WO2019158634A1

WO2019158634A1 - Deuterated derivatives of 9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

Info

Publication number: WO2019158634A1
Application number: PCT/EP2019/053646
Authority: WO
Inventors: Carmen ALMANSA-ROSALES; Monica Garcia-Lopez; Carlos ALEGRET-MOLINA; Marina VIRGILI-BERNADO
Original assignee: Esteve Pharmaceuticals SA
Current assignee: Esteve Pharmaceuticals SA
Priority date: 2018-02-16
Filing date: 2019-02-14
Publication date: 2019-08-22
Anticipated expiration: 2020-08-16

Abstract

The present invention relates to deuterated derivatives of 9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one having pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

Description

Deuterated derivatives of 9-i2,5-difluorophenethyl)-4-ethyl-2 -methyl-1 -oxa-4,9- diazaspiror5.5lundecan-3-one

FIELD OF THE INVENTION The present invention relates to deuterated derivatives of 9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one having pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain. BACKGROUND OF THE INVENTION

The adequate management of pain constitutes an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved [Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet 377, 2226-2235 (2011 )]. Pain affects a big portion of the population with an estimated prevalence of around 20% and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which lead to important productivity losses and socio-economical burden [Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 1 1 , 770 (2011 )]. Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.

(R)-9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3- one is described as Example 70 in the PCT publication WO2015/185209. It is described as having pharmacological activity for use in therapy in particular for the treatment of pain and shows good m and s1 dual binding. Based on this analgesically very active compound it was tried to further modulate the biological activity of such an active analgesic to fulfil the constant need of improving the treatment of pain, with good/improved metabolic stability being the main goal.

Thus, the technical problem can therefore be formulated as providing new derivatives of 9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one exhibiting a improved/modulated metabolic stability.

SUMMARY OF THE INVENTION

In this invention deuterated derivatives of 9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1- oxa-4,9-diazaspiro[5.5]undecan-3-one were identified which showed a good metabolic stability.

The invention is directed in a main aspect to a compound of general formula (I) with at least one deuterium substitution.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to deuterated derivatives of 9-(2,5-difluorophenethyl)-4-ethyl- 2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.

The applicant has surprisingly found that deuterated derivatives of 9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one fulfil the requirement of exhibiting a surprisingly good metabolic stability thus solving the above problem.

In a particular aspect, the present invention is directed to compounds of general formula

(I):

wherein

Ri, Rr, Rr, R2, R2’, R3, R₄, R_4', R5, R5’, R6, R6’, R7, R7’, Re, Re’, R9, R9’, R10, R10’, R11 , Rir, R11 R12, R13 and R_M are independently selected from hydrogen and deuterium, wherein at least one of Ri, Rr, Rr, R2, R2', R3, R₄, R₄·, Rs, Rs·, R6, R6·, R7, R7', Rs, Rs·, R₉, Rg·, R10, Rio·, R11 , Rir, R11” R12, R13 and RM is deuterium;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.

The term“salt” is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes via ionic interactions. The term“physiologically acceptable salt” means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.

These physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals. The salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH₄, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.

Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals. By this is understood in particular, in the context of this invention, the salt formed with a physiologically tolerated acid, that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals. Examples of physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.

The compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid.

Any compound that is a solvate of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. The term“solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non- covalent binding another molecule (most likely a polar solvent). Especially preferred examples include hydrates and alcoholates, like methanolates or ethanolates.

Any compound that is a prodrug of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention. The term“prodrug” is used in its broadest sense and encompasses those Derivatives that are converted in vivo to the compounds of the invention. Such Derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following Derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al.“Textbook of Drug design and Discovery” Taylor & Francis (April 2002).

The compounds of formula (I) as well as their salts or solvates of the compounds are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I) or, or of its salts. This applies also to its solvates or prodrugs.

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound of general formula (G)

In a preferred embodiment in the compound according to the invention according to general formula (I) or general formula (G)

1 to 26 of Ri, Rr, Rr, R2, R2’, R3, R4, R4’, Rs, Rs¹, R6, R6’, R7, R7’, Rs, Rs¹, Rg, Rg¹, R10,

Rio·, R11 , Rir, Rn” R12, R13 and R14 are deuterium.

1 to 26 is meaning, that 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25 or 26 of R1 , Rr, Rr, R2, R2’, R3, R4, R4’, Rs, Rs , R6, R6’, R7, R7’, Rs, Rs·, Rg, Rg·, R10, Rio·, R11 , Rir, R11” R12, R13 and RM being deuterium.

In another preferred embodiment in the compound according to the invention according to general formula (I) or general formula (G)

1 to 20 of R1, Rr, Rr, R2, R2’, R3, R4, R4’, Rs, Rs , R6, R6’, R7, R7’, Rs, Rs , Rg, Rg , R10,

Rio·, R11 , Rir, R11” R12, R13 and RM are deuterium.

1 to 20 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 of Ri, Rr, R1 ', R2, R2’, R3, R4, R4’, Rs, Rs , R6, R6’, R7, R7’, Rs, Rs , Rg, Rg , R10, R10’, R11 , Rir, R11” R12, R13 and RM being deuterium. In another preferred embodiment in the compound according to the invention according to general formula (I) or general formula (G)

1 to 15 of Ri, Rr, R-r, R₂, R2’, R3, R4, R_4’, Rs, Rs , R6, R6’, R7, R7’, Re, Re , R9, R9’, R10, Rio·, R11 , Rir, R11” R12, R13 and RM are deuterium.

1 to 15 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or 15 of R1 , Rr, Rr, R2, R2’, R3, R₄, R_4’, Rs, Rs , Re, R6’, R7, R7’, Rs, Re’, R9, R9’, R10, R10’, R11 , Rir, R11 R12, R13 and R_M being deuterium.

In another preferred embodiment in the compound according to the invention according to general formula (I) or general formula (I’)

1 to 12 of Ri, Rr, Rr, R2, R2’, R3, R₄, R_4’, Rs, Rs , R6, R6’, R7, R7’, Rs, Re , R9, R9’, R10, Rio·, R11 , Rir, R11” R12, R13 and RM are deuterium.

1 to 12 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 of Ri, Rr, Ri ", R2, R2', R3, R₄, R_4’, Rs, Rs , Re, R6’, R7, R7’, Re, Rs , R9, R9’, R10, R10’, R11 , Rir, R11” R12, R13 and RM being deuterium.

1 to 10 of Ri, Rr, Rr, R2, R2’, R3, R₄, R_4’, Rs, Rs , R6, R6’, R7, R7’, Rs, Rs , R9, R9’, R10, Rio·, R11 , Rir, R11” R12, R13 and RM are deuterium.

1 to 10 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9 or 10 of Ri, Rr, Rr, R2, R2', R3, R₄, R₄·, Rs, Rs·, R6, R6', R7, R7', Rs, Rs·, R9, R9', R10, R10', R1 1, Rir, R11 R12, R13 and RM being deuterium.

1 to 9 of Ri, Rr, Rr’, R2, R2’, R3, R₄, R_4’, Rs, Rs , R6, R6’, R7, R7’, Re, Re , R9, R9’, R10, Rio·, R11 , Rir, R11” R12, R13 and RM are deuterium. 1 to 9 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, or 9 of Ri , Rr, Rr, R2, R2', R₃, F , R_4’, Rs, Rs·, R6, R6', R7, R7', Rs, Re’, R9, R9', R10, R10', R11 , Rir, R11”’ R12, R13 and RM being deuterium.

In another preferred embodiment the compound according to the invention according to general formula (I) is a compound of general formula (II”)

I”), wherein Ri, Rr, Rr, R₂, R2', R3, R₄, R₄·, Rs, Rs·, R6 and R6· are independently selected from hydrogen and deuterium, wherein at least one of Ri, Rr, Rr, R2, R2', R₃, R₄, R₄·, Rs, Rs·, R6 and Re· is deuterium;

optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof. ln a preferred embodiment the compound according to the invention according to general formula (II”) is a compound of formula (II’)

0

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound of formula (II’)

OO- In a preferred embodiment in the compound according to the invention according to general formula (II”) or general formula (II’)

1 to 12 of Ri, Rr, Rr, R₂, R₂·, R3, R₄, Rr, Rs, Rs·, R6 and R6· is deuterium. 1 to 12 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 of Ri, Rr, Rr, R2, R2', R3,

R₄, Rr, R₅, R_S·, R₆ and R₆· being deuterium.

In a preferred embodiment in the compound according to the invention according to general formula (II”) or general formula (II’)

1 to 10 of Ri, Rr, Rr, R2, R2', R3, R₄, Rr, Rs, Rs·, R6 and R6· is deuterium. 1 to 10 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9 or 10 of Ri, Rr, Rr, R2, R2', R3, R₄, Rr,

Rs, Rs·, R6 and Re· being deuterium.

1 to 9 of Ri, Rr, Ri , R2, R2', R3, R₄, Rr, Rs, Rs·, R6 and R6· is deuterium. 1 to 9 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, or 9 of Ri, Rr, Rr, R2, R2', R3, R₄, Rr, Rs,

Rs·, R₆ and Re· being deuterium.

In a preferred embodiment in the compound according to the invention according to general formula (I), (I’), (II”) or (II’) (including all embodiments described above) at least Ri, Rr, Rr, R₂, and R₂· are deuterium.

In a preferred embodiment the compound according to the invention according to general formula (I) is selected from the group consisiting of:

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound wherein R₁, Rr, Rr, R₂ and R_2' are deuterium, whereas R3, R₄, R₄·, Rs, Rs·, R6 and R6· are hydrogen.

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound wherein R₃ is deuterium, whereas R₁, Rr, Rr, R₂,

R2’, R₄, R_4’, R5, R5’, Re, R6’, R7, R7’, Re, Re , R9, R9’, R10, R10’, R11 , Rir, R11 ', R12, R13 and R_M are hydrogen.

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound wherein R₃, R₄ and R₄· are deuterium, whereas R₁,

are hydrogen.

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound wherein R₁, Rr, Rr, R2, R2', R₄ and R₄· are deuterium, whereas R3, Rs, Rs·, R6, R6·, R7, R7’, Re, Re·, R9, R9', R10, Rio·, R11, Rn_\ R11 ", R12, R13 and Ri₄ are hydrogen.

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound wherein R3, R6 and R6· are deuterium, whereas Ri,

Rr, Rr, R2, R2', R₄, Rr, Rs, Rs", R7, R7’, Re, Re", R9, R9', R10, R10', R11 , Rir, R11 ", R12, R13 and Ri₄ are hydrogen.

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound wherein Ri , Rr, Rr, R₂, R2', R₄, Rr, Rs and R_5" are deuterium, whereas R3, R6, R6·, R7, R7’, Rs, Rs·, R9, R9', R10, Rio·, R11 , Ri r and Rn - are hydrogen.

In a preferred embodiment the compound according to the invention according to general formula (I) is a compound wherein R3, R₄, Rr, Rs, Rs·, are deuterium, whereas

Ri, Rr, Rr, R₂, R2’, Re, R6’, R7, R7’, Re, Re’, R9, R9’, R10, R10’, R11, Rir, Rn”, R12, R13 and Ri₄ are hydrogen.

In the following the phrase“compound of the invention” is used. This is to be understood as any compound according to the invention as described above according to general formulas (I), (I’), (II”) or (II’).

In general the processes are described below in the experimental part. The starting materials are commercially available or can be prepared by conventional methods.

As a further general remark, the use of“comprising” and“comprises” as used herein, especially when defining the steps of a process is to be understood as also disclosing “consisting of” and“consists of respectively etc. Thus, this also includes that the steps of the respective process are then to be also understood to be limited to the steps preceded by this“comprising” or“comprises” etc. A preferred aspect of the invention is also a process for the production of a compound according to formula I

wherein

Ri, Rr, Rr, R2, R2’, R3, R4, R_4’, R5, R5’, R6, R6’, R7, R7’, Re, Re R9, R9’, R10, R10’, R11 , Rir, R11 ^■, R12, R13 and R14 are independently selected from hydrogen and deuterium, wherein at least one of Ri, Rr, Rr, R2, R2', R3, R₄, R₄·, Rs, Rs·, R6, R6·, R7, Rr, Rs, Rs·, Rg, Rg·, R10, Rio·, R11 , Rir, R11” R12, R13 and RM is deuterium. Preparation of the HCI salt: To a solution of the free base obtained, in a suitable solvent, preferably in anhydrous diethyl ether, HCI was added, and the mixture was stirred, preferably at room temperature, preferably for 1 h. The solvent was evaporated, preferably under vacuum, to give the corresponding HCI salt.

The term “leaving group” means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-) or mesylate. The optical isomers can be obtained by convenient enantioselective methods or via chiral HPLC separation or fractional crystallization of diastereomeric salts of the corresponding racemic mixtures.

The obtained reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography. Where the above described processes for the preparation of compounds of the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form of a compound of the invention is the crystalline form, including such form in pharmaceutical composition. In the case of salts and also solvates of the compounds of the invention the additional ionic and solvent moieties must also be non-toxic. The compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.

Another aspect of the invention refers to a pharmaceutical composition which comprises a compound according to the invention as described above according to general formulas (I), (I’), (II’) or (II”) or a pharmaceutically acceptable salt or steroisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The present invention thus provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.

As a general remark, the use of “comprising” and “comprises” as used herein, especially when defining the contents of a medicament or a pharmaceutical formulation is to be understood as also disclosing“consisting of” and“consists of respectively etc. Thus, this also includes that the contents of the respective medicament or pharmaceutical formulation are then to be also understood to be limited to the exact contents preceded by this“comprising” or“comprises” etc. Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.

Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated. Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.

Another aspect of the invention refers to the use of a compound of the invention or a pharmaceutically acceptable salt or isomer thereof in the manufacture of a medicament.

Another aspect of the invention refers to a compound of the invention according as described above according to general formulas (I), (I’), (II’) or (II”) ( or a pharmaceutically acceptable salt or isomer thereof), for use as a medicament

Another aspect of the invention refers to a compound of the invention according as described above according to general formulas (I), (I’), (II’) or (II”) ( or a pharmaceutically acceptable salt or isomer thereof), for use as a medicament for the treatment of pain. Preferably the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia. This may include mechanical allodynia or thermal hyperalgesia.

Another aspect of the invention refers to the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of pain.

In a preferred embodiment the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, also preferably including mechanical allodynia or thermal hyperalgesia.

Another aspect of this invention relates to a method of treating or preventing pain which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof. Among the pain syndromes that can be treated are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia.

The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.

EXAMPLES:

General Experimental Part (Methods and Equipment of the synthesis and analysis)

Two different general methods have been developed for obtaining the compounds of the invention, as described below in Schemes 1 and 2.

SCHEME 1

A 4-step process is described for the preparation of compounds of general formula (I) starting from a ketone of formula (II), as shown in the following scheme:

Scheme 1 wherein Ri , Rr, Rr, R₂, R₂·, R3, R4, R_4', Rs, Rs·, R6, R6', R7, R7’, Rs, Rs·, R9, R9', R10, R10', R11, Rir_, Rir, RI₂, R13 and R^ have the meanings as defined above for a compound of formula (I), W represents OH or a leaving group such as chloro or bromo, LG represents another leaving group such as halogen, mesylate, tosylate, nosylate or triflate, P represents a suitable protecting group (preferably Boc) and P’ represents another suitable protecting group (preferably 4-methoxybenzyl).

The 4 step-process is carried out as described below:

Stepl : A compound of formula (III) is prepared by treating a compound of formula (II) with a suitable methyl-transfer reagent such as trimethylsulfoxonium iodide or trimethylsulfonium iodide, in a suitable aprotic solvent such as dimethylsulfoxide or 1 ,2- dimethoxyethane or mixtures, and in the presence of a strong base such as sodium hydride or potassium tert- butoxide, at a suitable temperature, preferably comprised between 0 °C and 60 °C.

Alternatively, the preparation of a compound of formula (III) from a compound of formula (II) can be carried out in 2 steps by performing a Wittig olefination followed by epoxidation of the resulting olefine, using conventional procedures described in the literature. As a way of example, the Wittig reaction is carried out by treating a compound of formula (II) with methylenetriphenylphosphorane (prepared in situ from methyltriphenylphosphonium bromide and a strong base such as butyllithium), in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, preferably comprised between -78 °C and room temperature; and the epoxidation reaction is carried out by treating the olefin obtained in the Wittig reaction with a suitable oxidizing agent, such as hydrogen peroxide or an alkyl hydroperoxide in the presence of a metal catalyst, or preferably using a peroxyacid such as mefa-chloroperoxybenzoic acid in a suitable solvent such as dichloromethane or chloroform.

Step2: A compound of formula (V) is prepared by reacting a compound of formula (III) with an amine of formula (IV), in a suitable solvent such as an alcohol, preferably ethanol-water mixtures, at a suitable temperature comprised between room temperature and the reflux temperature, preferably at room temperature. Step3: A compound of formula (VII) is prepared by reacting a compound of formula (V) with an acylating agent of formula (VI). When W is a leaving group such as chloro or bromo, the acylation reaction is carried out in a suitable solvent, such as dichloromethane or ethyl acetate-water mixtures; in the presence of an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as K₂CO₃; and at a suitable temperature, preferably comprised between -78 °C and room temperature. Alternatively, when W is OH, the acylation reaction can be carried out using a suitable coupling reagent such as /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide (EDO), dicyclohexylcarbodiimide (DCC), /V-[(dimethylamino)-1 H- 1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-/V-methylmethanaminium

hexafluorophosphate N- oxide (HATU) or /V,/V,/V',/V'-tetramethyl-0-(1 H-benzotriazol-1- yl)uronium hexafluorophosphate (HBTU), optionally in the presence of 1- hydroxybenzotriazole, optionally in the presence of an organic base such as N- methylmorpholine or diisopropylethylamine, in a suitable solvent such as dichloromethane or dimethylformamide, and at a suitable temperature, preferably at room temperature.

Step4: The intramolecular cyclization of a compound of formula (VII) renders a compound of formula (I). The cyclization reaction is carried out in a suitable solvent, such as tetrahydrofuran; in the presence of a strong base such as potassium tert- butoxide or sodium hydride; and at a suitable temperature, comprised between -78 °C and room temperature, preferably cooling.

Alternatively, the group defined as B in Scheme 1 can be incorporated in the last step of the synthesis by reaction of a compound of formula (VII IH) with a compound of formula (IX) or (X), as shown in Scheme 1. A compound of formula (VIIIH) is obtained by deprotection of a compound of formula (VIIIP), wherein P represents a suitable protecting group, preferably Boc (tert- butoxycarbonyl). When the protecting group is Boc, the deprotection can be conducted by adding a solution of a strong acid such as HCI, in a suitable solvent such as diethyl ether, 1 ,4-dioxane, methanol or ethanol, or with trifluoroacetic acid in dichloromethane. A compound of formula (VIIIP) is prepared from a compound of formula (IIP) following the same sequence described for the synthesis of compounds of formula (I). The alkylation reaction between a compound of formula (VI 11 H ) (or a suitable salt such as trifluoroacetate or hydrochloride) and a compound of formula (IX) is carried out in a suitable solvent, such as acetonitrile, dichloromethane, 1 ,4-dioxane or dimethylformamide, preferably in acetonitrile; in the presence of an inorganic base such as K2CO₃ or CS2CO₃, or an organic base such as triethylamine or diisopropylethylamine, preferably K2CO_3; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. Additionally, an activating agent such as Nal can be used.

The reductive amination reaction between a compound of formula (VIIIH) and a compound of formula (X) is carried out in the presence of a reductive reagent, preferably sodium triacetoxyborohydride, in a suitable solvent, preferably tetrahydrofuran or dichloroethane, optionally in the presence of an acid, preferably acetic acid.

In another alternative approach, the substituent -C(R R ')C(R-iRrRr) present in a compound of formula (I) can be incorporated later in the sequence by the reaction of a compound of formula (XVII) with a compound of formula (XVIII). The alkylation reaction is carried out in an aprotic solvent, preferably dimethylformamide, in the presence of a strong base such as NaH, at a suitable temperature, preferably between room temperature and 60°C.

A compound of formula (XVII) is synthesized following an analogous sequence as described for the synthesis of compounds of formula (I), but effecting Step 2 using ammonia instead of an amine of formula (IV). Alternatively, a compound of formula (XVII) can be prepared by reaction of a compound of formula (XVIIH) (prepared from a compound of formula (XVIIP), wherein P represents a suitable protecting group) with a compound of formula (IX) or (X), as described above.

Additionally, a compound of formula (XVII) can be prepared from a compound of formula (XIV), wherein P’ represents a suitable protecting group, preferably a 4- methoxybenzyl group. The deprotection reaction is carried out with cerium ammonium nitrate in a suitable solvent such as mixtures of acetonitrile-water or by heating in trifluoroacetic acid or hydrochloric acid. A compound of formula (XIV) is synthesized from a compound of formula (III) and an amine of formula (XI) following an analogous sequence as described for the synthesis of compounds of formula (I). Alternatively, a compound of formula (XIV) can be prepared by reaction of a compound of formula (XIVH) (prepared from a compound of formula (XIVP), wherein P represents a suitable protecting group) with a compound of formula (IX) or (X), as described above.

The use of suitably deuterated compounds in the reactions described in Scheme 1 allows for the introduction of deuterium in the different positions of a compound of formula (I). The use of a deuterated compound of formula (II) allows for the introduction of deuterium in R₄, R₄·, Rs, Rs·, R7, Rr, Rs, Rs·, R9, RET, R10, R10 R12, R13 and RI_4. The use of a deuterated compound of formula (IIP) allows for the introduction of deuterium in R₇, Rr, Re, Re’, R9, R9', R10 and Rio·. The use of a deuterated compound of formula (IV) or (XVIII) allows for the introduction of deuterium in R1 , Rr, Rr, R2 and R2'. The use of a deuterated compound of formula (VI) allows for the introduction of deuterium in R3, R11 , R-irand Rn . The use of a deuterated compound of formula (IX) or (X) allows for the introduction of deuterium in R₄, R₄·, R₅, Rs·, R12, R13 and R_M. The use of a suitably deuterated methyl-transfer or phosphorane reagent in Step 1 allows for the introduction of deuterium in R6 and R6·.

SCHEME 2

The compounds of general formula (I) wherein R3 is deuterium (compounds of formula lb) can be alternatively prepared starting from a compound of formula (I) wherein R3 is hydrogen (compounds of formula la) by hydrogen-deuterium exchange as described in the following scheme:

wherein R1 , Rr, Rr, R₂, R2', R4, R_4', Rs, Rs·, R6, R6·, R7, R7’, Rs, Rs·, R9, R9', R10, R-is, R11, Rir, R11”, R12, R13 and Ri₄ ave the meanings as defined above for a compound of formula (I), LG represents a leaving group such as halogen, mesylate, tosylate, nosylate or triflate and P represents a suitable protecting group (preferably Boc).

The hydrogen-deuterium exchange reaction is carried out by treating a compound of formula (la) with a strong base such as potassium tert- butoxide or sodium hydride, in a suitable deuterated solvent, such as methanol-c/, methanol-c/4, ethanol-c/ or ethanol-cfe, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating.

Alternatively, the hydrogen-deuterium exchange reaction can be carried out at a previous stage by treating a suitable precursor of formula (VlllaP) under the reaction conditions described above to render a compound of formula (VlllbP). Finally, a compound of formula (VlllbP) is converted into a compound of formula (lb) under the same reaction conditions described in Scheme 1 for the conversion of a compound of formula (VIIIP) into a compound of formula (VIIIH) followed by reaction with a compound of formula (IX) or (X) to render a compound of formula (I). A compound of formula (la) or (VlllaP) is prepared from a compound of formula (II) or (IIP), respectively, following the same sequence described in Scheme 1 for the synthesis of compounds of formula (I).

The compounds of formula (II), (IIP), (IV), (VI), (IX), (X), (XI) and (XVIII) used in the methods and schemes disclosed above are commercially available or can be synthesized following common procedures described in the literature.

In addition, a compound of formula (I) can be obtained in enantiopure form by resolution of a racemic compound of formula (I) either by chiral preparative HPLC or by crystallization of a diastereomeric salt or co-crystal. Alternatively, the resolution step can be carried out at a previous stage, using any suitable intermediate.

Examples

The following abbreviations are used in the examples:

ACN: acetonitrile aq.: aq.

Boc: tert- butoxycarbonyl

CDCI3: chloroform-c/

CH: cyclohexane

DCM: dichloromethane DME: 1 ,2-dimethoxyethane

DMSO: dimethylsulfoxide

EtOAc: ethyl acetate

EtOD: ethanol-c/

EtOH: ethanol EX: example h: hour/s

HPLC: high performance liquid chromatography I NT: intermediate MeOD: methanol-c/

MeOH: methanol MS: mass spectrometry Min.: minutes Quant: quantitative Ret.: retention r.t: room temperature Sat: saturated s.m.: starting material Sol.: solution TEA: triethylamine

THF: tetrahydrofuran Wt: weight

The following method was used to determine the HPLC-MS spectra: Column: Kinetex EVO 50 x 4.6 mm, 2.6 urn

Temperature: 40 °C

Flow: 1.5 mL/min Gradient: NH₄HCO₃ pH 8 : ACN (95:5)— 0.5min— (95:5)— 6.5min— (0:100)— 2min— (0:100)

Sample dissolved approx. 1 mg/ml_ in NH₄HCO₃ PH 8/ ACN

Synthesis of Intermediates

Intermediate 1A: ferf-Butyl 1 -oxa-6-azaspiro[2.5]octane-6-carboxylate

To a solution of potassium tert- butoxide (36.6 g, 326 mmol) in DMSO (275 ml_), trimethylsulfoxonium iodide (80 g, 364 mmol) was added in portions keeping the temperature between 20-25 °C and the mixture was stirred at r.t. for 1 .5 h. DME (75 ml.) was added and the solution was cooled to 0-5 °C. Then, a solution of tert- butyl 4- oxopiperidine-1 -carboxylate (50 g, 251 mmol) in a mixture of DME (75 ml.) and DMSO (25 ml.) was added dropwise, keeping the temperature between 0-5 °C, and the reaction mixture was further stirred for 1 h at the same temperature. Water and ethyl acetate were added, the phases were separated and the aq. phase was extracted twice with ethyl acetate. The organic phases were combined, washed with water, dried over MgS0₄ and concentrated under vacuum to give the title compound (48.6 g, 91 % yield) as a white solid.

Intermediate 1 B: ferf-Butyl 1 -oxa-6-azaspiro[2.5]octane-6-carboxylate-2,2-d2

Step 1. ferf-Butyl 4-(methylene-c/₂)piperidine-1 -carboxylate: To a solution of (methyl-c/3)triphenylphosphonium bromide (prepared according to J.Org.Chem., 35, 4256 (1970)) (8.14 g, 22.6 mmol) in dry THF (36 ml_), cooled at -78 °C under an argon atmosphere, n-butyllithium solution (2.5 M in hexanes, 9 ml_, 22.5 mmol) was added dropwise and the mixture was stirred at -78 °C for 1 h. Then, a solution of tert- butyl 4- oxopiperidine-1 -carboxylate (3.0 g, 15.1 mmol) in dry THF (6 ml.) was added. The reaction mixture was allowed to warm up and it was stirred at r.t. overnight. The solvent was evaporated and deuterium oxide and ethyl acetate were added. The phases were separated and the aq. phase was back extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over MgS0₄, filtered and concentrated under vacuum to give the title compound (3 g, quant yield) as a crude product that was used as such without further purification.

Step 2. Title compound: To a solution of the crude product obtained in Step 1 (3 g, 15.1 mmol) in CDCI3 (120 ml_), cooled at 0 °C under an argon atmosphere, 3- chloroperbenzoic acid (4.0 g, 77 wt%, 23.3 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min, then it was allowed to warm up and it was stirred at r.t. overnight. It was diluted with additional CDC and the organic phase was consecutively washed with Na₂SC>₃ aq. sol., NaHCC>₃ sat. sol. and brine, dried over MgS0₄, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (1 .4 g, 43% yield).

Intermediate 2A: ferf-Butyl 4-((ethylamino)methyl)-4-hydroxypiperidine-1 - carboxylate

Boc

To a solution of intermediate 1A (48.6 g, 228 mmol) in a mixture of EtOH (787 ml.) and water (87 ml_), ethylamine (536 ml_, 70 wt% solution in water, 6.74 mol) was added and the reaction mixture was stirred at r.t. overnight. The solvent was removed under vacuum to give the title compound (59 g, quant yield).

Intermediate 2B: ferf-Butyl 4-((ethylamino)methyl-c/₂)-4-hydroxypiperidine-1 - carboxylate

Following the method described for the preparation of intermediate 2A but starting from intermediate 1 B (1.58 g, 7.34 mmol), the desired compound was obtained. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH/DCM (1 :4) to give the title compound (1.57 g, 82% yield).

Intermediate 2C: ferf-Butyl 4-(((ethyl-d₅)amino)methyl)-4-hydroxypiperidine-1 - carboxylate

To a solution of intermediate 1A (2 g, 9.38 mmol) in a mixture of EtOH (14.4 ml.) and water (1.6 ml_), ethan-c/5-1 -amine hydrochloride (4.06 g, 46.9 mmol) and TEA (7.8 ml_, 56.3 mmol) were added and the mixture was stirred at r.t. overnight. The solvent was removed under vacuum and 1 N NaOH aq. sol. and DCM were added. The phases were separated and the aq. phase was extracted with DCM. The organic phases were combined, dried over MgS0₄ and concentrated under vacuum. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH/DCM (1 :4) to give the title compound (1.38 g, 56% yield).

Intermediate 3A: (/?)-ferf-Butyl 4-ethyl-2-methyl-3-oxo-1 -oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate

Step 1. (S)-ferf-Butyl 4-((2-chloro-/V-ethylpropanamido)methyl)-4- hydroxypiperidine-1 -carboxylate: To a solution of intermediate 2A (58.9 g, 228 mmol) in ethyl acetate (550 ml_), a solution of K2CO3 (88.2 g, 638 mmol) in water (630 mL) was added. After cooling to 0 °C, a solution of (S)-2-chloropropanoyl chloride (39.3 g, 310 mmol) in ethyl acetate (300 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, the layers were separated and the aq. phase was extracted with ethyl acetate. The organic phases were combined, washed with cold 0.5 M HCI aq. solution and then NaHCC>3 sat. solution, dried over MgS0₄, filtered and concentrated to dryness to give the title compound (72 g, 91 % yield).

Step 2. Title compound: A solution of the crude product obtained in Step 1 (72 g, 206 mmol) in dry THF (1080 mL) was cooled to -78 °C using a dry ice/acetone bath under a N2 atmosphere. Potassium tert- butoxide solution (227 mL, 1 M in THF, 227 mmol) was slowly added and the reaction mixture was stirred at -78 °C for 30 min. NH₄CI sat. solution was then added, and the aq. phase was extracted with ethyl acetate. The organic phases were combined, dried over MgS0₄, filtered and concentrated under vacuum. The residue was crystallyzed from hot isopropyl acetate-heptane to give the title compound (39.9 g, 62% yield).

Intermediate 3B: (R)-tert-Buty\ 4-(ethyl-d₅)-2-methyl-3-oxo-1 -oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate

Following the method described for the preparation of intermediate 3A but starting from intermediate 2C (1 .66 g, 6.3 mmol) instead of intermediate 2A, the title compound was obtained (945 mg, 53% yield).

Intermediate 3C: ferf-Butyl 4-ethyl-2-methyl-3-oxo-1 -oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate-5,5-c/2

Boc

Following the method described for the preparation of intermediate 3A but starting from intermediate 2B (1 .57 g, 6 mmol) and 2-chloropropanoyl chloride (0.8 ml_, 8.2 mmol) as starting materials and omitting the final crystallization, the title compound was obtained (1 .33 g, 83% yield).

Intermediate 4A: ferf-Butyl 4-ethyl-2-methyl-3-oxo-1 -oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate-2-d

Boc

Potassium tert- butoxide (359 mg, 3.2 mmol) was added to a solution of intermediate 3A (500 mg, 1 .6 mmol) in MeOD (5 ml.) and the mixture was heated at 50 °C for 12 days under a N₂ atmosphere. Deuterium oxide (10 ml.) and ethyl acetate were added, the phases were separated and the aq. phase was back extracted with ethyl acetate. The organic phases were combined, dried over MgS0₄, filtered and concentrated under vacuum to obtain the title compound (370 mg, 73% yield).

Intermediate 4B: ferf-Butyl 4-ethyl-2-methyl-3-oxo-1 -oxa-4,9- diazaspiro[5.5]undecane-9-carboxylate-2,5,5-c/3

Following the method described for the preparation of intermediate 4A but starting from intermediate 3C (1.15 g, 3.66 mmol), the desired compound was obtained. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH/DCM (1 :9) to give the title compound (611 mg, 53% yield).

Intermediate 5A: 2,5-Difluorophenethyl 4-nitrobenzenesulfonate

A solution of 2-(2,5-difluorophenyl)ethanol (34.8 g, 220 mmol) in EtOAc (350 ml.) was cooled to -10 °C under a nitrogen atmosphere and TEA (33.7 ml_, 242 mmol) was slowly added. Then, a solution of 4-nitrobenzenesulfonyl chloride (53.6 g, 242 mmol) in EtOAc (80 ml.) was added keeping the temperature below -5 °C. The resulting mixture was stirred for additional 2 h at r.t. 1 N NaOH aq. solution was then added and the phases were separated. The aq. layer was extracted with EtOAc and the combined organic phases were washed with 1 N NaOH aq. solution and brine, dried over MgS0₄, filtered and concentrated to dryness. The crude product (65 g) was crystallized from hot toluene to give the title compound (37.9 g, 58% yield) as a white solid.

Intermediate 5B: 2-(2,5-Difluorophenyl)ethyl-1 ,1 -c/₂ 4-nitrobenzenesulfonate

Step 1. 2-(2,5-Difluorophenyl)ethan-1 ,1 -c/2-1 -ol: A solution of ethyl 2-(2,5- difluorophenyl)acetate (1.0 g, 5 mmol) in a mixture of EtOD (6 ml.) and deuterium oxide (1.5 ml.) was cooled to 0 °C under a nitrogen atmosphere. Calcium chloride (0.55 g, 5 mmol) was added and the mixture was stirred at 0-5 °C for 30 min. Then, sodium tetrahydroborate-c/₄ (418 mg, 10 mmol) was slowly added in portions and the reaction mixture was stirred at 0-5 °C for 1 h and then at r.t. overnight. 1 N HCI was added and the mixture was concentrated under vacuum. Deuterium oxide and ethyl acetate were added, the phases were separated and the aq. phase was back extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over MgS0₄, filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (462 mg, 58% yield).

Step 2. Title compound: Following the method described for the preparation of intermediate 5A but starting from the compound obtained in Step 1 (462 mg, 2.88 mmol), the desired compound was obtained. The crude product was alternatively purified by flash chromatography, Cie, gradient aq. NH4HCO₃ pH 8 to acetonitrile, to render the title compound (236 mg, 24% yield).

Intermediate 5C: 2-(2,5-Difluorophenyl)ethyl-1 ,1,2,2-d₄ 4-nitrobenzenesulfonate

Step 1. 2-(2,5-Difluorophenyl)acetic-2,2-d2 acid: A solution of 2-(2,5- difluorophenyl)acetic acid (5.0 g, 29 mmol) and potassium carbonate (20.47 g, 148 mmol) in deuterium oxide (25 ml.) was heated at 100 °C for 5 days. Then, it was cooled down to 0 °C, pH was adjusted to 2 with 6 M HCI and it was extracted with DCM. The organic phases were combined, dried over MgS0₄, filtered and concentrated to dryness to obtain the title compound (2.83 g, 56% yield).

Step 2. Ethyl 2-(2,5-difluorophenyl)acetate-c/2: To a solution of the compound obtained in Step 1 (2.83 g, 16.2 mmol) in EtOD (30 ml_), sulfuric acid (1 ml.) was added and the mixture was stirred at r.t. overnight. The solvent was partially evaporated and the residue was diluted with EtOAc and NaHCOs sat. sol. The phases were separated and the aq. phase was back-extracted with EtOAc. The combined organic phases were washed with water and brine, dried over MgS0₄, filtered and concentrated to dryness to give the title compound (3.3 g, quant yield).

Step 3. 2-(2,5-Difluorophenyl)ethan-1 ,1,2,2-c/₄-1-ol: Following the method described for the preparation of Step 1 of intermediate 5B but starting from the compound obtained in Step 2 (1.58 g, 7.8 mmol), the title compound was obtained (815 mg, 64% yield).

Step 4. Title compound: Following the method described for the preparation of intermediate 5A but starting from the compound obtained in Step 3 (815 mg, 5 mmol), the desired compound was obtained. It was further purified by flash chromatography, silica gel, gradient DCM to MeOH/DCM (1 :9) to give the title compound (954 mg, 55% yield).

Synthesis of Examples

Example 1 : 9-(2,5-Difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one-2-d hydrochloride

Step 1. (/?)-4-Ethyl-2-methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride. Hydrochloric acid 37% (58.6 ml_, 762 mmol) was slowly added to a solution of intermediate 3A (23.8 g, 76 mmol) in ethanol (298 ml.) and the reaction mixture was stirred at 30 °C overnight. Then, it was concentrated to dryness and the crude product was dried under high vacuum to give the title compound (26.0 g, overweight; theoretical weight 18.95 g assuming quantitative yield).

Step 2. (/?)-9-(2,5-Difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one: A mixture of intermediate 5A (1.95 g, 5.67 mmol), K2CO3 (2.85 g, 20.6 mmol) and the crude product obtained in Step 1 (1.76 g crude, 73 wt%, 1.28 g theory, 5.2 mmol) in ACN (16 ml.) was heated at 40 °C overnight. The precipitated solids were filtered off and the solvent was evaporated. Water was added and it was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over MgS0₄, filtered and concentrated to dryness to give the title compound (1.82 g, quant yield) as a crude product that was used as such without further purification.

Step 3. 9-(2,5-Difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one-2-d: Following the method described for the preparation of intermediate 4A but starting from the product obtained in Step 2 (200 mg, 0.57 mmol), the desired compound was obtained. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH/DCM (1 :4) to give the title compound (149 mg, 74% yield).

Step 4. Title compound: To a solution of the free base obtained in Step 3 (149 mg, 0.42 mmol) in anhydrous diethyl ether (2 ml_), HCI (2 M solution in diethyl ether, 0.25 ml_, 0.5 mmol) was added, and the mixture was stirred at r.t. for 1 h. The solids were filtered, washed with cold diethyl ether and dried under vacuum to give the title hydrochloride salt (133 mg, 81 % yield).

HPLC retention time: 4.39 min; MS: 354.1 (M+H).

Example 2: (/?)-9-(2-(2,5-Difluorophenyl)ethyl-1 ,1 ,2,2-c/₄)-4-(ethyl-c/₅)-2-methyl-1 - oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride

Following the experimental procedures described in Steps 1 , 2 and 4 of Example 1 , but using intermediates 3B and 5C as starting materials, the title compound was obtained.

HPLC retention time: 4.32 min; MS: 362.2 (M+H). Example 3: 9-(2-(2,5-Difluorophenyl)ethyl-1 ,1 - /₂)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one-2-d hydrochloride

Following the experimental procedures described in Steps 1 , 2 and 4 of Example 1 , but using intermediates 4A and 5B as starting materials, the title compound was obtained.

HPLC retention time: 4.41 min; MS: 356.1 (M+H).

Example 4: 9-(2-(2,5-Difluorophenyl)ethyl-1 ,1,2,2-c/₄)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one-2-d hydrochloride

Following the experimental procedures described in Steps 1 , 2 and 4 of Example 1 , but using intermediates 4A and 5C as starting materials, the title compound was obtained.

HPLC retention time: 4.38 min; MS: 358.1 (M+H).

Example 5: (/?)-9-(2,5-Difluorophenethyl)-4-(ethyl-c/₅)-2 -methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one

Following the experimental procedures described in Steps 1 and 2 of Example 1 , but using intermediates 3B and 5A as starting materials, the title compound was obtained.

HPLC retention time: 4.40 min; MS: 358.2 (M+H).

Example 6: 9-(2,5-Difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one-2,5,5-c/3

Following the experimental procedures described in Steps 1 and 2 of Example 1 , but using intermediates 4B and 5A as starting materials, the title compound was obtained.

HPLC retention time: 4.39 min; MS: 356.2 (M+H).

Example 7: (/?)-9-(2-(2,5-Difluorophenyl)ethyl-1 ,1 -c/₂)-4-(ethyl-c/₅)-2-methyl-1 -oxa- 4,9-diazaspiro[5.5]undecan-3-one

Following the experimental procedures described in Steps 1 and 2 of Example 1 , but using intermediates 3B and 5B as starting materials, the title compound was obtained.

HPLC retention time: 4.41 min; MS: 360.2 (M+H).

BIOLOGICAL ACTIVITY

Pharmacological study

Experimental Part :

In vitro metabolic stability in liver microsomes. The assay was carried out in a robotic liquid handling system (Freedom Evo, Tecan). All incubations were performed individually for each test compound. Compounds (1 mM) were incubated in 96-well plates at 37 °C during 1 h under standard incubation conditions: sodium-potassium phosphate buffer (50 mM, pH 7.4), MgCI₂ (3 mM), the NADPH-regenerating system and CYP content (0.3 nmol/mL). Liver microsomes from mice and mini-pigs used were a male pool. At preset times (0, 10, 20, 40 and 60 min) aliquots of the reaction mixture were stopped with an equal volume of cold acetonitrile. Upon centrifugation of the resultant mixture, supernatants were analyzed by a generic UPLC-MS/MS method. Metabolic stability was determined by the disappearance of compound over time.^1,2 Ln- linear plots of the % of compound remaining based on chromatographic peak area versus time were plotted, and the slope was calculated by linear fitting of the curve. The in vitro metabolic half-life (t-i_/2) was estimated by using the equation 0.693/k where k is the biotransformation rate constant and corresponds to the slope of the In-linear curve. The liver microsomes intrinsic clearance (CW) was calculated using the equation: C W = 0.693/[ti_/2 x (mg of microsomal protein/volume of incubation)]. (1 ) Obach, R. S. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes. Am. Soc. Pharmacol. Exp. Then, 1999 27, 1350-1359.

(2) Di, L; Kerns, E. H.; Hong, Y.; Kleintop T. A.; McConnell, O. J.; Huryn, D. M. Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidates. J. Biomol Screen. 2003 8, 453-462.

The seven deuterated examples (Ex. 1 to Ex. 7) synthesized as described above were tested in this test of biological activity for their In vitro metabolic stability in liver microsomes. As a comparative Example (Comp. Ex.) the non-deuterated Example 70 ((R)-9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one) described in the PCT publication WO2015/185209 was used.

The results shown as % of Parent Compound remaining (1 h, 1 mM, Liver Microsoms) can be seen in Table 1 and 2 below:

Table 1 :

Table 2:

As can be seen in Table 1 , comparing metabolic stability of the non-deuterated comparative compound and its deuterated analogues in mice, the deuterated analogues show better metabolic stability.

In addition, in Table 2, the data in Mini-Pig show that analogues - being deuterated in the N-e thyl moiety - have improved metabolic stability in minipig.

Claims

CLAIMS:

1. Compound of Formula I

wherein

Ri, Rr, Rr, R2, R2’, R3, R₄, R_4', R5, R5’, R6, R6’, R7, R7’, Re, Re’, R9, R9’, R10, R10’, R11 , Rir, R11 ^■, R12, R13 and R_I4 are independently selected from hydrogen and deuterium, wherein at least one of Ri, Rr, Rr, R2, R2', R3, R₄, R₄·, Rs, Rs·, R6, R6·, R7, R7', Rs, Rs·, R₉, Rg·, R10, Rio·, R11 , Rir, R11” R12, R13 and RM is deuterium;

2. Compound according to claim 1 , wherein the compound is a compound according to general formula (I’)

3. Compound according to claim 1 in which the compound is a compound according to general formula (II”)

(II”), wherein Ri, Rr, Rr, R₂, R2', R3, R₄, R₄·, Rs, Rs·, R6 and R6· are independently selected from hydrogen and deuterium, wherein at least one of R₁, Rr, Rr, R₂, R_2', R₃, R₄, R₄·, Rs, Rs·, R6 and Re· is deuterium;

4. Compound according to claim 3, wherein the compound is a compound according to general formula (II’)

5. Compound according to any one of claims 1 , 2, 3 or 4 selected from the group consisiting of:

6. Compound according to claim 1 in that Ri , Rr, Rr, R₂ and R₂· are deuterium, whereas R3, R₄, R₄·, R5, R5', R6 and R6· are hydrogen.

7. Compound according to claim 1 in that R₃ is deuterium, whereas R1 , Rr, Rr, R₂, R₂·, R₄, R_4’, R5, R5’, R6, R6’, R7, R7’, Re, Re’, R9, R9’, R10, R10’, R11 , Rir, R11”, R12, R13 and RI₄ are hydrogen.

8. Compound according to claim 1 in that R₃, R₄ and R₄· are deuterium, whereas R1 , R₂,

R_2', R5, R5', R6, R6', R7, R7', Re, Re·, R9, R9', R10, R10', R11 , Rir, R11 ", R12, R13 and RM are hydrogen.

9. Compound according to claim 1 in that R1 , Rr, Rr, R2, R2', R₄ and R₄· are deuterium, whereas R3, Rs, Rs·, R6, R6·, R7, R7', Re, Re·, R9, R9', R10, Rio·, R11 , Rir, R11 ", R12, R13 and Ri₄ are hydrogen.

10. Compound according to claim 1 in that R3, R₆ and R_6’ are deuterium, whereas R1 , Rr,

R-i ', R₂, R2’, R4, R_4’, R5, R5’, R7, R7’, Re, Re R9, R9’, R10, R10’, R11 , Rir, R11 R12, R13 and

Ri₄ are hydrogen.

1 1. Compound according to claim 1 in that R1 , Rr, Rr, R₂, R_?, R₄, R₄·, Rs and R₅· are deuterium, whereas R3, R6, R6·, R7, R7’, Rs, Rs·, R9, R9’, R10, Rio·, R11 , Ri r and Rn_’are hydrogen.

12. Compound according to claim 1 in that R3, R₄, R₄·, Rs, Rs·, are deuterium, whereas R1 , Rr, Ri”, R2, R2’, R6, R6’, R7, R7’, Rs, Re’, R9, R9’, R10, R10’, R11 , Rir, R11”, R12, R13 and RM are hydrogen.

13. A pharmaceutical composition which comprises a compound as defined in any of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

14. A compound as defined in any of claims 1 to 12 for use as a medicament.

15. A compound as defined in any of claims 1 to 12 for use as a medicament for the treatment of pain, especially medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia.