eq .) and also 2-propanol/acetone (3:1, 0.8 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 33 mg (60% of theoretical yield).

LC-MS (method 4): R _t =2.06 min; MS (ESIpos): m/z=546 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.77-10.66 (m, 1H), 8.37-8.31 (m, 1H), 8.05-7.96 (m, 1H), 7.89 (d, 1H ), 7.57-7.32 (m, 4H), 6.48-6.35 (m, 1H), 5.63 (dd, 1H), 4.81-4.66 (m, 1H), 4.45 (s, 3H), 4.10-4.02/3.85— 3.76 (2m, 1H), 3.14-2.96 (m, 2H), 2.64-2.52 (m, 1H, partially hidden), 2.26-2.08 (m, 2H), 0.99-0.84 (m, 3H). Additional minor rotamer signals were also detected.

Example 36.

(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-N-[2-(difluoromethyl)-2H-indazol-5-yl]butanamide (sole stereoisomer)

General Method 7 was performed with (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (33.9 mg, 103 µmol, 1.0 eq.), (2R)-2-6pom-N-[2(difluoromethyl)-2H-indazol-5-yl]butanamide (sole stereoisomer) (57.0 mg, 90% purity, 154 µmol, 1.5 eq.) and 1,1,3,3-tetramethylguanidine (37 µl, 290 µmol, 2.84 eq.) in a mixture of 2propanol/acetone (4:1, 1.25 ml), including the following variations of the procedure: After stirring the reaction mixture at room temperature overnight, more 1,1,3,3-tetramethylguanidine (19 μL, 150 μmol, 1.5 eq.) was added and the mixture was stirred again overnight. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 1:95). Yield: 23.0 mg (38% of theoretical yield).

LC-MS (method 3): R _t =3.80 min; MS (ESIpos): m/z=581 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.61/10.57 (2br s, 1H), 8.80 (s, 1H), 8.33-8.23 (m, 1H), 8.22/8.10 (2s , 1H), 8.04-7.94 (m, 1H), 7.72 (d, 1H), 7.57-7.47 (m, 1H), 7.49-7.35 (m, 3H), 6.44/6.39 (2s, 1H), 5.72-5.52 (m, 1H), 4.85-4.64 (m, 1H), 3.88/3.79 (2t, 1H), 3.27-2.93 (m, 2H), 2.63-2.53 (m, 1H), 2.24-2.15 (m, 1H) , 2.15-2.03 (m, 1H), 0.94/0.91 (2t, 3H). Additional minor rotamer signals were also detected.

Example 37.

(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-N-[2-(trifluoromethyl)-2H-indazol-5-yl]butanamide (sole stereoisomer)

General method 7 was performed with (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (71.7 mg, 217 µmol, 1.0 eq.), (2R)-2-6pom-N-[2(trifluoromethyl)-2H-indazol-5-yl]butanamide (sole stereoisomer) (177 mg, 86% purity, 435 µmol, 2.0 eq.) and 1,1,3,3-tetramethylguanidine (77 µl, 620 µmol, 2.83 eq.) in a mixture of 2propanol/acetone (4:1, 3.8 ml), including the following variations of the procedure: After stirring the reaction mixture at room temperature overnight, more 1,1,3,3-tetramethylguanidine (41 µl,

- 104 044932

330 µmol, 1.5 eq.) was added and the mixture was stirred again overnight. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 1:95). Yield: 86.0 mg (66% of theoretical yield).

LC-MS (method 3): R _t =4.13 min; MS (ESIpos): m/z=599 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.67/10.63 (2s, 1H), 9.07/9.06 (2s, 1H), 8.30/8.27 (2s, 1H), 7.99/7.96 ( 2s, 1H), 7.75 (d, 1H), 7.57-7.30 (m, 4H), 6.44/6.38 (2s, 1H), 5.67-5.57 (m, 1H), 4.81-4.64 (m, 1H), 3.79 ( t, 1H), 3.17-2.92 (m, 2H), 2.60-2.52 (m, 1H), 2.26-2.14 (m, 1H), 2.14-2.03 (m, 1H), 0.94/0.91 (2t, 3H). Additional minor rotamer signals were also detected.

Example 38.

4-( {2-[(7R)-11 -Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1 c]pyridine-3 -yl]pentanoyl}amino)benzamide (mixture of two diastereomers)

1,1,3,3-Tetramethylguanidine (35 μL, 0.28 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (31 mg, 0.09 mmol) in 2-propanol/acetone (3:1, 0.8 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4[(2-bromopentanoyl)amino]benzamide (racemate) (33 mg, 92% purity, 0.10 mmol, 1.1 eq.) and more 2propanol/acetone (3:1 , 0.8 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 37 mg (73% of theoretical yield).

LC-MS (method 4): R _t =1.92 min; MS (ESIpos): m/z=548 [M+H]+.

¹ H-NMP (400 MHz, DMSO-d ₆ ): δ [ppm]=10.76-10.65 (m, 1H), 7.99 (d, 1H), 7.90-7.80 (m, 3H), 7.68 (d, 2H) , 7.57-7.32 (m, 3H), 7.30-7.20 (m, 1H), 6.46-6.35 (m, 1H), 5.75-5.63 (m, 1H), 4.81-4.66 (m, 1H), 4.10-3.73 ( m, 1H), 3.28-2.98 (m, 2H), 2.62-2.5 (m, 1H, partially hidden), 2.21-2.02 (m, 2H), 1.43-1.19 (m, 2H), 0.94 (t, 3H) . Additional minor rotamer signals were also detected.

Example 39.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin3-yl ]-3-cyclobutylpropanamido}-2-fluorobenzamide (mixture of two diastereomers)

General Method 7 was performed with (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (29.0 mg, 78% purity, 68.5 µmol, 1.0 eq.), 4-(2bromo-3-cyclobutylpropanamido)-2-fluorobenzamide (racemate) (31.0 mg, 91% purity, 82.2 µmol, 1.2 eq.), and 1.1 ,3,3-tetramethylguanidine (26 µl, 210 µmol, 3.0 eq.) in 2-propanol/acetone (4:1, 1.25 ml), including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 20.0 mg (49% of theoretical yield).

LC-MS (method 3): Rt=3.89/3.94 min; MS (ESIpos): m/z=592 [M+H]+.

Example 40.

4-({(2R)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-3-cyclobutylpropanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

Separation of diastereomers 15 mg 4-{2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c]pyridine -3-yl]-3-cyclobutylpropanamido}-2-fluorobenzamide (a mixture of two diastereomers), Example 39, gave a single stereoisomer 1 (title compound 40) (chiral HPLC: Rt=4.66 min, 99% de ): 6.5 mg (14% of theoretical yield), single stereoisomer 2 (chiral HPLC: Rt=7.07 min): 8.8 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 55% nheptane/45% 2-propanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx4.6 mm; eluent: 55% isohexane/45% 2-propanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 5): Rt=1.45 min; MS (ESIneg): m/z=590 [M-N] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.87/10.80 (2s, 1H), 7.96 (s, 1H), 7.72-7.67 (m, 1H), 7.67-7.62 (m, 1H), 7.57-7.35 (m, 6H), 6.41/6.37 (2s, 1H), 5.66-5.54 (m, 1H), 4.81-4.62 (m, 1H), 3.78 (t, 1H), 3.07 (br d , 2H), 2.60-2.55 (m, 1H), 2.27-2.15 (m, 3H), 2.02-1.88 (m, 2H), 1.84-1.73 (m, 3H), 1.67-1.58 (m, 1H). Additional minor rotamer signals were also detected.

Example 41.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin3-yl ]-3-[(2S)-5,5-dimethyltetrahydrofuran-2-yl]propanamido}benzamide (mixture of two diastereomers) ci

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-3 -[(2S)-5,5-dimethyloxolan-2-yl]propanoic acid (mixture of two diastereomers) (98 mg, 87% purity, 0.17 mmol), pyridine (15 μl, 0.19 mmol, 1.1 eq.) and T3P ( 152 µl, 50% solution in ethyl acetate, 0.26 mmol, 1.5 eq.) was added under argon at room temperature to a solution of 4-aminobenzamide (26 mg, 0.19 mmol, 1.1 eq.) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 1.5 h and poured into ice water. After phase separation, the organic phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 67 mg (64% of theoretical yield).

LC-MS (method 1): R _t =1.08 min; MS (ESIpos): m/z=618 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.72-10.52 (m, 1H), 8.02-7.95 (m, 1H), 7.87 (br s, 1H), 7.84 (d, 2H) , 7.69 (d, 2H), 7.56-7.31 (m, 3H), 7.25 (br s, 1H), 6.44-6.32 (m, 1H), 5.85-5.60 (m, 1H), 4.80-4.64 (m, 1H ), 4.09-3.70 (m, 2H), 3.14-2.99 (m, 2H), 2.79-2.70/2.60-2.5 (2m, 1H, partially hidden), 2.42-2.19 (m, 2H), 2.04-1.94 (m , 1H), 1.74-1.55 (m, 3H), 1.15/1.09 (2s, 6H). Additional minor rotamer signals were also detected.

Example 42.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-3-[(2S)-5,5-dimethyloxolan-2-yl]propanoyl}amino)benzamide (sole stereoisomer)

Separation of diastereomers 64 mg 4-{2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c]pyridine -3-yl]-3-[(2S)-5,5-dimethyltetrahydrofuran-2-yl]propanamido}benzamide (mixture of two diastereomers), Example 41, gave a single stereoisomer 1 (titled compound Example 42) (chiral HPLC : R _t =2.50 min, >99% de): 47 mg, single stereoisomer 2 (chiral HPLC: R _t =3.90 min, >99% de): 10 mg.

Separation method: HPLC: column: Daicel Chiralpak OZ-H 5 µm, 250 mmx20 mm; eluent: 70% nheptane/30% ethanol; temperature: 40°C; flow rate: 25 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak OZ-3 3 μm, 50 mmx4.6 mm; eluent: 80% ngexane/20% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.72-10.50 (m, 1H), 7.97 (s, 1H), 7.91-7.80 (m, 3H), 7.68 (d, 2H), 1.51-132 (m, 3H), 7.24 (br s, 1H), 6.45-6.32 (m, 1H), 5.78-5.60 (m, 1H), 4.81-4.64 (m, 1H), 4.09-3.71 (m, 2H), 3.14-2.99 (m, 2H), 2.81-2.69/2.60-2.5 (2m, 1H, partially hidden), 2.42-2.18 (m, 2H), 2.04-1.93 (m, 1H),

- 106 044932

1.75-1.55 (m, 3H), 1.15/1.09 (2s, 6H). Additional minor rotamer signals were also detected.

Example 43.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

C.I.

1,1,3,3-Tetramethylguanidine (45 μL, 0.36 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (40 mg, 0.12 mmol) in 2-propanol/acetone (3:1, 0.8 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4({(2R)-2-bromo-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)-2-fluorobenzamide ( the only stereoisomer) (49 mg, 0.13 mmol, 1.1 eq.) and another 2-propanol/acetone (3:1, 0.8 ml). The reaction mixture was stirred at room temperature overnight. Another 1,1,3,3-tetramethylguanidine (15 μl, 0.12 mmol, 1.0 eq.) was added. The reaction mixture was stirred for 4 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 41 mg (55% of theoretical yield).

LC-MS (method 4): R _t =2.08 min; MS (ESIpos): m/z=622 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.89-10.62 (m, 1H), 8.03-7.87 (m, 1H), 7.72-7.60 (m, 2H), 7.59-7.32 (m , 6H), 6.44-6.32 (m, 1H), 5.82-5.61 (m, 1H), 4.80-4.64 (m, 1H), 4.13-4.00/3.91-3.72 (2m, 2H), 3.33.18 (m, 2H, partially hidden), 3.18-2.97 (m, 2H), 2.62-2.5 (m, 1H, partially hidden), 2.31-2.08 (m, 2H), 1.83-1.70 (m, 1H), 1.67-1.56 (m , 1H), 1.49-1.19 (m, 4H). Additional minor rotamer signals were also detected.

Example 44.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (sole stereoisomer)

C.I.

1,1,3,3-Tetramethylguanidine (75 μL, 0.60 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (69 mg, 0.20 mmol) in 2-propanol/acetone (4:1, 2.5 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4({(2R)-2-bromo-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzamide (single stereoisomer) (78 mg, 0.22 mmol, 1.1 eq.) and another 2-propanol/acetone (4:1, 2.5 ml). The reaction mixture was stirred at room temperature for 4 days and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 77 mg (64% of theoretical yield).

LC-MS (method 4): R _t =1.97 min; MS (ESIpos): m/z=604 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.72-10.52 (m, 1H), 8.05-7.80 (m, 4H), 7.73-7.66 (m, 2H), 7.56-7.32 (m , 3H), 7.31-7.22 (m, 1H), 6.45-6.32 (m, 1H), 5.85-5.66 (m, 1H), 4.79-4.66 (m, 1H), 4.10-4.01/3.903.73 (2m, 2H), 3.3-3.20 (m, 2H), 3.17-2.98 (m, 2H), 2.62-2.5 (m, 1H, partially hidden), 2.32-2.10 (m, 2H), 1.81-1.71 (m, 1H) , 1.67-1.57 (m, 1H), 1.48-1.20 (m, 4H). Additional minor rotamer signals were also detected.

Example 45.

4-({(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-methoxypentanoyl}amino)-2-fluorobenzamide (mixture of two diastereomers)

- 107 044932

ci

4-Amino-2-fluorobenzamide (38 mg, 0.25 mmol, 1.1 eq.), N,N-diisopropylethylamine (97 µl, 0.56 mmol, 2.5 eq.) and HATU solution (110 mg, 0.29 mmol, 1.3 eq.) in N,N-dimethylformamide (2 ml) was added under argon at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2-oxo-7(trifluoromethyl)-2,6,7,8 -tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methylL-glyceropentonic acid (mixture of two diastereomers) (128 mg, 80% accepted purity of crude product, 0.22 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was stirred at room temperature for 5.5 h and concentrated under reduced pressure. The residue was crystallized using water, filtered, washed with water and dried in vacuum. This residue was dissolved in dichloromethane and purified by column chromatography (silica gel, eluent: dichloromethane/methanol gradient). Yield: 52 mg (39% of theoretical yield).

LC-MS (method 4): R _t =1.95 min; MS (ESIpos): m/z=596 [M+H]+.

'H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.92-10.73 (m, 1H), 8.06-7.97 (m, 1H), 7.72-7.61 (m, 2H), 7.59-7.33 ( m, 6H), 6.46-6.34 (m, 1H), 5.84-5.71 (m, 1H), 4.79-4.66 (m, 1H), 4.08-3.95/3.92-3.74 (2m, 1H), 3.33.00 (m , 6H, partially hidden), 2.83-2.74/2.62-2.5 (2m, 'H, partially hidden), 2.40-2.16 (m, 2H), 1.191.08 (m, 3H). Additional minor rotamer signals were also detected.

Example 46.

4-({(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-4-methoxypentanoyl} amino)-2-fluorobenzamide (single stereoisomer)

C.I.

Separation of diastereomers 50 mg 4-({(4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzoxocino[2, 1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)-2-fluorobenzamide (mixture of two diastereomers), Example 45, gave a single stereoisomer 1 (titled compound Example 46) (chiral SFC: R _t =0.61 min, >99% de): 17 mg, single stereoisomer 2 (chiral SFC: R _t =0.86 min, >99% de): 21 mg.

Separation method: SFC: column: Daicel Chiralpak IG 5 µm, 250 mmx20 mm; eluent: 70% carbon dioxide/30% methanol; temperature: 40°C; flow rate: 80 ml/min; UV detection: 210 nm.

Method of analysis: SFC: column: Daicel Chiralpak IG 3 µm, 50 mmx4.6 mm; eluent: 70% carbon dioxide/30% 2-propanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 220 nm.

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.92-10.71 (m, 1H), 8.05-7.96 (m, 1H), 7.73-7.60 (m, 2H), 7.58-7.32 ( m, 6H), 6.46-6.33 (m, 1H), 5.84-5.68 (m, 1H), 4.80-4.64 (m, 1H), 4.10-3.97/3.84-3.72 (2m, 1H), 3.32.98 (m , 6H, partially hidden), 2.84-2.73/2.63-2.5 (2m, 1H, partially hidden), 2.31-2.16 (m, 2H), 1.15 (d, 3H). Additional minor rotamer signals were also detected.

Example 47.

4-({(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (mixture of two diastereomers)

ci

4-Aminobenzamide (33 mg, 0.25 mmol, 1.1 eq.), N,N-diisopropylethylamine (97 µl, 0.56 mmol, 2.5 eq.) and HATU solution (110 mg, 0.29 mmol, 1.3 eq.) in N,N- dimethylformamide (2 ml) was added under argon at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H -[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers) (128 mg, 80% accepted purity crude product - 108 044932 t, 0.22 mmol) in N,N-dimethylformamide (4 ml). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was crystallized using water, filtered, washed with water and dried in vacuum. This residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate gradient). Yield: Two batches were isolated, 67 mg and 16 mg (64% of theoretical yield for both batches combined).

mg batch: LC-MS (method 4): R _t =1.88 min; MS (ESIpos): m/z=578 [M+H]+.

Example 48.

4-({(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-4-methoxypentanoyl} amino)benzamide (single stereoisomer)

Separation of diastereomers 82 mg 4-({(4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8 tetrahydro-3H-[3]benzoxocino[2 ,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (a mixture of two diastereomers), Example 47, gave a single stereoisomer 1 (the title compound, Example 48) (chiral SFC: R _t =4.44 min, >99% de): 19 mg, single stereoisomer 2 (chiral SFC: R _t =6.31 min, >99% de): 22 mg.

Separation method: SFC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 65% carbon dioxide/35% methanol; temperature: 40°C; flow rate: 80 ml/min; UV detection: 210 nm.

Analysis method: SFC: column: Daicel Chiralpak IE, 50 mmx4.6 mm; eluent: 70% carbon dioxide/30% methanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.75-10.58 (m, 1H), 8.05-7.97 (m, 1H), 7.91-7.79 (m, 3H), 7.70 (d, 2H), 7.57-7.32 (m, 3H), 7.25 (br s, 1H), 6.46-6.33 (m, 1H), 5.86-5.73 (m, 1H), 4.80-4.64 (m, 1H), 4.103.95 /3.84-3.71 (2m, 1H), 3.3-2.97 (m, 6H, partially hidden), 2.85-2.73/2.63-2.5 (2m, 1H, partially hidden), 2.30-2.15 (m, 2H), 1.16 (d , 3H). Additional minor rotamer signals were also detected.

Alternative synthesis route.

1,1,3,3-Tetramethylguanidine (93 μL, 0.74 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (82 mg, 0.25 mmol) in 2-propanol/acetone (4:1, 2 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R,4S)-2-bromo-4-methoxypentanoyl]amino}benzamide (single stereoisomer) (90 mg, 0.27 mmol, 1.1 eq.) and more 2-propanol/acetone (4:1, 2 ml). The reaction mixture was stirred at room temperature for 5 days and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 106 mg (74% of theoretical yield).

LC-MS (method 1): R _t =1.00 min; MS (ESIpos): m/z=578 [M+H] ⁺ .

'h-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.75-10.56 (m, 1H), 8.07-7.97 (m, 1H), 7.92-7.80 (m, 3H), 7.70 (d, 2H), 7.57-7.32 (m, 3H), 7.25 (br s, 1H), 6.46-6.33 (m, 1H), 5.88-5.73 (m, 1H), 4.81-4.64 (m, 1H), 4.103.97 /3.92-3.72 (2m, 1H), 3.3-2.97 (m, 6H, partially hidden), 2.87-2.73/2.63-2.5 (2m, 1H, partially hidden), 2.30-2.15 (m, 2H), 1.16 (d , 3H). Additional minor rotamer signals were also detected.

Another alternative synthesis route.

1,1,3,3-Tetramethylguanidine (2.19 mL, 17.5 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (2.00 g, 96% purity, 5.82 mmol) in 2propanol/acetone (4:1, 136 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R,4S)-2-bromo-4-methoxynentanoyl]amino}benzamide (single stereoisomer) (3.26 g, 9.90 mmol, 1.7 eq.). The reaction mixture was stirred at room temperature for 3 days and then poured into 0.05 N aqueous hydrochloride solution (700 ml). After extraction with ethyl acetate (2 x 100 ml), the combined organic phases were washed with saturated aqueous sodium chloride (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage Isolera, 100 g SNAP-Ultra cartridge, eluent: dichloromethane (5 cv), dichloromethane/acetonitrile 75:25, 50:50, 25:75 (5 cv each), acetonitrile (20 cv), yielding two fractions: Yield: 2.00 g (59% theoretical yield, >98% de), 1.00 g (29% theoretical yield, >49% de).

Chiral SFC: R _t =4.03 min, >98% de.

- 109 044932

Analysis method: SFC: column: Chiralcel AZ-3, 3 µm, 100 mmx4.6 mm, eluent: isocratic 80% carbon dioxide/20% isopropanol, 10 min, temperature: 40°C; flow rate: 3.0 ml/min; UV detection: 210 nm, back pressure: 130 bar.

Another alternative synthesis route.

1,1,3,3-Tetramethylguanidine (68.5 mL, 546 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (60.0 g, 182 mmol) in 2-propanol/acetone (4:1, 2.1 L). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R,4S)-2-bromo-4-methoxypentanoyl]amino}benzamide (single stereoisomer) (89.9 g, 273 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for 3 days and then neutralized with acetic acid (31.3 ml, 546 mmol, 3.0 eq.). The reaction mixture was concentrated to 1/4 of the initial volume and then poured into a 0.02 N aqueous hydrochloride solution (4.5 L). The precipitate was filtered off under reduced pressure, washed with water and dried in air (yield: 119 g). The crude material was purified by SFC to obtain the product as a single stereoisomer. Yield: 77.8 g (73% theoretical yield, >99% de).

Separation method: SFC: column: Chiralpak AZ 20 µm, 350 mmx50 mm, eluent: isocratic 70% carbon dioxide/30% isopropanol, 4 min, temperature: 30°C; flow rate: 300 ml/min; UV detection: 210 nm; back pressure: 100 bar.

Chiral SFC: R _t =1.39 min, >99% de.

Analysis method: SFC: column: Chiralcel AZ-3, 3 µm, 100 mmx4.6 mm, eluent: isocratic 70% carbon dioxide/30% isopropanol, 10 min, temperature: 40°C; flow rate: 3.0 ml/min; UV detection: 210 nm, back pressure: 130 bar.

Chiral HPLC: R _t =3.15 min, >99% de.

Method of analysis: HPLC: column: Chiralcel OZ-3, 3 µm, 50 mmx4.6 mm, eluent: isocratic 80% heptane/20% ethanol, 10 min, temperature: 50°C; flow rate: 1.0 ml/min; UV detection: 210 nm.

LC-MS (method 3): R _t =3.12 min; MS (ESIpos): m/z=578 [M+H]+.

'h-NMR (600 MHz, DMSO-d6): δ [ppm]=10.70-10.53 (m, 1H), 8.05-7.94 (m, 1H), 7.85 (br d, 3H), 7.70 (d, 2H) , 7.58-7.32 (m, 3H), 7.21 (br s, 1H), 6.48-6.31 (m, 1H), 5.91-5.71 (m, 1H), 4.83-4.64 (m, 1H), 4.093.97/3.87 -3.68 (2m, 1H), 3.39-2.99 (m, 6H, partially hidden), 2.85-2.74/2.65-2.50 (2m, 1H, partially hidden), 2.34-2.15 (m, 2H), 1.16 (d, 3H ). Additional minor rotamer signals were also detected.

' ³ C-NMR (126 MHz, DMSO-d6): δ [ppm]=168.03 (s, 1С), 167.17 (s, 1С), 159.71 (s, 1С), 146.90 (s, 1С), 140.97 (2 overlapping s, 2C), 136.48 (s, 1C), 135.92 (s, 1C), 131.89 (s, 1C), 131.62 (d, 1CH), 129.74 (d, 1CH), 129.33 (overlapping d, 1CH), 129.33 (overlapping s, 1C), 128.27 (d, 2CH), 128.02 (d, 1CH), 126.24 [s, ICF3 (J=280.8 Hz)], 118.78 (d, 2CH), 116.67 (d, 1CH), 75.08 ( t, ICH2), 73.54 (d, 1CH), 55.45 (q, ICH3O), 55.37 (d, 1CH), 44.23 (d, 1CH), 37.33 (t, ICH2), 29.72 (t, ICH2), 18.55 (q , 1CH ₃ ).

Example 49.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)pentanamide (mixture of two diastereomers)

[1,2,4]T riazolo[1,5-a]pyridin-7-amine hydrochloride (23 mg, 0.13 mmol, 1.1 eq.), pyridine (28 μl, 0.35 mmol, 3.0 eq.) and T3P (102 µl, 50% solution in ethyl acetate, 0.17 mmol, 1.5 eq.) was added under argon at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2, 6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers ) (57 mg, 93% purity, 0.12 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature overnight before all volatile compounds were removed under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 44 mg (66% of theoretical yield).

LC-MS (method 1): R _t =0.99 min; MS (ESIpos): m/z=576 [M+H] ⁺ .

'h-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=11.06-10.87 (m, 1H), 8.87 (d, 1H), 8.39/8.38 (2s, 1H), 8.22-8.16 (m, 1H), 8.09-7.91 (m, 1H), 7.56-7.29 (m, 4H), 6.46-6.36 (m, 1H), 5.87-5.74 (m, 1H), 4.80-4.69 (m, 1H), 4.113. 75 (m, 1H), 3.3-2.98 (m, 3H, partially hidden), 3.19/3.12 (2s, 3H), 2.84-2.72/2.60-2.46 (2m, 1H, partially hidden), 2.43-2.20 (m, 2H), 1.20-1.11 (m, 3H). Additional minor rotamer signals were also detected.

Example 50.

(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin- 3-yl]-4-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)pentanamide (sole stereoisomer)

Separation of diastereomers 41 mg (4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-с] pyridin-3-yl]-4-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)pentanamide (a mixture of two diastereomers), Example 49, gave a single stereoisomer 1 ( title compound, example 50) (chiral HPLC: R _t =2.31 min, 99% de): 10 mg, single stereoisomer 2 (chiral HPLC: R _t =3.41 min, 99% de): 21 mg.

Separation method: HPLC: column: Daicel Chiralpak IC 5 µm, 250 mmx20 mm; eluent: 60% nheptane/40% 2-propanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IC 3 µm, 50 mmx4.6 mm; eluent: 60% isoheptane/40% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=11.09-10.88 (m, 1H), 8.87 (d, 1H), 8.39 (s, 1H), 8.23-8.17 (m, 1H) , 8.08-7.99 (m, 1H), 7.57-7.30 (m, 4H), 6.47-6.35 (m, 1H), 5.89-5.72 (m, 1H), 4.82-4.66 (m, 1H), 4.133.98/ 3.82-3.74 (2m, 1H), 3.3-2.97 (m, 3H, partially hidden), 3.19 (s, 3H), 2.85-2.73/2.63-2.5 (2m, 1H, partially hidden), 2.32-2.20 (m, 2H), 1.17 (d, 3H). Additional minor rotamer signals were also detected.

Example 51.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-X-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)pentanamide (mixture of two diastereomers)

2-Methyl[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (24 mg, 0.13 mmol, 1.1 eq.), pyridine (10 µl, 0.13 mmol, 1.1 eq.) and T3P (102 µl, 50% solution in ethyl acetate, 0.17 mmol, 1.5 eq.) was added under argon at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl) 2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture two diastereomers) (57 mg, 93% purity, 0.12 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 1 hour before all volatile compounds were removed under reduced pressure. The residue was dissolved in pyridine (1 ml). T3P (68 μl, 50% solution in ethyl acetate, 0.12 mmol, 1.0 eq.) was added under argon at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then all volatile compounds were removed under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 43 mg (63% of theoretical yield).

LC-MS (method 1): R _t =0.99 min; MS (ESIpos): m/z=590 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=11.01-10.82 (m, 1H), 8.73 (d, 1H), 8.09-7.90 (m, 2H), 7.56-7.32 (m, 3H ), 7.28-7.19 (m, 1H), 6.46-6.34 (m, 1H), 5.86-5.72 (m, 1H), 4.80-4.67 (m, 1H), 4.08-3.75 (m, 1H), 3.253.00 (m, 3H), 3.18/3.11 (2s, 3H), 2.84-2.73/2.59-2.46 (2m, 1H, partially hidden), 2.44-2.20 (m, 2H), 2.42/2.41 (2s, 3H), 1.19 -1.12 (m, 3H). Additional minor rotamer signals were also detected.

Example 52.

(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin- 3-yl]-4-methoxy-X-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-7-yl)pentanamide (sole stereoisomer)

- 111 044932

Separation of diastereomers 40 mg (4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1 -с] pyridin-3-yl]-4-methoxy-N-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-7yl)pentanamide (a mixture of two diastereomers), example 51, gave a single stereoisomer 1 (titled compound example 52) (chiral HPLC: R _t =1.64 min, 99% de): 11 mg, single stereoisomer 2 (chiral HPLC: R _t =2.51 min, 99% de): 25 mg.

Separation method: HPLC: column: Daicel Chiralpak IC 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% 2-propanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IC 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% 2-propanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=11.02-10.82 (m, 1H), 8.74 (d, 1H), 8.10-7.99 (m, 2H), 7.57-7.31 (m, 3H) , 7.29-7.21 (m, 1H), 6.46-6.34 (m, 1H), 5.89-5.69 (m, 1H), 4.81-4.66 (m, 1H), 4.12-3.94/3.87-3.74 (2m, 1H), 3.3-2.98 (m, 3H, partially hidden), 3.18 (s, 3H), 2.84-2.74/2.63-2.5 (2m, 1H, partially hidden), 2.42 (s, 3H), 2.31-2.20 (m, 2H) , 1.19-1.12 (m, 3H). Additional minor rotamer signals were also detected.

Example 53.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-X-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pentanamide (mixture of two diastereomers) o' ^CH *

IF A ^CH 3 ^F < Gn ^F Ήϊ π ΧϊΑ WX° HA/

X

Cl

[1,2,4]Triazolo[1,5-a]pyridin-6-amine (17 mg, 0.13 mmol, 1.1 eq.), N,N-diisopropylethylamine (51 μl, 0.29 mmol, 2.5 eq.) and solution HATU (53 mg, 0.14 mmol, 1.2 eq.) in N,N-dimethylformamide (1 ml) was added under argon at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2-oxo- 7(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methylL-glycero -pentonic acid (mixture of two diastereomers) (57 mg, 93% purity, 0.12 mmol) in N,Ndimethylformamide (3 ml). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 49 mg (72% of theoretical yield).

LC-MS (method 4): R _t =1.92/1.93 min; MS (ESIpos): m/z=576 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.95-10.75 (m, 1H), 9.42 (s, 1H), 8.46/8.44 (2s, 1H), 8.09-7.92 (m, 1H ), 7.86 (d, 1H), 7.76-7.68 (m, 1H), 7.56-7.32 (m, 3H), 6.47-6.35 (m, 1H), 5.89-5.74 (m, 1H), 4.80-4.65 (m , 1H), 4.14-3.74 (m, 1H), 3.3-2.98 (m, 3H, partially hidden), 3.19/3.12 (2s, 3H), 2.85-2.73/2.64-2.5 (2m, 1H, partially hidden), 2.45-2.18 (m, 2H), 1.21-1.11 (m, 3H). Additional minor rotamer signals were also detected.

Example 54.

(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin- 3-yl]-4-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pentanamide (sole stereoisomer)

Separation of diastereomers 45 mg (4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro- 112 044932

3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pentanamide ( mixture of two diastereomers), example 53, gave a single stereoisomer 1 (titled compound example 54) (chiral HPLC: R _t =2.38 min, 99% de): 16 mg, single stereoisomer 2 (chiral HPLC: R _t =3.25 min , 99% de): 22 mg.

Separation method: HPLC: column: Daicel Chiralpak IE 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% 2-propanol; temperature: 60°C; flow rate: 25 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IE 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% 2-propanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.97-10.73 (m, 1H), 9.43 (s, 1H), 8.46 (s, 1H), 8.04 (br s, 1H), 7.86 (d, 1H), 7.73 (dd, 1H), 7.57-7.33 (m, 3H), 6.48-6.35 (m, 1H), 5.90-5.73 (m, 1H), 4.82-4.65 (m, 1H), 4.143.99/3.87-3.72 (2m, 1H), 3.3-2.97 (m, 3H, partially hidden), 3.19 (s, 3H), 2.86-2.73/2.64-2.5 (2m, 1H, partially hidden), 2.32- 2.15 (m, 2H), 1.16 (d, 3H). Additional minor rotamer signals were also detected.

Example 55.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-N-(2-methyl-2H-benzotriazol-5-yl)pentanamide (mixture of two diastereomers) o' ^CH3

F A ^CH h ^F \L ί N

I II N-CHo kAA, about ³ w

Cl

2-Methyl-2H-benzotriazol-5-amine (19 mg, 0.13 mmol, 1.1 eq.), pyridine (11 μl, 0.13 mmol, 1.1 eq.) and T3P (104 μl, 50% solution in ethyl acetate, 0.18 mmol, 1.5 equiv.) was added under an argon atmosphere at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[ 3] benzoxocin [2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers) (57 mg, 95% purity, 0.12 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 30 min before all volatile compounds were removed under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 58 mg (80% of theoretical yield).

LC-MS (method 4): R _t =2.10/2.12 min; MS (ESIpos): m/z=590 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.75-10.59 (m, 1H), 8.36-8.30 (m, 1H), 8.10-7.93 (m, 1H), 7.90-7.84 ( m, 1H), 7.58-7.32 (m, 4H), 6.46-6.34 (m, 1H), 5.91-5.79 (m, 1H), 4.80-4.66 (m, 1H), 4.45/4.45 (2s, 3H), 4.08-3.75 (m, 1H), 3.25-2.99 (m, 3H), 3.19/3.12 (2s, 3H), 2.84-2.73/2.61-2.5 (2m, 1H, partially hidden), 2.43-2.19 (m, 2H ), 1.20-1.11 (m, 3H). Additional minor rotamer signals were also detected.

Example 56.

(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin- 3-yl]-4-methoxy-N-(2-methyl-2H-benzotriazol-5-yl)pentanamide (single stereoisomer)

Separation of diastereomers 55 mg (4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c] pyridin-3-yl]-4-methoxy-N-(2-methyl-2H-benzotriazol-5-yl)pentanamide (a mixture of two diastereomers), Example 55, gave a single stereoisomer 1 (titled compound Example 56) (chiral HPLC: R _t =1.18 min, 99% de): 14 mg, single stereoisomer 2 (chiral HPLC: R _t =1.76 min, 99% de): 29 mg.

Separation method: HPLC: column: Daicel Chiralpak IC 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% 2-propanol; temperature: 60°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IC 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% 2-propanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.77-10.60 (m, 1H), 8.33 (br s, 1H), 8.05 (br s, 1H), 7.88 (d, 1H), 7.58 -7.30 (m, 4H), 6.46-6.34 (m, 1H), 5.91-5.77 (m, 1H), 4.81-4.65 (m, 1H), 4.45 (s, 3H), 4.12-3.97/3.873.72 ( 2m, 1H), 3.3-2.97 (m, 3H, partially hidden), 3.19 (s, 3H), 2.86-2.73/2.64-2.5 (2m, 1H, partially hidden), 2.35-2.18 (m, 2H), 1.16 (d, 3H). Additional minor rotamer signals were also detected.

- 113 044932 wife.

Example 57.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluormethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6yl)pentanamide (mixture of two diastereomers)

CH ₃ o z

C.I.

6-Amino-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (26 mg, 0.13 mmol, 1.1 equiv.), pyridine (28 μl, 0.35 mmol , 3.0 eq.) and T3P (102 μl, 50% solution in ethyl acetate, 0.17 mmol, 1.5 eq.) were added under argon at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2- oxo-7(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methylL -glycero-pentonic acid (mixture of two diastereomers) (57 mg, 93% purity, 0.12 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 3 days and filtered through Celite®. The filtrate was removed under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 57 mg (81% of theoretical yield).

LC-MS (method 4): R _t =1.88 min; MS (ESIpos): m/z=606 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.65-10.48 (m, 1H), 8.54-8.41 (m, 1H), 8.06-7.90 (m, 1H), 7.56-7.33 (m , 3H), 7.31-7.24 (m, 2H), 6.46-6.34 (m, 1H), 5.87-5.70 (m, 1H), 4.79-4.66 (m, 1H), 4.08-3.74 (m, 1H), 3.53 /3.53 (2s, 3H), 3.3-2.98 (m, 3H, partially hidden), 3.18/3.12 (2s, 3H), 2.85-2.71/2.60-2.5 (2m, 1H, partially hidden), 2.40-2.14 (m , 2H), 1.18-1.10 (m, 3H). Additional minor rotamer signals were also detected.

Example 58.

(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin- 3-yl]-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-6yl)pentanamide (sole stereoisomer)

F ^F <LF^^f\o

Cl

Separation of diastereomers 54 mg (4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c] pyridin-3-yl]-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3a]pyridin-6-yl)pentanamide (a mixture of two diastereomers), example 57, gave a single stereoisomer 1 (titled compound example 58) (chiral HPLC: R _t =6.45 min, >99% de): 17 mg, single stereoisomer 2 (chiral HPLC: R _t =10.03 min, >99% de): 32 mg.

Separation method: HPLC: column: Daicel Chiralcel OX-H 5 µm, 250 mmx20 mm; eluent: 60% nheptane/40% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralcel OX-H 5 µm, 250 mmx4.6 mm; eluent: 60% isohexane/40% ethanol; temperature: 30°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.66-10.46 (m, 1H), 8.46 (s, 1H), 8.04-7.94 (m, 1H), 7.56-7.32 (m, 3H ), 7.31-7.25 (m, 2H), 6.46-6.33 (m, 1H), 5.83-5.69 (m, 1H), 4.79-4.65 (m, 1H), 4.10-3.98/ 3.83-3.74 (2m, 1H) , 3.53 (s, 3H), 3.3-2.99 (m, 3H, partially hidden), 3.18 (s, 3H), 2.85-2.73/2.63-2.5 (2m, 1H, partially hidden), 2.27-2.14 (m, 2H ), 1.15 (m, 3H). Additional minor rotamer signals were also detected.

Example 59.

4-({(2S,4R)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-4-cyclopropyl-4-methoxybutanoyl}amino)benzamide (single stereoisomer)

- 114 044932

1,1,3,3-Tetramethylguanidine (30 μL, 0.24 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (27 mg, 0.08 mmol) in 2-propanol/acetone (4:1, 1.0 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R,4R)-2-bromo-4-cyclopropyl-4-methoxybutanoyl]-amino}-benzamide (single stereoisomer) (31 mg, 0.09 mmol, 1.1 eq.) and more 2-propanol/acetone (4:1, 1.0 ml). The reaction mixture was stirred at room temperature for 7 days and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 28 mg (58% of theoretical yield).

LC-MS (method 16): Rt=4.51 min; MS (ESIpos): m/z=604 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.76-10.47 (m, 1H), 8.11-7.93 (m, 1H), 7.92-7.78 (m, 3H), 7.70 (d, 2H ), 7.58-7.31 (m, 3H), 7.22 (br s, 1H), 6.46-6.32 (m, 1H), 5.91-5.73 (m, 1H), 4.81-4.65 (m, 1H), 4.114.00/ 3.84-3.71 (2m, 1H), 3.29-3.17 (m, 3n), 3.13-2.96 (m, 2H), 2.82-2.72/2.63-2.5 (2m, 2H, partially hidden), 2.44-2.20 (m, 2H ), 0.90-0.77 (m, 1H), 0.63-0.52 (m, 1H), 0.46-0.27 (m, 2H), 0.11-0.0 (m, 1H). Additional minor rotamer signals were also detected.

Example 60.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin3-yl ]-4-(difluoromethoxy)butanamido}-2-fluorobenzamide (mixture of two diastereomers)

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3 yl]- 4-(difluoromethoxy)butanoic acid (a mixture of two diastereomers) (63 mg, 0.13 mmol), pyridine (12 μl, 0.14 mmol, 1.1 eq.) and T3P (114 μl, 50% solution in ethyl acetate, 0.20 mmol, 1.5 eq. ) was added under argon at room temperature to a solution of 4-amino-2-fluorobenzamide (22 mg, 0.14 mmol, 1.1 eq.) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 74 mg (92% of theoretical yield).

LC-MS (method 4): Rt=1.94 min; MS (ESIpos): m/z=618 [M+H] ⁺ .

'h-NMR (600 MHz, DMSO-d6): δ [ppm]=10.94-10.63 (m, 1H), 8.03-7.91 (m, 1H), 7.73-7.60 (m, 2H), 7.59-7.32 (m , 6H), 6.64/6.63 (2t, 1H), 6.47-6.35 (m, 1H), 5.81-5.58 (m, 1H), 4.78-4.63 (m, 1H), 4.17-3.73 (m, 3H), 3.28 -2.96 (m, 2H), 2.84-2.72/2.64-2.4 (2m, 3H, partially hidden). Additional minor rotamer signals were also detected.

Example 61.

4-{[(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-(difluoromethoxy)butanoyl]amino}-2-fluorobenzamide (single stereoisomer)

Separation of diastereomers 72 mg 4-{2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c]pyridine -3-yl]-4-(difluoromethoxy)butanamido}-2-fluorobenzamide (a mixture of two diastereomers), example 60, gave a single stereoisomer 1 (title compound example 61) (chiral SFC: R _t =1.41 min, >99% de): 26 mg, single stereoisomer 2 (chiral SFC:

Rt=2.01 min, 95% de): 23 mg.

Separation method: SFC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 82% carbon dioxide/18% methanol; temperature: 40°C; flow rate: 80 ml/min; UV detection: 210 nm.

Method of analysis: SFC: column: Daicel Chiralpak ID, 50 mmx4.6 mm; eluent: 80% carbon dioxide/20% methanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.93-10.63 (m, 1H), 7.96 (br s, 1H), 7.74-7.32 (m, 8H), 6.63 (t, 1H) , 6.46-6.33 (m, 1H), 5.82-5.56 (m, 1H), 4.81-4.62 (m, 1H), 4.18-3.71 (m, 3H), 3.16-2.96 (m, 2H), 2.862.74/ 2.65-2.4 (2m, 3H, partially hidden). Additional minor rotamer signals were also detected.

Example 62.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin3-yl ]-4-(difluoromethoxy)butanamido}benzamide (mixture of two diastereomers)

C.I.

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]niridin-3yl]-4 -(difluoromethoxy)butanoic acid (a mixture of two diastereomers) (77 mg, 0.16 mmol), pyridine (14 μl, 0.18 mmol, 1.1 eq.) and T3P (140 μl, 50% solution in ethyl acetate, 0.24 mmol, 1.5 eq.) was added under argon at room temperature to a solution of 4-aminobenzamide (24 mg, 0.18 mmol, 1.1 eq.) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 83 mg (84% of theoretical yield).

LC-MS (method 4): Rt=1.87 min; MS (ESIpos): m/z=600 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.77-10.51 (m, 1H), 8.04-7.93 (m, 1H), 7.92-7.81 (m, 3H), 7.68 (d, 2H), 7.57-7.32 (m, 3H), 7.26 (br s, 1H), 6.64/6.62 (2t, 1H), 6.46-6.34 (m, 1H), 5.84-5.63 (m, 1H), 4.79-4.64 (m, 1H), 4.13-3.73 (m, 3H), 3.28-2.97 (m, 2H), 2.84-2.72/2.63-2.4 (2m, 3H, partially hidden). Additional minor rotamer signals were also detected.

Example 63.

4-{[(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-(difluoromethoxy)butanoyl]amino}benzamide (single stereoisomer)

Separation of diastereomers 80 mg 4-{2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c]pyridine -3-yl]-4-(difluoromethoxy)butanamido}benzamide (mixture of two diastereomers), example 62, gave a single stereoisomer 1 (titled compound example 63) (chiral HPLC: R _t =1.41 min, >99% de) : 20 mg, single stereoisomer 2 (chiral HPLC: R _t =1.74 min, >99% de): 17 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 70% nheptane/30% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID-3 3 µm, 50 mmx4.6 mm; eluent: 70% n-hexane/30% ethanol; temperature: 30°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.77-10.48 (m, 1H), 7.97 (br s, 1H), 7.92-7.80 (m, 3H), 7.68 (d, 2H), 7.59-7.31 (m, 3H), 7.25 (br s, 1H), 6.64 (t, 1H), 6.48-6.34 (m, 1H), 5.85-5.61 (m, 1H), 4.82-4.61 (m, 1H) , 4.15-3.69 (m, 3H), 3.17-2.96 (m, 2H), 2.86-2.73/2.65-2.4 (2m, 3H, partially hidden). Additional minor rotamer signals were also detected.

Example 64.

4-{[(4R)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1- 116 044932

c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (mixture of two diastereomers)

(2ξ)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-D-glycero-pentonic acid (mixture of two diastereomers) (99 mg, 0.20 mmol), pyridine (18 μl, 0.22 mmol, 1.1 eq.) and T3P (175 µl, 50% solution in ethyl acetate, 0.30 mmol, 1.5 eq.) was added under argon at room temperature to a solution of 4-aminobenzamide (30 mg, 0.22 mmol, 1.1 eq.) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 101 mg (82% of theoretical yield).

LC-MS (method 4): R _t =1.93 min; MS (ESIpos): m/z=614 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.82-10.56 (m, 1H), 8.05-7.93 (m, 1H), 7.92-7.80 (m, 3H), 7.72-7.63 (m , 2H), 7.58-7.32 (m, 3H), 7.25 (br s, 1H), 6.62/6.59 (2t, 1H), 6.47-6.33 (m, 1H), 5.90-5.67 (m, 1H), 4.81- 4.64 (m, 1H), 4.20-3.99/3.92-3.72 (2m, 2H), 3.16-2.97 (m, 2H), 2.84-2.70/2.65-2.5 (2m, 1H, partially hidden), 2.5-2.28 (m , 2H, partially hidden), 1.36-1.25 (m, 3H). Additional minor rotamer signals were also detected.

Example 65.

4-{[(2S,4R)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (single stereoisomer)

Separation of diastereomers 99 mg 4-{[(4R)-2-[(7R)-1P-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8 tetrahydro-3H-[3]benzoxocino[2 ,1-c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (a mixture of two diastereomers), Example 64, gave a single stereoisomer 1 (titled compound Example 65) (chiral HPLC: R _t = 4.38 min, 99% de): 58 mg, single stereoisomer 2 (chiral HPLC: R _t =6.11 min, 99% de): 25 mg.

Separation method: HPLC: column: Daicel Chiralpak OZ-H 5 µm, 250 mmx20 mm; eluent: 55% nheptane/45% ethanol; temperature: 55°C; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak OZ-H 5 µm, 250 mmx4.6 mm; eluent: 50% isohexane/50% ethanol; temperature: 50°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.80-10.57 (m, 1H), 7.97 (br s, 1H), 7.91-7.80 (m, 3H), 7.68 (d, 2H) , 7.58-7.32 (m, 3H), 7.24 (br s, 1H), 6.59 (t, 1H), 6.47-6.33 (m, 1H), 5.86-5.68 (m, 1H), 4.81-4.63 (m, 1H ), 4.23-3.99/3.85-3.72 (2m, 2H), 3.17-2.97 (m, 2H), 2.83-2.73/2.65-2.5 (2m, 1H, partially hidden), 2.5-2.29 (m, 2H, partially hidden ), 1.30 (d, 3H). Additional minor rotamer signals were also detected.

Example 66.

4-{[(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (mixture of two diastereomers)

(2ξ)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1

- 117 044932

c]pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-L-glyceropentonic acid (mixture of two diastereomers) (93 mg, 89% purity, 0.17 mmol), pyridine ( 15 μl, 0.18 mmol, 1.1 eq.) and T3P (146 μl, 50% solution in ethyl acetate, 0.25 mmol, 1.5 eq.) were added under argon at room temperature to a solution of 4-aminobenzamide (25 mg, 0.18 mmol, 1.1 eq. .) in tetrahydrofuran (3.6 ml). The reaction mixture was stirred at room temperature for 0.5 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 89 mg (87% of theoretical yield).

LC-MS (method 4): R _t =1.97 min; MS (ESIneg): m/z=612 [MH] ^- .

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.81-10.53 (m, 1H), 8.07-7.94 (m, 1H), 7.92-7.80 (m, 3H), 7.72-7.64 (m , 2H), 7.57-7.31 (m, 3H), 7.26 (br s, 1H), 6.64/6.59 (2t, 1H), 6.45-6.35 (m, 1H), 5.88-5.70 (m, 1H), 4.80- 4.65 (m, 1H), 4.25-3.73 (m, 2H), 3.13-2.96 (m, 2H), 2.83-2.72/2.64-2.5 (2m, 1H), 2.5-2.30 (m, 2H, partially hidden), 1.36-1.25 (m, 3H). Additional minor rotamer signals were also detected.

Example 67.

4-{[(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (single stereoisomer)

Separation of diastereomers 89 mg 4-{[(4S)-2-[(7R)-11l-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3] benzoxocino [2, 1-c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (a mixture of two diastereomers), Example 66, gave a single stereoisomer 1 (the title compound, Example 67) (chiral HPLC: R _t =4.18 min, 99% de): 29 mg, single stereoisomer 2 (chiral HPLC: R _t =4.85 min, 99% de): 44 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 30°C; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx4.6 mm; eluent: 50% isohexane/50% ethanol; temperature: 30°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.75-10.50 (m, 1H), 7.98 (br s, 1H), 7.92-7.80 (m, 3H), 7.67 (d, 2H), 7.57-7.31 (m, 3H), 7.25 (br s, 1H), 6.64 (t, 1H), 6.47-6.35 (m, 1H), 5.89-5.70 (m, 1H), 4.80-4.64 (m, 1H) , 4.27-4.15 (m, 1H), 4.11-3.98/3.84-3.71 (2m, 1H), 3.16-2.96 (m, 2H), 2.85-2.72/2.64-2.5 (2m, 1H), 2.5-2.30 (m , 2H, partially hidden), 1.31 (d, 3H). Additional minor rotamer signals were also detected.

Example 68.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin3-yl ]-4-(trifluoromethoxy)butanamido}-2-fluorobenzamide (mixture of two diastereomers)

4-Amino-2-fluorobenzamide (12 mg, 76 µmol, 1.1 eq.), N,N-diisopropylethylamine (30 µl, 170 µmol, 2.5 eq.) and HATU solution (34 mg, 89 µmol, 1.3 eq.) in N,N-dimethylformamide (1.0 ml) was added under argon at room temperature to a solution of 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H- [3]Benzoxocin[2,1-c]pyridin-3-yl]-4-(trifluoromethoxy)butanoic acid (mixture of two diastereomers) (35 mg, 69 µmol) in N,N-dimethylformamide (3.0 ml). The reaction mixture was stirred at room temperature for 1.5 h, followed by the addition of more 4-amino-2fluorobenzamide (3 mg, 21 µmol, 0.3 eq), N,N-diisopropylethylamine (6 µl, 34 µmol, 0.5 eq) and HATU (13 mg, 34 µmol, 0.5 eq.). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 35 mg (80% of theoretical

- 118 044932 exit).

LC-MS (method 1): Rt=1.08 min; MS (ESIpos): m/z=636 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.94-10.86/10.65-10.59 (2m, 1H), 8.01 (d, 1H), 7.72-7.60 (m, 2H), 7.60-7.46 (m, 3H), 7.46-7.33 (m, 3H), 6.47-6.36 (m, 1H), 5.87-5.79/5.63-5.54 (2m, 1H), 4.79-4.64 (m, 1H), 4.24-4.16 ( m, 1H), 4.16-4.01/3.94-3.73 (2m, 2H), 3.15-3.00 (m, 2H), 2.64-2.5 (m, 3H, partially hidden). Additional minor rotamer signals were also detected.

Example 69.

4-{[(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-(trifluoromethoxy)butanoyl]amino}-2-fluorobenzamide (single stereoisomer)

Separation of diastereomers 24 mg 4-{2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c]pyridine -3-yl]-4-(trifluoromethoxy)butanamido}-2-fluorobenzamide (mixture of two diastereomers), Example 68, gave a single stereoisomer 1 (titled compound Example 69) (chiral HPLC: Rt=1.55 min, 94% de ): 13 mg, single stereoisomer 2 (chiral HPLC: R=2.31 min, 99% de): 9 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 80% nheptane/20% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 210 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID-3 3 µm, 50 mmx4.6 mm; eluent: 80% isohexane/20% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.94-10.86/10.67-10.58 (m/br s, 1H), 7.99 (s, 1H), 7.73-7.60 (m, 2H), 7.60 -7.46 (m, 3H), 7.46-7.23 (m, 3H), 6.48-6.36 (m, 1H), 5.86-5.78/5.64-5.54 (2m, 1H), 4.80-4.63 (m, 1H), 4.24- 4.16 (m, 1H), 4.15-4.00/3.82-3.72 (2m, 2H), 3.15-2.98 (m, 2H), 2.67-2.5 (m, 3H, partially hidden). Additional minor rotamer signals were also detected.

Example 70.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin3-yl ]-4-(trifluoromethoxy)butanamido}benzamide (mixture of two diastereomers)

4-Aminobenzamide (9 mg, 63 µmol, 1.1 eq.), N,N-diisopropylethylamine (25 µl, 140 µmol, 2.5 eq.) and a solution of HATU (28 mg, 74 µmol, 1.3 eq.) in N,N- dimethylformamide (1.0 ml) was added under argon at room temperature to a solution of 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzoxocino[ 2,1-c]pyridin-3-yl]-4-(trifluoromethoxy)butanoic acid (mixture of two diastereomers) (29 mg, 57 µmol) in X,X-dimethylformamide (2.0 ml). The reaction mixture was stirred at room temperature for 4 h, followed by the addition of more 4-aminobenzamide (4 mg, 28 µmol, 0.5 eq), N,N-diisopropylethylamine (5 µl, 28 µmol, 0.5 eq) and HATU (11 mg, 28 µmol, 0.5 eq.). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 20 mg (56% of theoretical yield).

LC-MS (method 3): Rt=3.46 min; MS (ESIpos): m/z=618 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.76-10.70/10.54-10.47 (2m, 1H), 8.01 (d, 1H), 7.91-7.81 (m, 3H), 7.67 (d , 2H), 7.56-7.46 (m, 1H), 7.46-7.32 (m, 2H), 7.30-7.20 (m, 1H), 6.47-6.36 (m, 1H), 5.90-5.79/5.705.60 (2m, 1H), 4.80-4.65 (m, 1H), 4.23-4.15 (m, 1H), 4.15-3.96/3.94-3.71 (2m, 2H), 3.13-2.98 (m, 2H), 2.722.52 (m, 3H , partially hidden). Additional minor rotamer signals were also detected.

Example 71.

4-{[2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-(2,2-difluoroethoxy)butanoyl]amino}benzamide (mixture of two diastereomers)

- 119 044932

2-[(7R)-11-Chloro-2-oxo-7-(triftΌrmethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4 -(2,2-difluoroethoxy)butanoic acid (a mixture of two diastereomers) (85 mg, 0.17 mmol), pyridine (15 μl, 0.19 mmol, 1.1 eq.) and T3P (150 μl, 50% solution in ethyl acetate, 0.26 mmol, 1.5 equiv.) was added under argon at room temperature to a solution of 4-aminobenzamide (26 mg, 0.19 mmol, 1.1 equiv.) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 2.5 h before adding water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 91 mg (86% of theoretical yield).

LC-MS (method 3): R _t =3.37 min; MS (ESIpos): m/z=614 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.74-10.55 (m, 1H), 8.03-7.93 (m, 1H), 7.91-7.79 (m, 3H), 7.68 (d, 2H ), 7.56-7.32 (m, 3H), 7.26 (br s, 1H), 6.45-6.32 (m, 1H), 6.21-5.90 (m, 1H), 5.80-5.67 (m, 1H), 4.79-4.64 ( m, 1H), 4.12-3.46 (m, 5H), 3.15-2.95 (m, 2H), 2.87-2.71/2.65-2.5 (m, 1H, partially hidden), 2.48-2.32 (m, 2H). Additional minor rotamer signals were also detected.

Example 72.

4-{[(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-(2,2-difluoroethoxy)butanoyl]amino}benzamide (single stereoisomer)

Separation of diastereomers 89 mg 4-{[2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino [2,1-c] pyridin-3-yl]-4-(2,2-difluoroethoxy)butanoyl]amino} benzamide (mixture of two diastereomers), example 71, gave a single stereoisomer 1 (chiral HPLC: R _t =6.40 min, 99% de): 36 mg, single stereoisomer 2 (titled compound example 72) (chiral HPLC: R _t =8.95 min, 99% de): 35 mg.

Separation method: HPLC: column: Daicel Chiralpak IG 5 µm, 250 mmx20 mm; eluent: 40% nheptane/60% ethanol; temperature: 60°C; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IG 5 µm, 250 mmx4.6 mm; eluent: 50% isohexane/50% ethanol; temperature: 60°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.73-10.52 (m, 1H), 7.98 (br s, 1H), 7.91-7.80 (m, 3H), 7.68 (d, 2H) , 7.56-7.33 (m, 3H), 7.25 (br s, 1H), 6.46-6.33 (m, 1H), 6.07 (tt, 1H), 5.80-5.67 (m, 1H), 4.80-4.64 (m, 1H ), 4.13-3.43 (m, 5H), 3.16-2.95 (m, 2H), 2.87-2.76/2.64-2.5 (2m, 1H, partially hidden), 2.48-2.34 (m, 2H). Additional minor rotamer signals were also detected.

Example 73.

4-( {2-[(7R)-11 -Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1 c]pyridine-3 -yl]-4-[(propan-2-yl)oxy]butanoyl}amino)-2-fluorobenzamide (mixture of two diastereomers)

4-Amino-2-fluorobenzamide (27 mg, 0.17 mmol, 1.1 eq.), X,X-diisopropylethylamine (68 μl, 0.39 mmol, 2.5 eq.) and HATU solution (78 mg, 0.20 mmol, 1.3 eq.) in X,X-dimethylformamide (1 ml) was added

- 120 044932 in an argon atmosphere at room temperature into a solution of 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1-c]pyridin-3-yl]-4-[(propan-2-yl)oxy]butanoic acid (mixture of two diastereomers) (81 mg, 92% purity, 0.16 mmol) in N,N-dimethylformamide (4 ml ). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 64 mg (66% of theoretical yield).

LC-MS (method 4): Rt=2.05 min; MS (ESIpos): m/z=610 [M+H]+.

1H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.92-10.67 (m, 1H), 8.04-7.93 (m, 1H), 7.72-7.61 (m, 2H), 7.60-7.30 (m, 6H), 6.46-6.33 (m, 1H), 5.79-5.64 (m, 1H), 4.79-4.64 (m, 1H), 4.10-3.94/3.92-3.72 (2m, 1H), 3.53-3.38 (m, 2H ), 3.15-2.98 (m, 2H), 2.81-2.69/2.63-2.4 (2m, 1H, partially hidden), 2.43-2.25 (m, 2H), 1.05-0.90 (m, 6H). Additional minor rotamer signals were also detected.

Example 74.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-[(propan-2-yl)oxy]butanoyl}amino)-2-fluorobenzamide (sole stereoisomer)

Separation of diastereomers 60 mg 4-({2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c] pyridin-3-yl]-4-[(propan-2-yl)oxy]butanoyl}amino)-2-fluorobenzamide (a mixture of two diastereomers), Example 73, gave a single stereoisomer 1 (the title compound Example 74) (chiral HPLC: Rt=1.29 min, >99% de): 16 mg, single stereoisomer 2 (chiral HPLC: Rt=2.03 min, >99% de): 14 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 70% nheptane/30% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID 3 µm, 50 mmx4.6 mm; eluent: 70% nheptane/30% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.87-10.67 (m, 1H), 7.97 (s, 1H), 7.75-7.60 (m, 2H), 7.58-7.31 (m, 6H ), 6.47-6.32 (m, 1H), 5.81-5.63 (m, 1H), 4.81-4.62 (m, 1H), 4.13-3.99/3.83-3.70 (2m, 1H), 3.55-3.39 (m, 2H) , 3.16-2.97 (m, 2H), 2.82-2.69/2.63-2.4 (2m, 1H, partially hidden), 2.43-2.25 (m, 2H), 1.05-0.93 (m, 6H). Additional minor rotamer signals were also detected.

Example 75.

4-({(2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с]pyridine-3 -yl]-4-[(propan-2-yl)oxy]butanoyl}amino)benzamide (mixture of two diastereomers)

4-Aminobenzamide (24 mg, 0.17 mmol, 1.1 eq.), N,N-diisopropylethylamine (68 µl, 0.39 mmol, 2.5 eq.) and a solution of HATU (78 mg, 0.20 mmol, 1.3 eq.) in N,N- dimethylformamide (1 ml) was added under argon at room temperature to a solution of 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzoxocino[ 2,1-c]pyridin-3-yl]-4-[(propan-2-yl)oxy]butanoic acid (mixture of two diastereomers) (81 mg, 92% purity, 0.16 mmol) in N,N-dimethylformamide ( 4 ml). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was crystallized using water, filtered, washed with water and dissolved in acetonitrile. This solution was used for purification by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 55 mg (59% of theoretical yield).

LC-MS (method 4): Rt=1.98 min; MS (ESIpos): m/z=592 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.75-10.55 (m, 1H), 8.05-7.94 (m, 1H), 7.88 (br s, 1H), 7.85 (d, 2H) , 7.70 (d, 2H), 7.57-7.32 (m, 3H), 7.27 (br s, 1H), 6.45-6.33 (m, 1H), 5.82-5.69 (m, 1H), 4.80-4.65 (m, 1H ), 4.10-3.95/3.92-3.72 (2m, 1H), 3.54-3.39 (m, 2H), 3.16-2.97 (m, 2H), 2.80-2.70/2.62-2.45 (2m, 1H, partially hidden), 2.44 -2.26 (m, 2H), 1.05-0.91 (m, 6H). Additional minor rotamer signals were also detected.

- 121 044932

Example 76.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-4-[(propan-2-yl)oxy]butanoyl}amino)benzamide (single stereoisomer)

Separation of diastereomers 55 mg 4-({(2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c ]pyridin-3-yl]-4-[(propan-2-yl)oxy]butanoyl}amino)benzamide (mixture of two diastereomers), Example 75, gave a single stereoisomer 1 (titled compound Example 76) (chiral SFC: R _t =4.13 min, >99% de): 19 mg, single stereoisomer 2 (chiral SFC: R _t =6.13 min, >99% de): 15 mg.

Separation method: SFC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 74% carbon dioxide/26% methanol; temperature: 40°C; flow rate: 80 ml/min; UV detection: 210 nm.

Analysis method: SFC: column: Daicel Chiralpak IE, 50 mmx4.6 mm; eluent: 70% carbon dioxide/30% methanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.72-10.53 (m, 1H), 7.97 (s, 1H), 7.92-7.79 (m, 3H), 7.69 (d, 2H), 7.57-7.33 (m, 3H), 7.24 (br s, 1H), 6.46-6.33 (m, 1H), 5.80-5.68 (m, 1H), 4.81-4.64 (m, 1H), 4.123.99/3.84- 3.71 (2m, 1H), 3.54-3.39 (m, 2H), 3.15-2.97 (m, 2H), 2.80-2.71/2.64-2.5 (2m, 1H, partially hidden), 2.44-2.25 (m, 2H), 1.06-0.94 (m, 6H). Additional minor rotamer signals were also detected.

Example 77.

4-({4-tert-Butoxy-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1 -c]pyridin-3-yl]butanoyl}amino)benzamide (mixture of two diastereomers)

4-tert-Butoxy-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridine -3-yl]butanoic acid (a mixture of two diastereomers) (53 mg, 0.11 mmol), pyridine (9 μl, 0.12 mmol, 1.1 eq.) and T3P (92 μl, 50% solution in ethyl acetate, 0.16 mmol, 1.5 eq. ) was added under argon at room temperature to a solution of 4-aminobenzamide (16 mg, 0.12 mmol, 1.1 eq.) in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 2.5 h before adding water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 51 mg (80% of theoretical yield).

LC-MS (method 3): Rt=3.62 min; MS (ESIpos): m/z=606 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.75-10.55 (m, 1H), 8.02/7.97 (2s, 1H), 7.86 (br s, 1H), 7.85 (d, 2H) , 7.70 (d, 2H), 7.57-7.31 (m, 3H), 7.25 (br s, 1H), 6.46-6.33 (m, 1H), 5.83-5.70 (m, 1H), 4.79-4.66 (m, 1H ), 4.09-3.94/3.91-3.72 (2m, 1H), 3.63-3.57/3.47-3.3 (2m, 2H, partially hidden), 3.15-3.01 (m, 2H), 2.762.67/2.62-2.5 (2m, 1H, partially hidden), 2.42-2.25 (m, 2H), 1.04/1.01 (2s, 9H). Additional minor rotamer signals were also detected.

Example 78.

4-({(2S)-4-tert-Butoxy-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino [2,1-c]pyridin-3-yl]butanoyl}amino)benzamide (sole stereoisomer)

- 122 044932

Separation of diastereomers 50 mg 4-({4-tert-butoxy-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino [2,1-c]pyridin-3-yl]butanoyl}amino)benzamide (a mixture of two diastereomers), example 77, gave a single stereoisomer 1 (the title compound is example

78) (chiral HPLC: R _t =1.18 min, >99% de): 18 mg, single stereoisomer 2 (chiral HPLC:

R _t =1.71 min, 99% de): 17 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 70% nheptane/30% ethanol; temperature: 40°C; flow rate: 25 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID 3 µm, 50 mmx4.6 mm; eluent: 70% n-hexane/30% ethanol; temperature: 30°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.70-10.55 (m, 1H), 7.97 (s, 1H), 7.89-7.81 (m, 3H), 7.70 (d, 2H) , 7.57-7.31 (m, 3H), 7.24 (br s, 1H), 6.45-6.34 (m, 1H), 5.83-5.70 (m, 1H), 4.80-4.66 (m, 1H), 4.093.96/3.85 -3.72 (2m, 1H), 3.48-3.3 (m, 2H, partially hidden), 3.15-3.00 (m, 2H), 2.76-2.67/2.62-2.5 (2m, 1H, partially hidden), 2.40-2.26 (m , 2H), 1.04 (s, 9H). Additional minor rotamer signals were also detected.

Example 79.

4-{[2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-(cyclopropyloxy)butanoyl]amino}benzamide (mixture of two diastereomers)

2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3yl]-4 -(cyclopropyloxy)butanoic acid (a mixture of two diastereomers) (66 mg, 0.14 mmol), pyridine (12 μl, 0.15 mmol, 1.1 eq.) and T3P (123 μl, 50% solution in ethyl acetate, 0.21 mmol, 1.5 eq.) was added under argon at room temperature to a solution of 4-aminobenzamide (21 mg, 0.15 mmol, 1.1 eq.) in tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 2.5 h before adding water. The resulting precipitate was filtered, washed with water and dried in vacuum. Yield: 33 mg (40% of theoretical yield).

The combined filtrates were extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Yield: 24 mg (28% of theoretical yield).

mg batch: LC-MS (method 4): R _t =1.93 min; MS (ESIpos): m/z=590 [M+H]+.

mg batch: ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.74-10.57 (m, 1H), 8.04-7.93 (m, 1H), 7.87 (br s, 1H), 7.85 (d, 2H), 7.69 (d, 2H), 7.57-7.32 (m, 3H), 7.26 (br s, 1H), 6.46-6.33 (m, 1H), 5.80-5.66 (m, 1H), 4.80- 4.66 (m, 1H), 4.10-3.95/3.93-3.72 (2m, 1H), 3.57-3.3 (m, 2H, partially hidden), 3.27-3.20 (m, 1H), 3.14-2.99 (m, 2H), 2.82-2.71/2.63-2.5 (2m, 1H, partially hidden), 2.44-2.25 (m, 2H), 0.45-0.23 (m, 4H). Additional minor rotamer signals were also detected.

Example 80.

4-{[(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-(cyclopropyloxy)butanoyl]amino}benzamide (sole stereoisomer)

Separation of diastereomers 55 mg 4-{[2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1 -с] pyridin-3-yl]-4-(cyclopropyloxy)butanoyl]amino}benzamide (mixture of two diastereomers), Example 79, gave single stereoisomer 1 (chiral HPLC: R _t =7.13 min, 99% de): 24 mg, single stereoisomer 2 (titled compound example 80) (chiral HPLC: R=11.69 min, 99% de): 26 mg.

Separation method: HPLC: column: Daicel Chiralpak IG 5 µm, 250 mmx20 mm; eluent: 40% nheptane/60% ethanol; temperature: 60°C; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak IG 5 µm, 250 mmx4.6 mm; eluent: 50% isohex-123 044932 san/50% ethanol; temperature: 60°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.72-10.55 (m, 1H), 7.97 (br s, 1H), 7.91-7.80 (m, 3H), 7.68 (d, 2H) , 7.57-7.33 (m, 3H), 7.24 (br s, 1H), 6.46-6.33 (m, 1H), 5.80-5.66 (m, 1H), 4.81-4.65 (m, 1H), 4.103.99/3.83 -3.72 (2m, 1H), 3.58-3.3 (m, 2H, partially hidden), 3.27-3.20 (m, 1H), 3.14-2.99 (m, 2H), 2.822.74/2.63-2.5 (2m, 1H, partially hidden), 2.44-2.25 (m, 2H), 0.46-0.29 (m, 4H). Additional minor rotamer signals were also detected.

Example 81.

4-({2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с]pyridine-3 - yl]-4-[(1-methylcyclopropyl)oxy]butanoyl}amino)-2-fluorobenzamide (mixture of two diastereomers)

C.I.

4-Amino-2-fluorobenzamide (15 mg, 0.10 mmol, 1.1 eq.), N,N-diisopropylethylamine (38 μl, 0.22 mmol, 2.5 eq.) and HATU solution (43 mg, 0.11 mmol, 1.3 eq.) in N,N-dimethylformamide (1 ml) was added under argon at room temperature to a solution of 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H- [3]benzoxocino[2,1-c]pyridin-3-yl]-4-[(1-methylcyclopropyl)-oxy]butanoic acid (mixture of two diastereomers) (45 mg, 93% purity, 0.09 mmol) in N, N-dimethylformamide (2 ml). After stirring at room temperature for 4.5 h, more 4-amino-2-fluorobenzamide (7 mg, 0.04 mmol, 0.5 eq.) and HATU (16 mg, 0.04 mmol, 0.5 eq.) were added. The reaction mixture was stirred for 2 days and concentrated under reduced pressure.

The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 10 mg (19% of theoretical yield).

LC-MS (method 4): R _t =2.10 min; MS (ESIpos): m/z=622 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.90-10.70 (m, 1H), 8.01/7.96 (2s, 1H), 7.72-7.61 (m, 2H), 7.59-7.47 (m , 3H), 7.46-7.33 (m, 3H), 6.46-6.33 (m, 1H), 5.76-5.63 (m, 1H), 4.78-4.66 (m, 1H), 4.10-3.94/3.913.73 (2m, 1H), 3.57-3.45 (m, 1H), 3.15-3.01 (m, 2H), 2.80-2.70/2.62-2.5 (2m, 1H, partially hidden), 2.412.27 (m, 2H), 1.27-1.16 ( m, 3H), 0.64-0.56 (m, 1H), 0.54-0.38 (m, 1H), 0.35-0.22 (m, 2H). One proton is hidden. Additional minor rotamer signals were also detected.

Example 82.

4-({2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с]pyridine-3- yl]-4-[(1-methylcyclopropyl)oxy]butanoyl}amino)benzamide (mixture of two diastereomers) sn ₃ l

C.I.

4-Aminobenzamide (39 mg, 0.29 mmol, 1.1 eq.), N,N-diisopropylethylamine (113 µl, 0.65 mmol, 2.5 eq.) and a solution of HATU (129 mg, 0.34 mmol, 1.3 eq.) in N,N- dimethylformamide (1 ml) was added under argon at room temperature to a solution of 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzoxocino[ 2,1-c]pyridin-3-yl]-4-[(1-methylcyclopropyl)oxy]butanoic acid (mixture of two diastereomers) (136 mg, 93% purity, 0.26 mmol) in N,N-dimethylformamide (4 ml ). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure with a water bath temperature of 50°C. The residue was crystallized using water, filtered, washed with water and dried in vacuum. This residue was purified by column chromatography (silica gel, eluent: dichloromethane/methanol gradient). Yield: Two batches were isolated, 83 mg and 48 mg (82% of theoretical yield for both batches combined).

Both batches: LC-MS (method 4): R _t =2.03 min; MS (ESIpos): m/z=604 [M+H]+.

mg-batch: ¹ H-NMR (500 MHz, DMSO4): δ [ppm]=10.72-10.56 (m, 1H), 8.01/7.96 (2s, 1H), 7.86 (br s, 1H), 7.84 (d, 2H), 7.69 (d, 2H), 7.56-7.33 (m, 3H), 7.25 (br s, 1H), 6.46-6.34 (m, 1H), 5.78-5.66 (m, 1H), 4.80-4.66 (m , 1H), 4.09-3.96/3.92-3.72 (2m, 1H), 3.66-3.45 (m, 1H), 3.3-3.20 (m, 1H, partially hidden), 3.17-3.01 (m, 2H), 2.78-2.71 /2.60-2.5 (2m, 1H, partially hidden), 2.42-2.25 (m, 2H), 1.29-1.18 (m, 3H),

- 124 044932

0.66-0.56 (m, 1H), 0.54-0.39 (m, 1H), 0.36-0.22 (m, 2H). Additional minor rotamer signals were also detected.

Example 83.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-4-[(1-methylcyclopropyl)oxy]butanoyl}amino)benzamide (sole stereoisomer)

Separation of diastereomers 122 mg 4-({2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c] pyridin-3-yl]-4-[(1-methylcyclopropyl)oxy]butanoyl}amino)-benzamide (mixture of two diastereomers), Example 82, gave a single stereoisomer 1 (titled compound Example 83) (chiral HPLC: R _t =2.49 min, 99% de): 75 mg, single stereoisomer 2 (chiral HPLC: R _t =3.43 min, 98% de): 45 mg.

Separation method: HPLC: column: Daicel Chiralpak OZ-H 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 25 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak OZ-H 3 µm, 50 mmx4.6 mm; eluent: 50% isohexane/50% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.71-10.55 (m, 1H), 7.96 (s, 1H), 7.90-7.80 (m, 3H), 7.69 (d, 2H), 7.57-7.33 (m, 3H), 7.24 (br s, 1H), 6.46-6.33 (m, 1H), 5.79-5.66 (m, 1H), 4.80-4.65 (m, 1H), 4.104.00/3.83- 3.72 (2m, 1H), 3.67-3.44 (m, 1H), 3.37-3.3 (m, 1H, partially hidden), 3.18-3.00 (m, 2H), 2.792.69/2.63-2.5 (2m, 1H, partially hidden hidden), 2.89-2.25 (m, 2H), 1.28-1.18 (m, 3H), 0.66-0.58 (m, 1H), 0.55-0.44 (m, 1H), 0.37-0.25 (m, 2H). Additional minor rotamer signals were also detected.

Example 84.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin3-yl ]-4-(cyclobutyloxy)butanamido}benzamide (mixture of two diastereomers) coq νη ₂ ⁰

C.I.

General method 11 was carried out with 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridin- 3-yl]-4-(cyclobutyloxy)butanoic acid (mixture of two diastereomers) (8.0 mg, 16 µmol, 1.0 eq.), 4-aminobenzamide (3.36 mg, 25 µmol, 1.5 eq.) and T3P (39 µl, 50 % solution in ethyl acetate, 66 µmol, 4.0 eq.) in pyridine (0.5 ml), including the following variations of the procedure: The reaction mixture was stirred at 50°C for 2 h, concentrated under reduced pressure and purified by preparative HPLC (reverse phase, eluent : water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 2.3 mg (22% of theoretical yield).

LC-MS (method 3): Rt=3.58 min; MS (ESIpos): m/z=604 [M+H]+.

Example 85.

4-{[(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-(cyclobutyloxy)butanoyl]amino}benzamide (sole stereoisomer)

General method 11 was performed twice: first time with 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1 -c]pyridin-3-yl]-4-(cyclobutyloxy)butanoic acid

- 125 044932 (mixture of two diastereomers) (74.0 mg, 152 µmol, 1.0 eq.), 4-aminobenzamide (31.1 mg, 228 µmol, 1.5 eq.) and T3P (360 µl, 50% solution in ethyl acetate, 610 µmol, 4.0 eq.) in pyridine (4.6 ml) and a second time with 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino [2,1-c]pyridin-3yl]-4-(cyclobutyloxy)butanoic acid (mixture of two diastereomers) (30.0 mg, 62 µmol, 1.0 eq.), 4-aminobenzamide (12.6 mg, 93 µmol, 1.5 eq.) and T3P (147 µl, 50% solution in ethyl acetate, 247 µmol, 4.0 eq.) in pyridine (1.9 ml), including the following variations of the procedure: Reaction mixtures were stirred for 4 hours at 50°C, concentrated under reduced pressure and purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Two batches of products were combined and 50 mg of 4-{2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzokCOcino[2,1- c]pyridin-3-yl]-4-(cyclobutylkC and)butanamido}benzamide (a mixture of two diastereomers) was further purified by resolution of the diastereomers to give: single stereoisomer 1 (title compound 85) (chiral HPLC: R _t =1.00 min, 92% de): 12.8 mg (10% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =1.03 min): 13.2 mg.

Separation method: HPLC: column: Daicel Chiralpak IF 5 µm, 250 mmx20 mm; eluent: 40% nheptane/60% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiraltek IC 3 µm, 50 mmx4.6 mm; eluent: 50% n-heptane/50% ethanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 1): Rt=1.11 min; MS (ESIpos): m/z=604 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.73 (s, 1H), 8.03 (s, 1H), 7.90-7.80 (m, 3H), 7.73-7.60 (m, 2H), 7.53 (br d, 1H), 7.47-7.33 (m, 2H), 7.24 (br s, 1H), 6.44/6.40 (2s, 1H), 5.84-5.78 (m, 1H), 4.77-4.69 (m, 1H ), 3.86 (t, 1H), 3.27-3.14 (m, 1H), 3.14-2.99 (m, 2H), 2.48-2.34 (m, 2H), 2.13-1.90 (m, 1H), 1.85-1.72 (m , 1H), 1.72-1.58 (m, 2H), 1.57-1.38 (m, 2H), 1.30-1.14 (m, 3H). Additional minor rotamer signals were also detected.

Example 86.

4-{2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzokocino[2,1-c]pyridin3-yl ]-4-[(1-methylcyclobutyl)oxy]butanamido}benzamide (mixture of two diastereomers)

General method 11 was carried out with 2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c]pyridin- 3-yl]-4-[(1-methylcyclobutyl)oxy]butanoic acid (mixture of two diastereomers) (44.5 mg, 89.0 µmol, 1.0 eq.), 4-aminobenzamide (18.2 mg, 134 µmol, 1.5 eq.) and T3P (210 µl, 50% solution in ethyl acetate, 360 µmol, 4.0 eq.) in pyridine (2.7 ml), including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80 :20 - 5:95). Yield: 35 mg (64% of theoretical yield).

LC-MS (method 1): R _t =1.12 min; MS (ESIpos): m/z=618 [M+H] ⁺ .

Example 87.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c] pyridin-3-yl]-4-[(1-methylcyclobutyl)oxy]butanoyl}amino)benzamide (sole stereoisomer)

Separation of diastereomers 28 mg 4-{2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzokocino[2,1-c]pyridine -3-yl]-4-[(1-methylcyclobutyl)oxy]butanamido}benzamide (a mixture of two diastereomers), Example 86, gave a single stereoisomer 1 (title compound 87) (chiral HPLC: R _t =5.44 min, 99 % de): 10.6 mg (19% of theoretical yield), single stereoisomer 2 (chiral HPLC: Rt=6.52 min): 6.2 mg.

Separation method: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 50% n- 126 044932 heptane/50% 2-propanol; temperature: 40°C; flow rate: 15 ml/min; UV detection: 235 nm.

Method of analysis: HPLC: column: Daicel Chiraltek IE 5 µm, 250 mmx4.6 mm; eluent: 50% n-heptane/50% 2-propanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 1): R _t =1.08 min; MS (ESIpos): m/z=618 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.70/10.62 (2br s, 1H), 7.98 (br s, 1H), 7.84 (br d, 3H), 7.70 (br d, 2H ), 7.52 (br s, 1H), 7.48-7.32 (m, 2H), 7.24 (br s, 1H), 6.44/6.40 (2s, 1H), 5.84-5.72 (m, 1H), 4.82-4.64 (m , 1H), 3.82-3.72 (m, 1H), 3.23-3.17 (m, 1H), 3.13-3.02 (m, 2H), 2.61-2.24 (m, 1H), 2.04-1.92 (m, 1H), 1.90 -1.80 (m, 1H), 1.77-1.29 (m, 6H), 1.28-1.21 (m, 1H), 1.18 (s, 3H). Additional minor rotamer signals were also detected.

Example 88.

4-({(2S,4R)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-5,5,5-trifluoro-4-hydroxypentanoyl}amino)benzamide (single stereoisomer)

Into a solution of 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro -3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-5,5,5-trifluoropentanoyl)amino]benzamide (mixture of two diastereomers) (87.0 mg, 57% purity, 67.7 µmol, 1.0 equiv .) in tetrahydrofuran (4.0 ml), a solution of tetra-n-butylammonium fluoride (200 μl, 1.0 M in tetrahydrofuran, 200 μmol, 3.0 eq.) was added at room temperature. The mixture was stirred for 3 hours and then concentrated under reduced pressure and further purified by separation of the diastereomers to give: single stereoisomer 1 (LC-MS (method 5): R _t =1.27 min): 2.4 mg, single stereoisomer 2 (indicated in title compound 88) (LC-MS (method 5): R _t =1.28 min, 99% de): 2.1 mg (5% of theoretical yield).

Separation method: HPLC: column: Phenomenex Kinetex C18 5 µm, 100x30 mm; eluent: 80% water with 2.0% formic acid/20% acetonitrile; temperature: room temperature; flow rate: 80 ml/min; UV detection: 220 nm.

Analysis method: LC-MS: method 5.

LC-MS (method 5): R _t =1.28 min; MS (ESIneg): m/z=616 [M-N] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.63 (br s, 1H), 7.93 (s, 1H), 7.89-7.81 (m, 3H), 7.68 (d, 2H), 7.59 -7.46 (m, 1H), 7.46-7.34 (m, 2H), 7.26 (br s, 1H), 6.52-6.34 (m, 2H), 5.86-5.66 (m, 1H), 4.75-4.62 (m, 1H ), 4.18-4.04 (m, 1H), 4.03-3.87 (m, 1H), 3.18-2.96 (m, 2H), 2.71-2.49 (m, 2H), 2.25-2.09 (m, 1H). Additional minor rotamer signals were also detected.

Example 89.

4-({(2S)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3] benzoxocino [2 ,1-c]pyridin-3-yl]butanoyl}amino)-2-fluorobenzamide (single stereoisomer)

General Method 7 was carried out with (7R)-11-chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro-3H[3]benzoxocino[2,1-c]pyridin-2(6H)-one ( single stereoisomer) (60.0 mg, 76% purity, 131 µmol, 1.0 eq.), 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (single stereoisomer) (47.7 mg, 157 µmol, 1.2 eq. .) and 1,1,3,3-tetramethylguanidine (49 µl, 390 µmol, 3.0 eq.) in 2propanol/acetone (4:1, 1.2 ml), including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 34.0 mg (41% of theoretical yield).

LC-MS (method 1): Rt=1.69 min; MS (ESIpos): m/z=570 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.90/10.83 (2s, 1H), 8.06/8.02 (2s, 1H), 7.74-7.59 (m, 3H), 7.58-7.47 (m , 2H), 7.44-7.36 (m, 1H), 7.34-7.28 (m, 1H), 6.55/6.49 (2d, 1H), 5.60-5.50 (m, 1H), 4.79-4.67 (m, 1H), 3.86 /3.78 (2t, 1H), 3.19-2.97 (m, 2H), 2.60-2.46 (m, 1H), 2.25-2.04 (m, 2H), 0.94-0.91 (2t, 3H). Additional minor rotamer signals were also detected.

Example 90.

- 127 044932

4-({(2S)-2-[(7R)-11 -Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino [2 ,1-c] pyridin-3 -yl] butanoyl } amino) benzamide (single stereoisomer) CH ₃ N N.

NH ₂

General Method 7 was carried out with (7R)-11-chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro-3H[3]benzoxocino[2,1-c]pyridin-2(6H)-one ( single stereoisomer) (60.0 mg, 76% purity, 131 µmol, 1.0 eq.), 4-{[(2R)-2-bromobutanoyl]amino}benzamide (single stereoisomer) (44.9 mg, 157 µmol, 1.2 eq.) and 1,1,3,3-tetramethylguanidine (49 µl, 390 µmol, 3.0 eq.) in 2propanol/acetone (4:1, 1.2 ml), including the following variations of the procedure:

The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 42.0 mg (57% of theoretical yield).

LC-MS (method 3): Rt=3.22 min; MS (ESIpos): m/z=552 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.73/10.67 (2s, 1H), 8.07/8.03 (2s, 1H), 7.93-7.79 (m, 3H), 7.74-7.60 ( m, 3H), 7.31 (d, 1H), 7.27-7.18 (m, 1H), 6.54/6.48 (2d, 1H), 5.64-5.55 (m, 1H), 4.79-4.67 (m, 1H), 3.78 ( t, 1H), 3.30-3.24 (m, 1H), 3.16-2.96 (m, 2H), 2.24-2.05 (m, 2H), 0.97-0.86 (m, 3H). Additional minor rotamer signals were also detected.

Example 91.

4- {[(4S)-2-[(7R)-11 -Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-

[3] benzoxocin [2, 1 -c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (a mixture of two diastereomers)

F.

F'

J—si ₃ ,nh ₂ (2ξ)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3 ]benzoxocino[2,1c]pyridin-3-yl]-2,3,5-trideoxy-4-O-(difluoromethyl)-b-glyceropentonic acid (mixture of two diastereomers) (116 mg, 60% purity, 135 µmol, 1.0 eq.) was dissolved in dichloromethane (5.0 ml), 1-χλορ-Ν,N,2trimethylprop-1-en-1-amine (23 µl, 180 µmol, 1.3 eq.) was added and the reaction mixture was stirred for 10 min. 4-Aminobenzamide (24.0 mg, 176 µmol, 1.3 eq.) was then added and the reaction mixture was stirred for 3 hours. All volatile compounds were removed under reduced pressure and the residue was dissolved in N,N-dimethylformamide (4.0 ml). HATU (77.3 mg, 203 µmol, 1.5 eq.) and N,Ndiisopropylethylamine (71 µl, 410 µmol, 3.0 eq.) were then added and the mixture was stirred at room temperature overnight and at 50°C for 1 h. Crude mixture purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 43.0 mg (49% of theoretical yield).

LC-MS (method 3): Rt=3.40 min; MS (ESIpos): m/z=632 [M+H] ⁺ .

Example 92.

4-{[(2S,4S)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino [2,1-c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (single stereoisomer)

Separation of diastereomers 37 mg 4-{[(4S)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3 ]benzoxocino[2,1-c]pyridin-3-yl]-4-(difluoromethoxy)pentanoyl]amino}benzamide (a mixture of two diastereomers), Example 91, gave a single stereoisomer 1 (titled compound 92) (chiral HPLC: R _t =7.95 min, 97% de): 9.0 mg (10% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =10.31 min): 22.0 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 80% nheptane/20% ethanol; temperature: RT; flow rate: 15 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx4.6 mm; eluent: 80% isohexane/20% ethanol; temperature: 50°C, flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 1): R=1.04 min; MS (ESIpos): m/z=632 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.73/10.56 (2s, 1H), 8.08/8.04 (2s, 1H), 7.92-7.79 (m, 3H), 7.74-7.60 (m , 3H), 7.35-7.27 (m, 1H), 7.27-7.18 (m, 1H), 6.80-6.77/6.66-6.60 (2m, 1H), 6.56-6.47 (m, 1H), 5.85/5.77 (dd, 1H), 4.78-4.67 (m, 1H), 4.30-4.13 (m, 1H), 3.85-3.71 (m, 1H), 3.14-2.90 (m, 2H), 2.68-2.53 (m, 1H), 2.48- 2.33 (m, 2H), 1.38-1.09 (m, 3H). Additional minor rotamer signals were also detected.

Example 93.

4-({(4R)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino[2 ,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (mixture of two diastereomers)

(2ξ)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-D-glyceropentonic acid (mixture of two diastereomers) (90.0 mg, 188 µmol, 1.0 eq.) was dissolved in dichloromethane (5.0 ml) ,1-chloro-N,N,2-trimethylprop-1ene-1-amine (32 µl, 240 µmol, 1.3 eq.) was added and the reaction mixture was stirred for 10 min. 4-Aminobenzamide (33.3 mg, 245 µmol, 1.3 eq) was then added and the reaction mixture was stirred overnight. All volatile compounds were removed under reduced pressure and the general method 11 was carried out on the residue using T3P (170 µl, 50% solution in ethyl acetate, 280 µmol, 1.5 eq.), pyridine (18 µl, 226 µmol, 1.2 eq.) in tetrahydrofuran (4.0 ml). The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 5:95). Yield: 58.0 mg (49% of theoretical yield).

LC-MS (method 3): R _t =3.24 min; MS (ESIpos): m/z=596 [M+H] ⁺ .

Example 94.

4-({(2S,4R)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H[3]benzoxocino [2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (single stereoisomer)

Separation of diastereomers 52 mg 4-({(4R)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)

2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (a mixture of two diastereomers), Example 93, gave a single stereoisomer 1 (title compound 94) (chiral HPLC: R _t =3.39 min, >99% de): 13.1 mg (12% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =6.91 min): 15.9 mg.

Separation method: HPLC: column: Daicel OZ 5 µm, 250 mmx20 mm; eluent: 50% n-heptane/50% 2propanol; temperature: RT; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralpak OX-3 3 µm, 50 mmx4.6 mm; eluent: 80% nheptane/20% ethanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 5): R=1.30 min; MS (ESIneg): m/z=594 [M-N] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.72/10.62 (2s, 1H), 8.08/8.07 (2s, 1H), 7.90-7.81 (m, 3H), 7.73-7.60 (m , 3H), 7.31 (d, 1H), 7.27-7.20 (m, 1H), 6.53/6.47 (2d, 1H), 5.86/5.80 (2dd, 1H), 4.80-4.67 (m, 1H), 3.77 (t , 1H), 3.20-3.04 (m, 6H), 2.62-2.55 (m, 1H), 2.38-2.19 (m, 2H), 1.20-1.08 (m, 3H). Additional minor rotamer signals were also detected.

Example 95.

4-({(2S,4S)-2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H- 129 044932

[3]benzoxocino[2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (single stereoisomer)

O^Siz

C.I.

General method 11 was carried out with (2ξ)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8tetrahydro-3H-[3]benzoxocino[2 ,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers) (139 mg, 290 µmol, 1.0 eq.), 4 -aminobenzamide (51.3 mg, 377 µmol, 1.3 eq.), T3P (259 µl, 50% solution in ethyl acetate, 435 µmol, 1.5 eq.) and pyridine (28 µl, 350 µmol, 1.2 eq.) in tetrahydrofuran (8.0 ml ) at room temperature, including the following variations of the procedure: after 3 h, additional amounts of 4-aminobenzamide (11.8 mg, 87 μmol, 0.3 eq.), pyridine (8.2 μl, 102 μmol, 0.35 eq.) and T3P (48 μl, 50 % solution in ethyl acetate, 81 µmol, 0.28 eq.) was added and stirring was continued overnight. The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95).

Separation of diastereomers 13 mg 4-({(4S)-2-[(7R)-11-chloro-12-fluoro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3 ]benzoxocino[2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (a mixture of two diastereomers) gave a single stereoisomer 1 (titled compound 95) (chiral HPLC: R _t =5.81 min, 99 % de): 5.2 mg (3% of theoretical yield), single stereoisomer 2 (chiral HPLC: R _t =8.47 min): 1.6 mg.

Separation method: HPLC: column: Daicel Chiralpak ID 5 µm, 250 mmx20 mm; eluent: 80% nheptane/20% ethanol; temperature: 40°C; flow rate: 25 ml/min; UV detection: 265 nm.

Method of analysis: HPLC: column: Daicel Chiraltek ID 3 µm, 250 mmx4.6 mm; eluent: 80% nheptane/20% ethanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 3): R=1.29 min; MS (ESIneg): m/z=594 [M-N] ^- .

¹ H-NMR (500 MHz, CDCl3): δ [ppm]=9.75/9.63 (2br s, 1H), 7.80 (br d, 2H), 7.74-7.67 (m, 2H), 7.60/7.59 (2s, 1H ), 7.48-7.41 (m, 1H), 7.08 (d, 1H), 6.66 (d, 1H), 5.93 (br dd, 1H), 6.20-5.58 (m, 2H), 4.75 (dd, 1H), 3.78 (t, 1H), 3.53-3.43 (m, 1H), 3.37-3.27 (m, 3H), 3.06 (br d, 1H), 2.79-2.68 (m, 1H), 2.65-2.53 (m, 2H), 1.97-1.89 (m, 1H), 1.27 (d, 3H). Additional minor rotamer signals were also detected.

Alternatively, general method 7 was carried out with (7R)-11-chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro3H-[3]benzoxocino[2,1-c]pyridin-2(6H)-one (single stereoisomer) (43.0 mg, 124 µmol, 1.0 eq.), 4-{[(2R,4S)-2-bromo-4-methoxypentanoyl]amino}benzamide (single stereoisomer) (44.9 mg, 124 µmol, 1.0 eq. .) and 1,1,3,3-tetramethylguanidine (47 µl, 371 µmol, 3.0 eq.) in 2propanol/acetone (4:1, 2.0 ml), including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 42.0 mg (57% of theoretical yield).

LC-MS (method 1): R _t =0.98 min; MS (ESIpos): m/z=596 [M+H]+.

¹ H-NMR (500 MHz, CDCl ₃ ): δ [ppm]=9.77 (br s, 1H), 7.80 (br d, 2H), 7.74-7.67 (m, 2H), 7.61 (s, 1H), 7.48 -7.41 (m, 1H), 7.08 (d, 1H), 6.66 (d, 1H), 5.93 (br dd, 1H), 6.20-5.63 (m, 2H), 4.75 (dd, 1H), 3.78 (t, 1H), 3.53-3.44 (m, 1H), 3.37-3.27 (m, 3H), 3.06 (br d, 1H), 2.80-2.68 (m, 1H), 2.65-2.53 (m, 2H), 1.97-1.89 (m, 1H), 1.27 (d, 3H). Additional minor rotamer signals were also detected.

Example 96.

4-({(2S,4R)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-5,5,5-trifluoro-4-methoxypentanoyl}amino)benzamide (single stereoisomer)

C.I.

General Method 7 was performed with (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (15.0 mg, 45.5 µmol, 1.0 eq.), 4-{[(2R,4R)-2-6pom5,5,5-trifluoro-4-methoxypentanoyl]amino}benzamide (single stereoisomer) (20.9 mg, 54.6 µmol, 1.2 eq. .) and 1,1,3,3-tetramethylguanidine (17 µl, 140 µmol, 3.0 eq.) in 2propanol/acetone (4:1, 0.8 ml), including the following variations of the procedure: The crude mixture was purified

- 130 044932 by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). By epimerization a mixture of stereoisomers (d.r. 3.6:1) was obtained.

Yield: 16.0 mg (55% of theoretical yield).

LC-MS (method 3): R _t =3.62/3.67 min; MS (ESIpos): m/z=632 [M+H]+ Separation of stereoisomers of 16.0 mg of this epimerized mixture provides: single stereoisomer 1 (chiral HPLC: R _t =1.25 min): 2.5 mg, single stereoisomer 2 (the title compound 96) (chiral HPLC: R _t =2.59 min, 99% de): 6.5 mg (23% of theoretical yield).

Separation method: HPLC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 50% nheptane/50% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 210 nm.

Method of analysis: HPLC: column: Daicel Chiralpak ID-3 3 µm, 50 mmx4.6 mm; eluent: 50% nheptane/50% ethanol; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 3): R _t =3.51; MS (ESIpos): m/z=632 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.69/10.48 (2br s, 1H), 8.00 (br s, 1H), 7.93-7.81 (m, 3H), 7.69 (br d , 2H), 7.58-7.44 (m, 1H), 7.44-7.33 (m, 2H), 7.26 (br s, 1H), 6.45/6.40 (2br s, 1H), 5.90/5.76 (2br s, 1H), 4.79-4.65 (m, 1H), 4.13-3.92 (m, 1H), 3.86-3.71 (m, 1H), 3.40 (s, 3H), 3.06 (br d, 2H), 2.69-2.54 (m, 2H) , 2.382.16 (m, 1H). Additional minor rotamer signals were also detected.

Example 97.

4-({(2S,4R)-2-[(7R)-11 -Chloro-7-methyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1 - c]pyridin3-yl]-5,5-difluoro-4-methoxypentanoyl}amino)benzamide (sole stereoisomer) to O ^ΝΗη ⁰

C.I.

1,1,3,3-Tetramethylguanidine (19 μL, 0.15 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-methyl-7,8-dihydro-3H-[ 3]benzoxocino[2,1-c]pyridin2(6H)-one (single stereoisomer) (14 mg, 0.05 mmol) in 2-propanol/acetone (4:1, 0.5 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4-{[(2R,4R)2-bromo-5,5-difluoro-4-methoxypentanoyl]amino}benzamide (single stereoisomer) (21 mg, 0.06 mmol, 1.1 eq.) and another 2-propanol/acetone (4:1, 0.5 ml). The reaction mixture was stirred at room temperature for 7 days and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 22 mg (79% of theoretical yield).

LC-MS (method 4): R _t =1.86 min; MS (ESIpos): m/z=560 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=10.84-10.46 (br s, 1H), 7.90-7.77 (m, 4H), 7.73-7.66 (m, 2H), 7.48-7.38 (m, 2H), 7.37-7.28 (m, 1H), 7.23 (br s, 1H), 6.43-6.34 (m, 1H), 6.25-6.00 (m, 1H), 5.91-5.76 (m, 1H), 4.52-4.45/4.32-4.24/3.91-3.81/3.59-3.47 (4m, 2H), 3.33 (s, 3H), 2.89-2.82/2.75-2.64 (2m, 2H), 2.47-2.15 (m, 2H), 2.14-1.96 (m, 2H), 0.95-0.83 (m, 3H). Additional minor rotamer signals were also detected.

Example 98.

4-({(2S,4R)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-5,5-difluoro-4-methoxypentanoyl} amino)benzamide (single stereoisomer)

1,1,3,3-Tetramethylguanidine (30 μL, 0.24 mmol, 3.0 equiv.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (26 mg, 0.08 mmol) in 2-propanol/acetone (4:1, 1.0 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R,4R)-2-bromo-5,5-difluoro-4-methoxypentanoyl]amino} benzamide (single stereoisomer) (33 mg, 0.09 mmol, 1.1 eq.) and more 2-propanol/acetone (4:1, 1.0 ml). The reaction mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Exit:

- 131 044932 mg (73% of theoretical yield).

LC-MS (method 1): Rt=1.00 min; MS (ESIpos): m/z=614 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.89-10.38 (m, 1H), 8.07-7.92 (m, 1H), 7.91-7.80 (m, 3H), 7.73-7.65 ( m, 2H), 7.56-7.32 (m, 3H), 7.25 (br s, 1H), 6.50-6.36 (m, 1H), 6.26-6.00 (m, 1H), 5.92-5.71 (m, 1H), 4.80 -4.64/4.11-3.97/3.92-3.84/3.82-3.72/3.64-3.49/3.3-3.18 (6m, 3H, partially hidden), 3.33 (s, 3H), 3.142.98 (m, 2H), 2.84-2.74 /2.65-2.55 (2m, 1H), 2.5-2.40/2.38-2.26/2.22-2.08 (3m, 2H, partially hidden). Additional minor rotamer signals were also detected.

Example 99.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]propanoyl} amino)-2-fluorobenzamide (single stereoisomer)

C.I.

1,1,3,3-Tetramethylguanidine (22 μL, 0.18 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (20 mg, 0.06 mmol) in 2-propanol/acetone (4:1, 1.0 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R)-2-bromopropanoyl]amino}-2-fluorobenzamide (single stereoisomer) (19 mg, 0.07 mmol, 1.1 eq) and more 2-propanol /acetone (4:1, 1.0 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 27 mg (85% of theoretical yield).

LC-MS (method 4): Rt=1.82 min; MS (ESIpos): m/z=538 [M+H] ⁺ .

'H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.92-10.36 (br s, 1H), 7.97-7.88 (m, 1H), 7.73-7.66 (m, 1H), 7.66-7.60 ( m, 1H), 7.56-7.32 (m, 6H), 6.45-6.32 (m, 1H), 5.57-5.47 (m, 1H), 4.78-4.64 (m, 1H), 4.15-4.05/3.983.77 (2m , 1H), 3.13-2.95 (m, 2H), 2.84-2.73/2.60-2.5 (2m, 1H, partially hidden), 1.75-1.64 (m, 3H). Additional minor rotamer signals were also detected.

Example 100.

4-({(2S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1с] pyridin-3-yl]propanoyl} amino)benzamide (single stereoisomer)

1,1,3,3-Tetramethylguanidine (23 μL, 0.18 mmol, 3.0 eq.) was added under argon at room temperature to a solution of (7R)-11-chloro-7-(trifluoromethyl)-7,8-dihydro-3H -[3]benzoxocino[2,1c]pyridin-2(6H)-one (single stereoisomer) (20 mg, 0.06 mmol) in 2-propanol/acetone (4:1, 1.0 ml). The mixture was stirred at room temperature for 15 min, followed by the addition of 4{[(2R)-2-bromopropanoyl]amino}benzamide (single stereoisomer) (18 mg, 0.07 mmol, 1.1 eq.) and more 2-propanol/acetone ( 4:1, 1.0 ml). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 21 mg (68% of theoretical yield).

LC-MS (method 4): Rt=1.75 min; MS (ESIpos): m/z=520 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.64-10.54 (m, 1H), 7.97-7.90 (m, 1H), 7.90-7.82 (m, 3H), 7.67 (d, 2H), 7.57-7.38 (m, 3H), 7.24 (br s, 1H), 6.44-6.35 (m, 1H), 5.61-5.52 (m, 1H), 4.80-4.64/4.16-4.04/3.88-3.76 ( 3m, 2H), 3.14-2.99 (m, 2H), 2.84-2.74/2.64-2.5 (2m, 1H, partially hidden), 1.75-1.64 (m, 3H). Additional minor rotamer signals were also detected.

Example 101.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin- 3-yl]-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl)-pentanamide (mixture two diastereomers)

- 132 044932

7-Amino-2-methyl[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (25 mg, 0.12 mmol, 1.1 eq.), pyridine (27 μl, 0.34 mmol , 3.0 equiv.) and T3P (98 μl, 50% solution in ethyl acetate, 0.17 mmol, 1.5 equiv.) were added under argon at room temperature to a solution of (2ξ)-2-[(7R)-11-chloro-2- oxo-7(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methylL -glycero-pentonic acid (mixture of two diastereomers) (55 mg, 93% purity, 0.11 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 45 minutes and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 59 mg (87% of theoretical yield).

LC-MS (method 1): R _t =0.99 min; MS (ESIpos): m/z=606 [M+H]+.

1H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.83-10.66 (m, 1H), 8.06-7.96 (m, 1H), 7.86-7.80 (m, 1H), 7.64-7.59 (m, 1H), 7.56-7.32 (m, 3H), 6.75-6.65 (m, 1H), 6.45-6.35 (m, 1H), 5.82-5.67 (m, 1H), 4.78-4.66 (m, 1H), 4.08- 3.74 (m, 1H), 3.48/3.48 (2s, 3H), 3.3-3.30 (m, 3H, partially hidden), 3.18/3.11 (2s, 3H), 2.842.71/2.60-2.5 (2m, 1H, partially hidden hidden), 2.41-2.17 (m, 2H), 1.18-1.10 (m, 3H). Additional minor rotamer signals were also detected.

Example 102.

(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin- 3-yl]-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3-a]pyridin-7-yl)pentanamide (single stereoisomer )

Separation of diastereomers 56 mg (4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3H-[3]benzoxocino[2,1-c] pyridin-3-yl]-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro[1,2,4]triazolo[4,3a]pyridin-7-yl)pentanamide (a mixture of two diastereomers), example 101, gave a single stereoisomer 1 (titled compound example 102) (chiral HPLC: R _t =8.43 min, >99% de): 16 mg, single stereoisomer 2 (chiral HPLC: R _t =10.76 min, >99% de): 30 mg.

Separation method: HPLC: column: Daicel Chiralcel OX-H 5 µm, 250 mmx20 mm; eluent: 70% nheptane/30% ethanol; temperature: 40°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralcel OX-H 5 µm, 250 mmx4.6 mm; eluent: 70% isohexane/30% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.89-10.71 (m, 1H), 8.06-7.98 (m, 1H), 7.89-7.83 (m, 1H), 7.68-7.61 (m , 1H), 7.57-7.32 (m, 3H), 6.74-6.67 (m, 1H), 6.46-6.35 (m, 1H), 5.83-5.66 (m, 1H), 4.79-4.66 (m, 1H), 4.08 -3.98/3.83-3.74 (2m, 1H), 3.48 (s, 3H), 3.30-2.98 (m, 3H), 3.17 (s, 3H), 2.82-2.76/ 2.60-2.5 (2m, 1H, partially hidden) , 2.34-2.18 (m, 2H), 1.15 (d, 3H). Additional minor rotamer signals were also detected.

Example 103.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-N-([1,2,4]triazolo[4,3-a]pyridin-7-yl)pentanamide (mixture of two diastereomers)

[1,2,4]Triazolo[4,3-a]pyridin-7-amine hydrochloride (22 mg, 0.13 mmol, 1.1 eq.), pyridine (28 µl, 0.35 mmol, 3.0 eq.) and T3P (102 µl , 50% solution in ethyl acetate, 0.17 mmol, 1.5 eq.) was added to the atmosphere

- 133 044932 argon sphere at room temperature into a solution of (2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro-3H-[3]benzoxocino [2,1-c]pyridin-3-yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers) (57 mg, 94% purity, 0.12 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature overnight. Also [1,2,4]triazolo[4,3-a]pyridin-7-amine hydrochloride (10 mg, 0.06 mmol, 0.5 eq.), pyridine (9 μl, 0.12 mmol, 1.0 eq.) and T3P (102 µl, 50% solution in ethyl acetate, 0.17 mmol, 1.5 eq.) was added. The reaction mixture was stirred at room temperature for an additional 3 days and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 31 mg (46% of theoretical yield).

LC-MS (method 4): R _t =1.76 min; MS (ESIpos): m/z=576 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d6): δ [ppm]=10.95-10.77 (m, 1H), 9.14/9.14 (2s, 1H), 8.53-8.47 (m, 1H), 8.17-8.10 (m , 1H), 8.08-8.00 (m, 1I), 7.62-7.32 (m, 3H), 7.14-7.05 (m, 1I), 6.46-6.30 (m, 1H), 5.87-5.73 (m, 1H), 4.80 -4.60 (m, 1H), 4.10-3.76 (m, 1H), 3.3-2.95 (m, 3H, partially hidden), 3.19/3.11 (2s, 3H), 2.842.72/2.60-2.46 (2m, 1H, partially hidden), 2.43-2.20 (m, 2H), 1.20-1.11 (m, 3H). Additional minor rotamer signals were also detected.

Example 104.

(2S,4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3I-[3]benzoxocino[2,1c]pyridin- 3-yl]-4-methoxy-N-([1,2,4]triazolo[4,3-a]pyridin-7-yl)pentanamide (single stereoisomer)

C.I.

Separation of diastereomers 29 mg (4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro3I-[3]benzoxocino[2,1-c] pyridin-3-yl]-4-methoxy-N-([1,2,4]triazolo[4,3-a]pyridin-7-yl)pentanamide (a mixture of two diastereomers), example 103, gave a single stereoisomer 1 ( title compound example 104) (chiral HPLC: R _t =3.11 min, 96% de): 4 mg, single stereoisomer 2 (chiral HPLC: R _t =4.15 min, 97% de): 8 mg.

Separation method: HPLC: column: Daicel Chiralcel OZ-H 5 µm, 250 mmx20 mm; eluent: 80% nheptane/20% ethanol; temperature: 50°C; flow rate: 30 ml/min; UV detection: 220 nm.

Method of analysis: HPLC: column: Daicel Chiralcel OZ-H 3 µm, 50 mmx4.6 mm; eluent: 70% nheptane/30% ethanol; temperature: 40°C; flow rate: 1 ml/min; UV detection: 220 nm.

¹ I-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=11.23-11.00 (m, 1H), 9.33 (br s, 1H), 8.69-8.59 (m, 1H), 8.308.22 (m , 1H), 8.08-7.97 (m, 1H), 7.57-7.33 (m, 3H), 7.32-7.22 (m, 1H), 6.48-6.33 (m, 1H), 5.86-5.67 (m, 1H), 4.83 -4.63 (m, 1H), 4.15-3.76 (m, 1H), 3.3-2.90 (m, 3H, partially hidden), 3.18 (s, 3H), 2.86-2.74/2.61-2.5 (2m, 1H, partially hidden ), 2.31-2.21 (m, 2H), 1.17 (m, 3H). Additional minor rotamer signals were also detected.

Example 105.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-N-(3-methyl[1,2,4]triazolo[4,3-a]pyridin-7-yl)pentanamide (mixture of two diastereomers)

ci

N,N-Diisopropylethylamine (54 μl, 0.31 mmol, 3.5 equiv.) and a solution of HATU (51 mg, 0.13 mmol, 1.5 equiv.) in N,N-dimethylformamide (1 ml) were added under argon at room temperature to the solution ( 2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridine-3 -yl]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers) (44 mg, 93% purity, 0.09 mmol) and 3-methyl[1,2,4 ]triazolo[4,3-a]pyridin-7-amine hydrochloride (21 mg, 0.11 mmol, 1.2 eq.) in N,N-dimethylformamide (4 ml). The reaction mixture was stirred at room temperature for 4 days. Another 3-methyl[1,2,4]triazolo[4,3-a]pyridin-7-amine hydrochloride (10 mg, 0.05 mmol, 0.6 eq.), N,N-diisopropylethylamine (22 μl, 0.13 mmol, 1.4 eq.) and HATU (27 mg, 0.05

- 134 044932 mmol, 0.8 eq.) was added.

The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 11 mg (21% of theoretical yield).

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=10.92-10.72 (m, 1H), 8.30 (d, 1H), 8.10-7.98 (m, 2H), 7.57-7.32 (m, 3H ), 7.12-7.03 (m, 1H), 6.47-6.35 (m, 1H), 5.82-5.71 (m, 1H), 4.81-4.67 (m, 1H), 4.10-3.75 (m, 1H), 3.33.00 (m, 3H), 3.18/3.11 (2s, 3H), 2.85-2.73/2.65-2.5 (2m, 1H, partially hidden), 2.45-2.18 (m, 2H), 2.42/2.41 (2s, 3H), 1.21 -1.10 (m, 3H). Additional minor rotamer signals were also detected.

Example 106.

(4S)-2-[(7R)-11-Chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine-3- yl]-4-methoxy-N-([1,2,4]triazolo[4,3-a]pyridin-6-yl)pentanamide (mixture of two diastereomers)

^O'sn *

IF A ^CH =

ΎΓϊ ^ν ΥΊΓ ^ν

OU/M-N O

Cl

N,N-Diisopropylethylamine (30 μl, 0.17 mmol, 4.0 eq.) and a solution of HATU (20 mg, 0.05 mmol, 1.2 eq.) in N,N-dimethylformamide (1 ml) were added under argon at room temperature to the solution ( 2ξ)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridin-3-yl ]-2,3,5-trideoxy-4-O-methyl-L-glyceropentonic acid (mixture of two diastereomers) (20 mg, 0.04 mmol) and [1,2,4]triazolo[4,3-a] pyridin-6-amine hydrochloride (10 mg, 80% purity, 0.05 mmol, 1.1 eq.) in N,N-dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase, eluent: acetonitrile/water gradient). Yield: 14 mg (58% of theoretical yield).

LC-MS (method 1): Rt=0.93 min; MS (ESIpos): m/z=576 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.84-10.67 (m, 1H), 9.33-9.20 (m, 2H), 8.08-7.95 (m, 1H), 7.79 (d, 1H ), 7.57-7.33 (m, 4H), 6.47-6.35 (m, 1H), 5.89-5.75 (m, 1H), 4.81-4.66 (m, 1H), 4.12-3.71 (m, 1H), 3.32.98 (m, 3H, partially hidden), 3.19/3.12 (2s, 3H), 2.85-2.72/2.64-2.5 (2m, 1H, partially hidden), 2.432.17 (m, 2H), 1.21-1.10 (m, 3H ). Additional minor rotamer signals were also detected.

Example 107.

4-{2-[(7R)-11-Chloro-12-fluoro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1c]pyridine -3-yl]propanamido}benzamide (mixture of two diastereomers)

General Method 7 was carried out with (7R)-11-chloro-12-fluoro-7-(trifluoromethyl)-7,8-dihydro-3H[3]benzoxocino[2,1-c]pyridin-2(6H)-one ( single stereoisomer) (35.0 mg, 95% purity, 95.6 µmol, 1.0 eq.), 4-{[(2R)-2-bromopropanoyl]amino}benzamide (single stereoisomer) (31.1 mg, 115 µmol, 1.2 eq.), 1,1,3,3-tetramethylguanidine (36 µl, 290 µmol, 3.0 eq.) in isopropanol/acetone (4:1, 1.4 ml) overnight, including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase , eluent: water with 0.05% formic acid/acetonitrile 80:20 - 5:95). Yield: 41.0 mg (80% of theoretical yield, mixture of two diastereomers due to epimerization).

LC-MS (method 3): R _t =2.78 min; MS (ESIpos): m/z=538 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=10.65/10.58 (2s, 1H), 8.05/8.03 (2s, 1H), 7.90-7.81 (m, 3H), 7.71-7.60 (m , 3H), 7.35-7.28 (m, 1H), 7.24 (br s, 1H), 6.53/6.51 (2d, 1H), 5.62-5.52 (m, 1H), 4.77-4.65 (m, 1H), 3.93/ 3.81 (2dd, 1H), 3.17-2.98 (m, 2H), 2.67-2.56 (m, 1H), 1.73/1.71 (2d, 3H).

Example 108.

4-{[(2S,4S)-2-(11-Chloro-7-ethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1-c]pyridin- 3-yl)-4methoxypentanoyl]amino}benzamide (mixture of two diastereomers)

- 135 044932

General method 7 was performed with 11-chloro-7-ethyl-7,8-dihydro-3H-[3]benzoxocino[2,1-c]pyridin-2(6H)one (racemate) (47.0 mg, 66% purity, 107 µmol, 1.0 eq.), 4-{[(2R,4S)-2-6pom-4methoxypentanoyl]amino}benzamide (single stereoisomer) (32.5 mg, 98.9 µmol, 1.2 eq.), 1,1,3,3 -tetramethylguanidine (40 µl, 320 µmol, 3.0 eq.) in isopropanol/acetone (4:1, 1.6 ml) overnight, including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 37.0 mg (64% of theoretical yield).

LC-MS (method 1): R _t =1.01 min; MS (ESIpos): m/z=538 [M+H]+.

Example 109.

4-({(2S,4S)-2-[(7R)-11-Chloro-7-ethyl-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2,1- c]pyridin-3yl]-4-methoxypentanoyl} amino)benzamide (single stereoisomer)

Separation of stereoisomers 37 mg 4-{[(2S,4S)-2-(11-chloro-7-ethyl-2-oxo-2,6,7,8-tetrahydro-3H[3]benzoxocino[2,1-c ]pyridin-3-yl)-4-methoxypentanoyl]amino}benzamide (mixture of two diastereomers), Example 108, provides: single stereoisomer 1 (chiral HPLC: Rt=2.89 min): 7.5 mg, single stereoisomer 2 (titled compound example 109) (chiral HPLC: R _t =3.90 min): 6.0 mg (10% of theoretical yield, 99% de).

Separation method: column: Daicel Chiralpak IC 3 µm, 50 mmx4.6 mm; eluent: 50% n-heptane/50% ethanol; temperature: 30°C; flow rate: 10 ml/min; UV detection: 220 nm.

Method of analysis: column: Daicel Chiralpak IC 3 µm, 50 mmx4.6 mm; eluent: 50% n-heptane/50% ethanol; temperature: 30°C; flow rate: 10 ml/min; UV detection: 220 nm.

LC-MS (method 1): Rt=1.01 min; MS (ESIpos): m/z=538 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.69/ 10.65 (2s, 1H), 7.90-7.80 (m, 4H), 7.70 (d, 2H), 7.46 (d, 1H), 7.40-7.30 (m, 2H), 7.25 (br s, 1H), 6.38/6.33 (s, 1H), 5.80 (dd, 1H), 4.53 (dd, 1H), 4.37-4.30 /3.48-3.35 (2m, 1H), 3.28-3.19 (m, 1H), 3.17 (s, 3H), 2.75 (d, 1H), 2.30-2.12 (m, 3H), 1.84-1.67 (m, 1H), 1.35-1.21 (m, 2H), 1.16 (d, 3H), 1.06/0.98 (2t, 3H).

Example 110.

4-({(4S)-2-[(7R)-11,12-Dichloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (mixture of stereoisomers)

General method 7 was carried out with (7R)-11,12-dichloro-7-(trifluoromethyl)-7,8-dihydro-3H

[3]benzoxocino[2,1-c]pyridin-2(6H)-one (single stereoisomer) (20.0 mg, 54.9 µmol, 1.0 eq.), 4-{[(2R,4S)-2-bromo-4 -methoxypentanoyl]amino}benzamide (single stereoisomer) (21.7 mg, 65.9 µmol, 1.2 eq.), 1,1,3,3-tetramethylguanidine (21 µl, 160 µmol, 3.0 eq.) in an isopropanol/acetone mixture (4: 1, 0.8 ml) overnight, including the following variations of the procedure: The crude mixture was purified by preparative HPLC (reverse phase, eluent: water with 0.05% formic acid/acetonitrile 90:10 - 5:95). Yield: 37.0 mg (64% of theoretical yield).

LC-MS (method 3): Rt=3.26/3.33 min; MS (ESIpos): m/z=612 [M+H]+.

Example 111.

4-({(2S,4S)-2-[(7R)-11,12-dichloro-2-oxo-7-(trifluoromethyl)-2,6,7,8-tetrahydro-3H- 136 044932

[3]benzoxocino[2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (single stereoisomer)

Separation of stereoisomers 22.9 mg 2,1-c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (mixture of stereoisomers), example 110, provides: single stereoisomer 1 (title compound example 111) (chiral HPLC: R _t =1.99 min ): 3.7 mg (11% of theoretical yield, 99% de), single stereoisomer 2 (chiral HPLC: R _t =2.96 min): 1.8 mg.

Separation method: column: Daicel Chiralpak IB 5 µm, 250 mmx20 mm; eluent: 80% n-heptane/20% ethanol; temperature: 30°C; flow rate: 20 ml/min; UV detection: 220 nm.

Method of analysis: column: Daicel Chiralpak IB 3 µm, 50 mmx4.6 mm; eluent: 80% n-heptane/20% ethanol; temperature: 30°C; flow rate: 1.0 ml/min; UV detection: 220 nm.

LC-MS (method 3): R _t =3.33 min; MS (ESIpos): m/z=612 [M+H]+.

¹ H-NMR (500 MHz, DMSO-d6): δ [ppm]=10.62 (s, 1H), 8.11 (s, 1H), 7.89-7.81 (m, 3H), 7.75-7.67 (m, 3H), 7.43 (d, 1H), 7.25 (br s, 1H), 6.48 (s, 1H), 5.83 (s, 1H), 4.78-4.65 (m, 1H), 3.76 (s, 1H), 3.29-3.24 (m , 1H), 3.16 (s, 3H), 3.13-3.00 (m, 2H), 2.63-2.54 (m, 1H), 2.28-2.19 (m, 2H), 1.15 (d, 3H).

Example 112.

4-({(2S,4S)-2-[(7R)-11-Chloro-7-(difluoromethyl)-2-oxo-2,6,7,8-tetrahydro-3H-[3]benzoxocino[2, 1c]pyridin-3-yl]-4-methoxypentanoyl}amino)benzamide (sole stereoisomer)

ci

General Method 7 was performed with 11-chloro-7-(difluoromethyl)-7,8-dihydro-3H-[3]benzoxocino[2,1c]pyridin-2(6H)-one (racemate) (550 mg, 1.76 mmol) , 4-{[(2R,4S)-2-6pom-4methoxypentanoyl]amino}benzamide (single stereoisomer) (987 mg, 3.0 mmol, 1.7 eq.) and 1,1,3,3-tetramethylguanidine (0.66 ml, 5.29 mmol, 3.0 eq.) in a mixture of 2-propanol/acetone (4:1, 20 ml) for 16 h, including the following variations of the procedure: The crude mixture was treated with acetic acid (0.3 ml, 5.29 mmol, 3.0 eq.), concentrated at under reduced pressure to 1/3 of the initial volume, treated with 0.02 N aqueous hydrochloric acid (43 ml) and stirred for 0.5 h. The resulting precipitate was filtered, washed with water and dried.

Resolution of diastereomers of 1.32 g of crude product gave: single stereoisomer 1 (title compound Example 112) (chiral SFC: R _t =4.53 min, >99% de): 309 mg (88% purity, 22% of theoretical yield), single stereoisomer 2 (chiral SFC: R _t =7.21 min, >99% de): 246 mg (19% of theoretical yield).

Separation method: SFC: column: Daicel Chiralpak IE 5 µm, 250 mmx20 mm; eluent: 58% carbon dioxide/42% ethanol; temperature: 40°C; flow rate: 85 ml/min; UV detection: 210 nm.

Method of analysis: SFC: column: Daicel Chiralpak IE 3 µm, 100 mmx4.6 mm; eluent: 70% carbon dioxide/30% ethanol; temperature: 40°C; flow rate: 3 ml/min; UV detection: 210 nm.

LC-MS (method 4): Rt=1.76 min; MS (ESIpos): m/z=560 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=10.70/10.65 (2s, 1H), 7.97 (s, 1H), 7.85 (br d, 3H), 7.70 (br d, 2H), 7.53-7.44 (m, 1H), 7.44-7.31 (m, 2H), 7.25 (br s, 1H), 6.40/6.39 (2s, 1H), 6.34-6.06 (m, 1H), 5.86-5.75 (m, 1H), 4.76-4.58 (2m, 1H), 3.72 (t, 1H), 3.28-3.19 (m, 2H), 3.17 (s, 3H), 2.96 (d, 1H), 2.43-2.34 (m, 1H) , 2.292.15 (m, 2H), 1.15 (br d, 3H). Additional minor rotamer signals were also detected.

B. Assessment of physiological effectiveness.

The usefulness of the compounds of the present invention for the treatment of thromboembolic disorders can be demonstrated using the following assay systems:

A. Descriptions of tests (in vitro).

A. 1. Measurement of FXIa inhibition.

The factor XIa inhibition of the substances of the present invention is determined using a biochemical test system that uses the reaction of a factor XIa peptide substrate to determine the enzymatic activity of human factor XIa. Here, factor XIa cleaves the C-terminal aminomethylcoumarin (AMC) from the factor XIa peptide substrate, the fluorescence of which is measured. Determinations are carried out on microtiter plates.

Test substances were dissolved in dimethyl sulfoxide and serially diluted with dimethyl sulfoxide (3000 μM to 0.0078 μM; final test concentrations: 50 μM to 0.00013 μM). In each case, 1 μl of diluted solutions of substances was added to the wells of white Greiner microtiter plates (384 wells). 20 µl assay buffer (50 mM Tris/HCl pH 7.4; 100 mM sodium chloride solution; 5 mM calcium chloride solution; 0.1% bovine serum albumin) and 20 µl factor XIa from Kordia (0.45 nM in assay buffer ) were then added sequentially. After 15 min of incubation, the enzyme reaction was started by adding 20 µl of factor XIa substrate Boc-Glu(OBzl)-Ala-Arg-AMC dissolved in assay buffer (10 µM in assay buffer) from Bachem, the mixture was incubated at room temperature (22°C) for 30 min and then fluorescence was measured (excitation: 360 nm, emission: 460 nm). Measured emissions from test lots with the test substance were compared with emissions from control lots without the test substance (dimethyl sulfoxide only instead of the test substance in dimethyl sulfoxide), and IC ₅₀ values were calculated from concentration/activity ratios. The activity data obtained from this test are listed in Table. Below (some as averages of several independent individual determinations):

_______________________________________Table A

Example No. 1C ₅₀ [nM] Example No. 1C ₅₀ [nM] 1 36 2 25 3 And 4 66 5 3.5 6 2.0 7 2.3 8 0.8 9 4.5 10 1.4 AND 2.8 12 3.4 13 6.2 14 14 15 50 16 AND 17 13 18 3.4 19 3.0 20 1.7 21 81 22 44 23 480 24 81 25 10 26 6.9 27 44 28 15 29 13 thirty 5.9 31 1.2 32 1.8 33 20 34 7.6 35 55 36 20 37 42 38 32 39 100 40 38

- 138 044932

41 14 42 9.8 43 5.8 44 1.8 45 19 46 3.8 47 6.8 48 1.3 49 17 50 5.5 51 10 52 3.5 53 25 54 5.6 55 26 56 8.5 57 45 58 13 59 6.2 60 10 61 4.7 62 5.9 63 0.9 64 100 65 13 66 4.1 67 2.8 68 34 69 25 70 13 71 28 72 6.6 73 31 74 8.1 75 4.4 76 2.7 77 5.4 78 2.7 79 6.5 80 3.0 81 AND 82 7.4 83 4.9 84 8.9 85 5.4 86 6.5 87 3.1 88 8.3 89 8.9 90 3.0 91 15 92 4.5 93 9.1 94 4.7 95 1.7 96 2.5 97 3.2 98 1.8 99 13 100 4.7 101 42 102 AND 103 15 104 14 105 14 106 17 107 6.2 108 7.4 109 5.4 110 21 111 19 112 1.5

a.2. Determination of selectivity.

To demonstrate the selectivity of the substances for FXIa inhibition, test substances were tested for their potential to inhibit other human serine proteases such as factor Xa, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol/l from Kordia), trypsin (83 mU/ml from Sigma) and plasmin (0.1 μg/ml from Kordia), these enzymes were dissolved (50 mmol/l Tris buffer [ C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/L NaCl, 0.1% BSA [bovine serum albumin], 5 mmol/L calcium chloride, pH 7.4) and incubated for 15 min with the test substance at various concentrations in dimethyl sulfoxide, as well as with dimethyl sulfoxide without the test substance. The enzymatic reaction was then started by adding the appropriate substrates (5 μmol/L Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin, 50

- 139 044932 µmol/l MeOSuc-Ala-Phe-Lys-AMC from Bachem for plasmin). After 30 min of incubation at 22°C, fluorescence was measured (excitation: 360 nm, emission: 460 nm). The measured emissions of test mixtures with the test substance were compared with the emissions of control mixtures without the test substance (dimethyl sulfoxide only instead of the test substance in dimethyl sulfoxide), and IC ₅₀ values were calculated from concentration/activity ratios.

a.3. Analysis of thrombin formation (thrombogram).

The effect of test substances in the Hemker thrombin generation assay was determined in vitro in human plasma (Octaplas® from Octapharma).

In the Hemker thrombin generation assay, plasma thrombin activity was determined by measuring the fluorescent degradation products of substrate 1-1140 (Z-Gly-Gly-Arg-AMC, Bachem). Reactions were carried out in the presence of various concentrations of the test substance or the appropriate solvent. To start the reaction, reagents from Thrombinoscope were used (recombinant tissue factor 30 to 0.1 pM, phospholipids 24 μM in HEPES). In addition, the thrombin calibrator from Thrombinoscope, whose amidolytic activity is required to calculate thrombin activity in a sample containing an unknown amount of thrombin, was used. The test was performed according to the manufacturer's instructions (Thrombinoscope BV): 4 μl of test substance or diluent, 76 μl of plasma and 20 μl of PPP reagent or thrombin calibrator were incubated at 37°C for 5 min. After adding 20 μL of 2.5 mM thrombin substrate to 20 mM Hepes, 60 mg/mL BSA, 102 mM calcium chloride, thrombin production was measured every 20 s for a period of 120 min. The measurement was carried out using a fluorometer (Fluoroskan Ascent) from Thermo Electron, equipped with a pair of 390/460 nm filters and a dispenser.

Using the Thrombinoscope software, the thrombogram is calculated and displayed graphically. The following parameters are calculated: time lag, time to peak, peak, ETP (endogenous thrombin potential) and initial tail.

a.4. Determination of anticoagulant activity.

The anticoagulant activity of the test substances was determined in vitro in human plasma and rat plasma. Fresh whole blood was collected directly at a sodium citrate/blood ratio of 1:9 using 0.11 molar sodium citrate as a receiver. Immediately after blood collection, it was thoroughly mixed and centrifuged at about 4000 g for 15 minutes. The supernatant was collected as platelet-poor plasma.

Prothrombin time (PT, synonyms: thromboplastin time, rapid test) was determined in the presence of various concentrations of the test substance or the corresponding solvent using a commercial test kit (Neoplastin® from Boehringer Mannheim or Nemolyapse® RecombiPlastin from Instrumentation Laboratory). Test compounds were incubated with plasma at 37°C for 3 min. Coagulation was then initiated by adding thromboplastin and the time point at which the sample coagulated was determined. The concentration of the test substance, which doubles the prothrombin time, was determined.

Activated partial thromboplastin time (ARTT) was determined in the presence of various concentrations of the test substance or the corresponding solvent using a commercial test kit (PTT reagent from Roche). Test compounds were incubated with plasma and PTT reagent at 37°C for 3 min. Coagulation was then started by adding 25 mM calcium chloride and the time at which coagulation occurred was determined. The concentration of the test substance that increases or doubles ARTT was determined.

a.5. Determination of activity against plasma kallikrein.

To determine the inhibition of plasma kallikrein by the substances of the present invention, a biochemical test system was used that uses the reaction of a plasma kallikrein peptide substrate to determine the enzymatic activity of human plasma kallikrein. Here, plasma kallikrein cleaves the C-terminal aminomethylcoumarin (AMC) from the plasma kallikrein peptide substrate, the fluorescence of which is measured. Determinations are carried out on microtiter plates.

Test substances were dissolved in dimethyl sulfoxide and serially diluted with dimethyl sulfoxide (3000 to 0.0078 μM; final test concentrations: 50 μM to 0.00013 μM). In each case, 1 μl of diluted solutions of substances was added to the wells of white Greiner microtiter plates (384 wells). 20 µl assay buffer (50 mM Tris/HCl pH 7.4; 100 mM sodium chloride solution; 5 mM calcium chloride solution; 0.1% bovine serum albumin) and 20 µl plasma kallikrein from Kordia (0.6 nM in assay buffer ) were then added sequentially. After 15 min of incubation, the enzyme reaction was started by adding 20 µl of H-Pro-Phe-ArgAMC substrate dissolved in assay buffer (10 µM in assay buffer) from Bachem, the mixture was incubated at room temperature (22°C) for 30 min and then measured fluorescence (excitation: 360 nm, emission: 460 nm). Measured emissions from test lots with the test substance were compared with emissions from control lots without the test substance (dimethyl sulfoxide only

- 140 044932 instead of the test substance in dimethyl sulfoxide), and IC50 values were calculated from concentration/activity ratios. The activity data obtained from this test are listed in Table. Below (some as averages of several independent individual determinations):

Table B

Example No. 1C ₅₀ [nM] Example No. 1C ₅₀ [nM] 1 760 2 440 3 250 4 190 5 200 6 170 7 150 8 51 9 330 10 110 eleven 120 12 210 13 93 14 180 15 850 16 210 17 460 18 130 19 BY 20 60 21 8700 22 1500 23 >10000 24 3900 25 2000 26 1300 27 540 28 170

- 141 044932

29 190 thirty 91 31 47 32 40 33 660 34 280 35 300 36 380 37 510 38 780 39 >10000 40 950 41 520 42 340 43 340 44 170 45 890 46 220 47 430 48 120 49 330 50 130 51 160 52 59 53 370 54 110 55 250 56 130 57 250 58 89 59 630 60 230 61 160 62 150 63 35 64 850 65 180 66 190 67 130 68 550 69 430 70 310 71 390 72 110 73 520 74 190 75 120 76 95 77 210 78 140 79 130 80 65 81 330 82 310 83 190 84 180 85 150 86 250 87 160 88 460 89 380 90 130 91 190 92 71

- 142 044932

93 200 94 110 95 44 96 220 97 110 98 110 99 480 100 190 101 430 102 130 103 190 104 170 105 720 106 490 107 200 108 660 109 350 110 1000 111 870 112 98

b. Determination of antithrombotic activity (in vivo).

b.1. A model of arterial thrombosis (ferric chloride-induced thrombosis) in combination with ear bleeding time in rabbits.

The antithrombotic activity of FXIa inhibitors was tested in a model of arterial thrombosis. Here, blood clot formation was triggered by causing chemical damage to the carotid artery area in rabbits. At the same time, the time of ear bleeding was determined.

Male rabbits (Crl: KBL (NZW) BR, Charles River), fed a normal diet and weighing 2.2-2.5 kg, were anesthetized by intramuscular injection of xylazine and ketamine (Rompun, Bayer, 5 mg/kg and Ketavet, Pharmacia & Upjohn GmbH, 40 mg/kg body weight). Anesthesia was maintained with intravenous administration of the same drugs (continuous infusion) through the right atrial vein.

The right carotid artery was exposed and vessel injury was induced by wrapping a piece of filter paper (10 mm x 10 mm) on a strip of Parafilm® (25 mm x 12 mm) around the carotid artery without disrupting blood flow.

The filter paper contains 100 μl of a 13% solution of ferric chloride (Sigma) in water. After 5 minutes, the filter paper was removed and the vessel was washed twice with an aqueous solution of sodium chloride with a concentration of 0.9%. Thirty minutes after injury, the injured portion of the carotid artery was surgically removed, and any thrombotic material was removed and weighed.

Test substances were administered either intravenously to anesthetized animals via the femoral vein or orally to awake animals via gastric tube, in each case 5 min and 2 h, respectively, before injury.

The time of ear bleeding was determined 2 minutes after injury to the carotid artery. To do this, the left ear was shaved and a 3 mm long incision was made (blade, article number 10-150-10, Martin, Tuttlingen, Germany) parallel to the longitudinal axis of the ear. Care must be taken here not to damage visible vessels. Any blood that was released was collected at 15 s intervals using precisely weighed pieces of filter paper, without directly touching the wound. Bleeding time was calculated as the time from the time of incision until the time when blood could not be detected on the filter paper. The volume of extravasated blood was calculated after weighing the pieces of filter paper.

With. Determination of permeability (Caso analysis).

Caco cells (obtained from Deutsche Sammlung fur Mikroorganismen and Zellkulturen, DSMZ) were cultured in 24-well Transwell plates for 15 or 16 days. The test was carried out using a Hamilton robot. The density of cell monolayers was confirmed by measuring Lucifer yellow permeability. Test compounds were dissolved in DMSO and then diluted with assay buffer to a concentration of 2 μM (final DMSO concentration 1%). Permeability was studied in both directions by adding solutions of the substance to the apical or basolateral compartment. Covered dishes were incubated at 37°C for 2 hours.

Concentrations in the two compartments were determined by LC-MS/MS, and Papp values were calculated according to Artursson and Karlsson (PMID: 1673839).

d. Determination of pharmacokinetic parameters after intravenous administration.

To examine the pharmacokinetic properties of a test substance, appropriate test substances are administered to animals by bolus injection, infusion or oral administration. In rats, the preferred formulation for intravenous administration of test substances is plasma/dimethyl sulfoxide at a ratio of 99:1. The test substance infusion solution for dogs and monkeys consists of polyethylene glycol/ethanol/water in a 50/10/40 ratio. Formulations for oral administration may be polyethylene glycol/ethanol/water or solu- 143 044932 tol/ethanol/water at a ratio of 50/10/40, or other formulations as appropriate (for example, water, tylose, self-emulsifying drug dispersion systems and etc.). The volume of administration for rats is 2-10 ml/kg, for dogs and monkeys - 0.5-5 ml/kg.

Blood samples were collected from test animals in tubes containing sodium EDTA (or other anticoagulant): in the case of bolus administration, blood samples were typically collected at time 0.033, 0.083, 0.167, 0.25, 0.283, 0.333, 0.5, 0.75, 1, 2, 3, 5, 7, 24 hours after administration of the test substance. For infusions, blood samples are typically collected at time points 0.083, 0.167, 0.25, 0.283, 0.333, 0.5, 0.75, 1, 2, 3, 5, 7, 24 hours after administration of the test substance. For oral administration, blood samples are typically collected at time points 0.083, 0.25, 0.5, 0.75, 1, 2, 3, 5, 7, 24 hours after administration of the test substance. If necessary, other time points can be selected.

After collection, blood samples were centrifuged at 1280 g for 10 minutes. The supernatant (plasma) was collected and either directly processed or frozen for later sample preparation. To obtain the sample, 50 μl of plasma was mixed with 250 μl of acetonitrile (acetonitrile precipitant also contains the ISTD internal standard for subsequent analytical determination) and kept at room temperature for 5 min. The mixture was then centrifuged at 16,000 g for 3 min. The supernatant was collected and 500 μl of buffer suitable for the mobile phase was added. The samples were then analyzed by LC-MS/MS (e.g. liquid chromatography using a Gemini 5 µm C18 110A 50 mm x 3 mm (or 150 mm x 3 mm) column from Phenomenex; mass spectrometry using API 5500 or API 6500; SCIEX, Canada) to determining the concentration of the test substance in individual samples.

In addition to plasma concentrations, the ratio of whole blood to plasma concentrations for the test substance in question was determined. To do this, the test substance was incubated at a certain concentration in whole blood for 20 minutes. The samples were then processed as described above to determine the plasma concentration of the test substance. The determined concentration divided by the concentration measured in plasma gives the Cb/Cr parameter.

Pharmacokinetic parameters were calculated using noncompartmental analysis (NCA). Algorithms for calculating parameters are defined in the internal description of the method and are based on rules published in general textbooks on pharmacokinetics.

The main pharmacokinetic parameters: clearance (CL) and volume of distribution (Vss) were calculated as follows:__________________________________________________________

Parameter Formula Сbplasma plasma) (clearance Cplasma = dose / AUC (AUC = subcurve area) Blood (blood clearance) Cblood = CLplasma / (Cb/Cp) Vss Vss = Cbplasma * MRTiv MRTiv MRTiv = AUMC/AUC AUMC λ _ζ AUMC - AUMC(0-t _nocjeflHee ) + last *С _П last, calculatedАг + С _|10С1С d _{Ня.calculated} / λ _ζ Rate constant for the final phase; calculated from log-linear regression of unweighted data from the end phase with data points above the detection limit AUC AUC - Ais(0-Last) + C last, calculated/U AINormalized AUC divided by dose (mg) per kg body weight

C. Working examples of pharmaceutical compositions.

The substances of the present invention can be converted into pharmaceutical preparations as follows.

Tablet.

Compound:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Receipt:

A mixture of the compound of Example 1, lactose and starch is granulated with a 5% (w/w) solution of PVP in water. After drying, the granules are mixed with magnesium stearate for 5 minutes. This mixture is pressed into

- 144 -

Claims (23)

a regular tablet press (tablet format, see above). Oral suspension. Compound: 1000 mg compound of example 1, 1000 mg ethanol (96%), 400 mg Rhodigel (xanthan gum) (from FMC, USA) and 99 g of water; 10 ml of oral suspension corresponds to one dose of 100 mg of the compound according to the present invention. Receipt: Rhodigel was suspended in ethanol, and the compound of the present invention was added to the suspension. Water was added while stirring. The mixture was stirred for about 6 hours until the swelling of Rhodigel was completed. CLAIM 1. A compound of the formula in which R ¹ represents methyl, ethyl, difluoromethyl or trifluoromethyl, R ² is hydrogen, methyl, difluoromethyl or trifluoromethyl, or R ¹ and R ² , together with the carbon atoms to which they are attached, form a cyclobutyl ring, R ³ represents methyl, ethyl or n-propyl, where methyl may be replaced by one substituent selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydro- 2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl and 1,4-dioxan-2-yl, where oxetan-2-yl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and 1 ,4-dioxan-2-yl may be substituted by 1 or 2 substituents independently selected from the group consisting of fluorine and methyl, or where methyl may be substituted by one substituent of a group of formula or a or where * indicates the site of attachment to the methyl group, R ⁹ is methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl or trifluoromethyl, R ¹⁰ represents methyl or difluoromethyl, and wherein ethyl may be replaced by one substituent selected from the group consisting of methoxy, ethoxy, isopropoxy, t-butoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2trifluoroethoxy, cyclopropyloxy and cyclobutyloxy, wherein cyclopropyloxy and cyclobutyloxy may be substituted by one substituent selected from the group consisting of fluorine and methyl, R ⁴ represents hydrogen, R ⁵ represents a group of the formula - 145 044932 where # indicates the site of attachment to the nitrogen atom, R ¹¹ represents hydrogen or fluorine, R ¹² represents methyl, difluoromethyl or trifluoromethyl, R ¹³ represents methyl, difluoromethyl or trifluoromethyl, R ¹⁴ represents hydrogen or methyl, R ¹⁵ represents hydrogen or methyl, R ¹⁶ represents hydrogen or methyl, R ¹⁷ represents hydrogen or methyl, R ⁶ , R ⁷ and R ⁸ have the following meanings: R ⁶ represents hydrogen, fluorine or chlorine, R ⁷ represents hydrogen, R ⁸ represents hydrogen, or R ⁶ represents hydrogen, R ⁷ represents fluorine or chlorine, R ⁸ represents hydrogen, or R ⁶ represents hydrogen, R ⁷ represents hydrogen, R ⁸ represents fluorine, or one of its salts. 2. The connection according to claim 1, characterized in that R ¹ represents methyl, ethyl or trifluoromethyl, R ² represents hydrogen or methyl, or R ¹ and R ² , together with the carbon atoms to which they are attached, form a cyclobutyl ring, R ³ represents methyl, ethyl or n-propyl, where methyl may be replaced by one substituent selected from the group consisting of cyclobutyl, tetrahydrofuran-2-yl, tetrahydro-2H-pyran-2-yl and 1,4-dioxan- 2-yl, wherein tetrahydrofuran-2-yl may be substituted with 1 or 2 methyl substituents, or where methyl may be substituted with one group substituent of the formula where * indicates the place of attachment to the methyl group, R ⁹ is methyl, cyclopropyl, difluoromethyl or trifluoromethyl, R ¹⁰ represents methyl or difluoromethyl, and wherein ethyl may be replaced by one substituent selected from the group consisting of methoxy, isopropoxy, t-butoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, cyclopropyloxy and cyclobutyloxy, wherein cyclopropyloxy and cyclobutyloxy may be replaced by one substituent selected from the group consisting of fluorine and methyl, R ⁴ represents hydrogen, R ⁵ represents a group of the formula - 146 044932 where # indicates the site of attachment to the nitrogen atom, R ¹¹ represents hydrogen or fluorine, R ¹² represents difluoromethyl or trifluoromethyl, R ¹³ represents methyl, R ¹⁴ represents hydrogen or methyl, R ¹⁵ represents hydrogen or methyl, R ¹⁶ represents hydrogen, R ¹⁷ represents hydrogen, R ⁶ , R ⁷ and R ⁸ have the following meanings: R ⁶ represents hydrogen, fluorine or chlorine, R ⁷ represents hydrogen, R ⁸ represents hydrogen, or one of its salts. 3. Connection according to claim 1 or 2, characterized in that R ¹ represents methyl or trifluoromethyl, R ² represents hydrogen, R ³ represents methyl, where methyl is replaced by one group substituent of the formula where * indicates the place of attachment to the methyl group, R ⁹ represents methyl, R ¹⁰ represents methyl or difluoromethyl, R ⁴ represents hydrogen, R ⁵ represents a group of the formula where # indicates the site of attachment to the nitrogen atom, R ¹¹ represents hydrogen, R ⁶ , R ⁷ and R ⁸ have the following meanings: R ⁶ represents hydrogen or fluorine, R ⁷ represents hydrogen, R ⁸ represents hydrogen, or one of its salts. 4. A compound according to any one of claims 1 to 3, characterized in that it has formula (Ia) - 147 044932 in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ have the meanings as defined in paragraphs 1-3. 5. The compound according to claim 1, which is 4-({(2S,4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro- 3H-[3]benzoxocino[2,1-c]pyridin-3-yl]-4-methoxy-pentanoyl}amino)benzamide or one of its salts. 6. The compound according to claim 1, which is 4-({(2S,4S)-2-[(7R)-11-chloro-2-oxo-7-(trifluoromethyl)2,6,7,8-tetrahydro- 3H-[3]benzoxino[2, 1-c]pyridin-3-yl]-4-methoxy-pentanoyl}amino)benzamide 7. A method for producing a compound of formula (I) or one that a compound of the formula from its salts according to claim 1, characterized in that in which R ¹ , R ² , R ³ , R ⁶ , R ⁷ and R ⁸ are as defined in claim 1, react with a compound of the formula in which R ⁴ and R ⁵ are as defined in claim 1, in the presence of a dehydrating agent to obtain a compound of formula (I). 8. A method for preparing a compound of formula (I) or one of its salts according to claim 1, characterized in that the compound of formula (II) as defined in claim 7 is converted in a one-pot reaction to the acid chloride of the compound of formula (II) and then the acid chloride is reacted with a compound of formula (III) as defined in claim 7 to obtain a compound of formula (I). 9. A method for preparing a compound of formula (I) or one of its salts according to claim 1, characterized in that the compound of formula in which R ¹ , R ² , R ⁶ , R ⁷ and R ⁸ are as defined in claim 1, is reacted with a compound of the formula - 148 044932 in which X ¹ represents bromine, iodine or trifluoromethanesulfonyloxy, in the presence of a base to obtain a compound of formula (I). 10. A biologically active agent having FXIa inhibitor properties, being a compound of formula (I) as defined in any of claims 1 to 6. 11. Use of the compound according to any one of paragraphs. 1-6 for the production of a medicinal product for the treatment and/or prevention of thrombotic or thromboembolic disorders. 12. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the treatment and/or prevention of coronary artery disorders, cerebrovascular artery disorders, and peripheral artery disorders. 13. Use according to claim 12, wherein coronary artery disorders include acute coronary syndrome (ACS), ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, stent thrombosis, reocclusions and restenosis after coronary interventions. 14. Use according to claim 13, wherein reocclusions and restenoses after coronary interventions include angioplasty, stent implantation or coronary artery bypass grafting. 15. Use according to claim 12, wherein cerebrovascular disorders include transient ischemic attack (TIA), ischemic strokes including cardioembolic strokes and non-cardioembolic strokes. 16. Use according to claim 15, wherein cardioembolic strokes include strokes resulting from atrial fibrillation. 17. Use according to claim 15, wherein non-cardioembolic strokes include lacunar stroke, strokes resulting from large or small artery disease or strokes of unknown cause, cryptogenic strokes, embolic strokes, embolic strokes of unknown origin, or events of thrombotic and/or thromboembolic origin leading to stroke or TIA. 18. Use according to claim 12, wherein peripheral arterial disorders include disorders leading to peripheral arterial disease, including peripheral artery occlusion, acute limb ischemia, amputation, reocclusions and restenoses after interventions. 19. Use according to claim 18, wherein reocclusions and restenoses after interventions include angioplasty, stent implantation or surgery or bypass. 20. A medicinal product containing a compound according to any one of claims 1 to 6 in combination with an inert, non-toxic, pharmaceutically acceptable excipient. 21. A medicinal product according to claim 20 for the treatment and/or prevention of thrombotic or thromboembolic disorders. 22. Use of a compound according to any one of claims 1 to 6 in a therapeutically effective amount for the treatment and/or prevention of thrombotic or thromboembolic disorders. 23. A method of treating and/or preventing thrombotic or thromboembolic disorders in humans and animals by administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 6 or a medicinal product according to claim 20. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 149-