NEW COMPOUNDS 955

Field of the invention The present invention relates to new compounds, to a pharmaceutical composition containing said compounds and to the use of said compounds in therapy. The present invention also relates to processes for the preparation of said compounds.

Background The current treatment regimes for pain conditions utilise compounds which exploit a very limited range of pharmacological mechanisms. One class of compounds, the opioids, stimulates the endogenous endorphine system; an example from this class is morphine. Compounds of the opioid class have several drawbacks that limit their use, e.g. emetic and constipatory effects and negative influence on respiratory capability. The second major class of analgesics, the non-steroidal antiinflammatory analgesics of the COX-I or COX-2 types, also have liabilities such as insufficient efficacy in severe pain conditions and at long term use the COX-I inhibitors cause ulcers of the mucosa. Mechanisms of analgesic effects of other currently used medicines are insufficiently characterized and/or have limited therapeutic potential.

Local anesthetics, that are known to block most types of sodium channels in nerves, are useful for relieving pain in small areas of the human body and for blocking nerve conduction from the periphery to the central nervous system. They can also be used in the last-mentioned way to block sensory signalling by instilling solutions of local anesthetics at the spinal cord. Due to their high toxicity, in particular heart toxicity, they can not, however, be used for systemic administration as generally useful analgesics. There remains thus a need for more selective modulators of sodium channels involved in pain signal conduction.

Nine sodium channel subtypes have been cloned and functionally expressed to date. (Wood JN, Baker M.. Current Opinion in Pharmacology 2001, 1, 17-21). They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels (NaV:s) are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. By application of genetic analysis it has been shown that a mutation in the gene coding for sodium channel NaVl .7, making this protein non- functional, can make a human become almost insensitive to pain (Cox JJ et al. Nature 2006, 444, 894-898).

It is well known that the voltage-gated sodium channels in nerves play a critical role in neuropathic pain (Baker MD and Wood JN. Trends in Pharmacological Sciences 2001, 22, 27-31). Injuries of the peripheral nervous system often result in neuropathic pain persisting long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. NaVl.7 is expressed in human neuromas, which are swollen and hypersensitive nerves and nerve endings that are often present in chronic pain states {Acta Neurochirurgica 2002, 144, 803-810).

In rat models of peripheral nerve injury, ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function (Mao J and Chen LL, Pain, 2000, 87, 7-17).

In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS).

EP1258484 discloses certain LPA (lysophosphatidic) receptor antagonists. US20060194850 discloses certain compounds with LPA inhibitory action.

DISCLOSURE OF THE INVENTION

According to the invention there is provided a compound of formula I,

wherein: R ¹ is hydrogen, halo, cyano, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, Ci _-3 alkoxy, C ₃ _ ₆ Cycloalkyl, Ci-efluoroalkoxy, Ci- _ό hydroxyalkyl, or Ci- ₆ cyanoalkyl;

R ² and R ³ is each and independently selected from halo, C^alkyl, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, C _3-7 cycloalkyl, Ci _-3 alkoxy, and cyano;

R ⁴ is hydrogen, or which may be optionally substituted by Ci _-3 alkoxy, halo, or cyano;

R ⁵ is halogen, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, C _3-6 cycloalkyl, Cβ-ioheterocycloalkyl, Ci _-6 fluoroalkyl, Ci _-6 fluoroalkoxy, CN, Ci _-3 alkoxyCi _-3 alkyl, hydroxyCi _-6 alkyl, or cyanoCi- ₆ alkyl;

m is 0 to 3; A is NH or O;

L is Ci_4alkylene, where each alkylene hydrogen may be optionally substituted by R ⁶ ;

R ⁶ is C _1-4 alkyl, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, C ₃ . ₆ cycloalkyl, Cβ.ioheterocycloalkyl, C _1-6 fluoroalkyl, Ci- _ό fluoroalkoxy, cyano, Ci _-6 hydroxyalkyl, or Ci- ₆ cyanoalkyl;

M is C _ό -ioaryl or Cs-ioheteroaryl, each optionally and independenly substituted by one or more substituents R ⁷ ;

R ⁷ is hydroxy, halo, cyano, nitro, Ci_6alkyl, C ₂ -6alkynyl, Ci_6alkoxy, Ci-6alkoxyalkyl, trifluoromethoxy, difluoromethoxy, mono- or polysubstituted Ci-ofluoroalkyl, mono- or polysubstituted Ci _-6 fluoroalkoxy, carbamoyl, sulphamoyl, Ci-6cyanoalkyl, phenyl, C3_6Cycloalkyl, Cβ-ecycloalkyloxy-, Cs-δheterocycloalkyl, Cs-δheterocycloalkyloxy, Cs- _ό heteroaryl, Ci. ₆ alkoxycarbonyl, λ/-(Ci. ₆ alkyl) _n carbamoyl wherein n is 0 to 2, Ci. ₆ alkylS(O) _a wherein a is 0 to 2, mono- or polysubstituted Ci _-6 fluoroalkylSO ₂ O, NR ⁹ R ¹⁰ , TV-(C i _-6 alkyl)sulphamoyl, or λ/,λ/-(Ci.6alkyl) ₂ Sulphamoyl; and

R ⁹ and R ¹⁰ is each and independently selected from hydrogen, or C _1-4 alkyl;

as well as a pharmaceutically acceptable salt, or isomer thereof, or a salt of said isomer;

with the exception of the compounds:

• 3-[[2,6-bis(dimethylamino)phenyl]methyl]- 1 -[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2- oxazol-4-yl]urea;

• l-[(2,6-dichlorophenyl)methyl]-3-[3-(2,6-dichlorophenyl)-5-m ethyl-l,2-oxazol-4- yl]urea; • 1 - [3 -(2,6-dichlorophenyl)-5 -methyl- 1 ,2-oxazol-4-yl] -3 - [3 ,3 ,3 -trifluoro-2-( 1 H-pyrrol-2- yl)propyl]urea;

• 1 - [3 -(2,6-dichlorophenyl)-5 -methyl- 1 ,2-oxazol-4-yl]-3-(3-imidazol- 1 -ylpropyl)urea;

• [3-(2,5-dimethylpyrrol- 1 -yl)thiophen-2-yl]methyl N-[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yl] carbamate; • [3-(2,5-dimethylpyrrol-l-yl)thiophen-2-yl]methyl N-[3-(2-chloro-6-fiuoro-phenyl)-5- methyl- 1 ,2-oxazol-4-yl] carbamate;

• (2,3,4,5,6-pentamethylphenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol- 4-yl]carbamate;

• (2-chloro-6-fluoro-phenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4- yl] carbamate;

• (3,5-dichlorophenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l ,2-oxazol-4- yljcarbamate; and • (2,6-dichloropyridin-4-yl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4- yljcarbamate.

One embodiment of the invention is related to compounds of formula I wherein R ¹ is such as methyl, ethyl, propyl, or butyl.

In a further embodiment R ¹ is such as methoxymethyl, ethoxymethyl or methoxy ethyl.

In still an embodiment of the invention, R ¹ is hydrogen.

A further embodiment of the invention is related to compounds of formula I wherein R ² is a halogen such as chlorine or fluorine.

In yet an embodiment R is such as methyl, ethyl, propyl, or butyl.

One embodiment of the invention is related to compounds of formula I wherein R ³ is halogen such as chlorine or fluorine.

In still an embodiment R ³ is such as methyl, ethyl, propyl, or butyl.

Still an embodiment of the invention is related to compounds of formula I wherein R ⁴ is hydrogen, or Ci _-4 alkyl such as methyl, ethyl, propyl, or butyl.

Yet an embodiment of the invention is related to compounds of formula I wherein A is O. A further embodiment is related to compounds of formula I wherein A is NH.

One embodiment of the invention is related to compounds of formula I wherein L is such as methylene, ethylene, propylene or butylene.

One embodiment of the invention is related to compounds of formula I wherein M is C _ό -ioaryl. In still an embodiment M is phenyl.

Yet an embodiment of the invention is related to compounds of formula I wherein M is Cs-ioheteroaryl. In still an embodiment M is pyridinyl or imidazolyl.

One embodiment of the invention is related to compounds of formula I wherein R ⁷ is halo, Ci-6alkyl, Ci_6alkoxy, mono or polysubstituted Ci-efluoroalkoxy, C3_6Cycloalkyl, Cβ-ecycloalkyloxy, Cs-όheterocycloalkyloxy-, Cs-όheteroaryl, or NR ⁹ R ¹⁰ where R ⁹ and R ¹⁰ is each and independently selected from hydrogen or C _1-4 alkyl.

In one embodiment R ⁷ is halo such as chlorine, fluorine or bromine.

In yet an embodiment R ⁷ is methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, or iso- butoxy.

In yet an embodiment R ⁷ is methyl, ethyl, n-propyl, iso-propyl, n-butyl, or iso-butyl.

In still an embodiment R ⁷ is amino or dimethylamino.

In yet an embodiment R ⁷ is cyclopentyloxy, or 4-tetrahydropyranyloxy.

In still an embodiment R ⁷ is pyrazolyl, or imidazolyl.

One embodiment of the invention is related to a compound of formula I, wherein R ¹ is hydrogen, C _1-4 alkyl, chloro or fluoro; R ² and R ³ is each and independently selected from halo or C _1-4 alkyl; R ⁴ is hydrogen, or C _1-4 alkyl; m is 0;

A is NH or O;

L is where each alkylene hydrogen may be optionally substituted by R ⁶ ;

R ⁶ is Ci _-4 alkyl;

M is C _ό -ioaryl or Cs.ioheteroaryl;

R ⁷ is halo, C _1-6 alkyl, Ci_6alkoxy, mono or polysubstituted d-efluoroalkoxy, Cβ-όCycloalkyl,

Cβ-όCycloalkyloxy-, Cs-όheterocycloalkyloxy-, Cs-όheteroaryl, Or NR ⁹ R ¹⁰ ; and

R ⁹ and R ¹⁰ is each and independently selected from hydrogen or C _1-4 alkyl.

Yet an embodiment of the invention is a compound selected from any one of:

(2-chloro-6-fluoro-phenyl)methyl N-[3-(2,6-dichlorophenyl)-5-ethyl-l,2-oxazol-4- yl] carbamate;

(2-chlorophenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yl] carbamate; (2,5-dichlorophenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l ,2-oxazol-4- yl] carbamate;

(3-dimethylaminophenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4- yl] carbamate;

(6-propan-2-yloxypyridin-3-yl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4- yl] carbamate;

(6-cyclopentyloxypyridin-3-yl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4- yl] carbamate;

(3-methylimidazol-4-yl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4- yl] carbamate; (2-chloro-6-fluoro-phenyl)methyl N-[3-(2-chloro-6-fluoro-phenyl)-5-methyl-l ,2-oxazol-4- yl] carbamate;

(2-chloro-6-fluoro-phenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4-yl]-N- methyl-carbamate;

(6-propan-2-yloxypyridin-3-yl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4- yl]-N-methyl-carbamate;

(2-chlorophenyl)methyl N-[3-(2,6-dichlorophenyl)-5-(methoxymethyl)l,2-oxazol-4- yl] carbamate;

(2-chloro-6-fluoro-phenyl)methyl N-[3-(2,6-dichlorophenyl) 1 ,2-oxazol-4-yl] carbamate; l-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4-yl]-3-[(3-fl uorophenyl)methyl]urea;, 3-[(2-chloro-6-fluoro-phenyl)methyl]-l-[3-(2,6-dichloropheny l)-5-methyl-l,2-oxazol-4- yl]urea;

3-[(2,4-dichlorophenyl)methyl]- 1 -[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yl]urea;

1 - [3 -(2,6-dichlorophenyl)-5 -methyl- 1 ,2-oxazol-4-yl] -3 - [(4-propan-2- y lpheny l)methy l]urea; ,

1 -[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yl]-3-[(2-methoxypyridin-3- yl)methyl]urea; l-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4-yl]-3-[(4-py razol-l- ylphenyl)methyl]urea;

1 -[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yl]- 1 -methyl-3-[(4-pyrazol-l - ylphenyl)methyl]urea;

1 -[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yl]-3-[(2-methoxypyridin-3-yl)methyl]- 1 -methyl-urea;

1 - [3 -(2,6-dichlorophenyl)-5 -methyl- 1 ,2-oxazol-4-yl] - 1 -methyl-3 - [ [6-(oxan-4- yloxy)pyridin-3 -yl]methyl]urea;

(2-chloro-6-fluoro-phenyl)methyl N-[3-(2,6-dimethylphenyl)-5-methyl-l,2-oxazol-4- yl] carbamate; 3-[(2-chloro-6-fluoro-phenyl)methyl]-l-[3-(2,6-dimethylpheny l)-5-methyl-l,2-oxazol-4- yl]urea; l-[3-(2,6-dimethylphenyl)-5-methyl-l,2-oxazol-4-yl]-3-[(6-pr opan-2-yloxypyridin-3- yl)methyl]urea; l-[3-(2,6-dimethylphenyl)-5-methyl-l,2-oxazol-4-yl]-3-[(4-py razol-l- ylphenyl)methyl]urea;

(4-bromophenyl)methyl N-[3-(2,6-dimethylphenyl) 1 ,2-oxazol-4-yl] carbamate;

(3-dimethylaminophenyl)methyl N-[3-(2,6-dimethylphenyl) 1 ,2-oxazol-4-yl] carbamate; l-[3-(2,6-dichlorophenyl)-5-(methoxymethyl)isoxazol-4-yl]-3- {[6-(tetrahydro-2H-pyran-4- y loxy)pyridin-3 -y ljmethy 1 } urea; 1 -[3-(2,6-dimethylphenyl)-5-methylisoxazol-4-yl]- 1 -methyl-3-[4-(lH-pyrazol- 1 - yl)benzyl]urea; l-[3-(2,6-dimethylphenyl)-5-methylisoxazol-4-yl]-3-[(6-isopr opoxypyridin-3-yl)methyl]-

1-methylurea; and

1 -[3-(2,6-dimethylphenyl)-5-methylisoxazol-4-yl]- 1 -methyl-3- {[6-(tetrahy dro-2H-pyran-4- yloxy)pyridin-3-yl]methyl}urea.

For the avoidance of doubt it is to be understood that in this specification 'C _1-6 ' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.

In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups and may be, but are not limited to methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl. The term is an alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl or tert-butyl.

In this specification, unless stated otherwise, the term "alkenyl" includes both straight and branched chain alkenyl groups. The term "C ₂ - ₆ alkenyl" is an alkenyl group having from 2 to 6 carbon atoms and one or two double bonds, such as vinyl, allyl, propenyl, butenyl, crotyl, pentenyl, or hexenyl. A butenyl group may for example be buten-2-yl, buten-3-yl or buten-4-yl.

In this specification, unless stated otherwise, the term "alkynyl" includes both straight and branched chain alkynyl groups. The term "C ₂ - ₆ alkynyl" is an alkynyl group having from 2 to 6 carbon atoms and one or two trippel bonds, such as etynyl, propargyl, pentynyl or hexynyl. A butynyl group may for example be butyn-3-yl or butyn-4-yl.

The term "alkoxy", unless stated otherwise, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. The term "Ci- ₆ alkoxy" may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, cyclopentylmethoxy, allyloxy or propargyloxy.

The term "alkanoyl", unless stated otherwise, refers to radicals of the general formula - C(O)-R, wherein R is selected from a hydrocarbon radical. The term "Ci- ₆ alkanoyl" may include, but is not limited to, acetyl, propanoyl or butanoyl.

In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system. The term "Cβ.iocycloalkyl" may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "cycloalkyloxy-" refers to a cycloalkyl group attached to the rest of the molecule via the 0-atom of the oxy-group.

In this specification, unless stated otherwise, the term "heterocycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system and which further comprises one or more heteroatoms selected from O, N or S. The term "Cβ.ioheterocycloalkyl" may be, but is not limited to, pyrrolidino, morpholino, pyrazolino, indolino or oxazolidino.

The term "heterocycloalkyloxy-" refers to a heterocycloalkyl group attached to the rest of the molecule via the O-atom of the oxy-group.

The term "aryl" used alone or as suffix or prefix, refers to a hydrocarbon group having one or more polyunsaturated carbon rings of aromatic character, having from 5 to 14 carbon atoms. The term "C _6-10 aryl", may without limitation be phenyl, naphthyl and the like.

The term "aryloxy", when used herein includes C _6-10 aryloxy groups such as phenoxy, naphthoxy and the like. For the avoidance of doubt, aryloxy groups referred to herein are attached to the rest of the molecule via the O-atom of the oxy-group. Unless otherwise specified, aryl and aryloxy groups may be substituted by one or more substituents including -OH, halo, cyano, nitro, Ci _-6 alkyl, Ci _-6 alkoxy or sulfamoyl.

The term "heteroaryl" used alone or as suffix or prefix, refers to an aromatic ring in which one or more of the from 5-14 atoms in the ring are elements other than carbon, such as N, S and O. Each heteroaryl may be bonded to the rest of the molecule either via a carbon atom of said heteroaryl, or via one nitrogen atom of said heteroaryl.

The term "Co-ioheteroaryl", may be, but is not limited to pyridinyl, imidazolyl, pyrazolyl, naphtyl, quinolinyl, quinazolinyl or indolyl.

The term "heteroaryloxy-" refers to a heteroaryl group attached to the rest of the molecule via the O-atom of the oxy-group.

In this specification, unless stated otherwise, the term "amine" or "amino" refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbon radical.

In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluorine, iodine, chlorine or bromine.

For the avoidance of doubt, it is to be understood that each alkylene hydrogen in the alkylene chain L may optionally and independently be substituted by one or two substituents R ⁶ .

It is also to be understood that M may optionally and independently be substituted by one or more substituents R ⁷ .

The phenyl ring bearing the substituents R ² and R ³ , may in addition bear 0, 1, 2 or 3 substituents R ⁵ . When m=0 this means that said phenyl ring does not bear any substituent R ⁵ . When m=l it means that said phenyl ring bears one substituent R ⁵ which may be at any position available for substitution. When m=2 it means that said phenyl ring bears two substituent R ⁵ which may be at any of the three positions available for substitution. When m=3 it means that said phenyl ring bears three substituent R ⁵ . Each substituent R ⁵ may be the same, or different from each other.

It will be appreciated that throughout the specification, the number and nature of substituents on rings in the compounds of the invention will be selected so as to avoid sterically undesirable combinations.

For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

The present invention relates to compounds of formula I as hereinbefore defined, as well as to pharmaceutically acceptable salts thereof. Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts.

Examples of useful pharmaceutically acceptable salts of a compound of the invention is, for example an acid-addition salt such as a salt formed with an inorganic or organic acid. A further example of useful salts is an alkali metal salt such as an alkaline earth metal salt; or a salt formed with an organic base.

Still other pharmaceutically acceptable salts useful in accordance with the invention and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18 ^th Edition, Mack Publishing Co.).

The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The wording "tautomerism" refers to a chemical equilibrium between a keto form and an enol form where the enol and keto forms are tautomers of each other.

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical isomerism, such as one or more enantiomers and/or diastereoisomers. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric esters by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

Compounds of the present invention have been named with the aid of computer software (ACDLabs 8.0 or 9.0/Name(IUPAC)).

Methods of Preparation

One aspect of the present invention is a process for preparing a compound of formula I, or a salt thereof.

Throughout the description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Green 's Protective Groups in Organic Synthesis " P. G. M. Wuts, T. W. Green, Wiley, New York,

2007. References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4 ^th ed. McGraw Hill (1992) or, "Organic Synthesis ", Smith, McGraw Hill, (1994). For representative examples of heterocyclic chemistry see for example "Heterocyclic Chemistry", J. A. Joule, K. Mills, G. F. Smith, 3 ^rd ed. Chapman and Hall (1995), p. 189-224 and "Heterocyclic Chemistry", T. L. Gilchrist, 2" ed. Longman Scientific and Technical (1992), p. 248-282.

The term "room temperature" and "ambient temperature" shall mean, unless otherwise specified, a temperature of from 16 to 25 ⁰ C.

Abbreviations:

Boc tert-butoxycarbonyloxy

DMF 7V,7V-dimethylformamide

DMSO Dimethyl sulphoxide M molar

NCS N-Chlorosuccinimide

PG protective group

THF tetrahydrofuran

One embodiment of the invention relates to a process for the preparation of a compound of formula I according to Method A and B respectively, wherein each substituent is as defined for formula I above unless otherwise specified.

Method A whereby a compound of formula Ia is obtained from the acid of formula II, wherein each substituent is as defined for formula I above, or can be converted to such a group after the compound of Formula Ia is obtained.

II Ia

Compounds of formula II are commercially available or can be readily synthesized by procedures descibed in the literature, for example as depicted in Scheme 1 (see for example Journal of Organic Chemistry 1980, 45, 3916 and Journal of Organic Chemistry 2006, 71, 3221).

Scheme 1

The synthesis of a compound of formula Ia may be obtained by employing a Curtius type rearrangement reaction on the acids of formula II to give a compound of formula Ia. A compound of formula II, an alcohol or an amine, and diphenyl phosphorylazide are mixed in a solvent, typically dioxane, and heated at a temperature of from 70 ⁰ C to 200 ⁰ C during a period of from 5 min to 16 h, typically at 180 ⁰ C for 5 min in a microwave oven.

Method B whereby the target compound of formula I is obtained from a compound of formula Ia by introducing the R ⁴ substituent using standard methods described in the literature, for example:

Ia Ib

Compounds of formula Ib may be prepared by dissolving a compound of formula Ia in an aprotic solvent such as DMSO and treating it with a base such as sodium hydride at a temperature of from 0 ⁰ C to room temperature such as at a temparature of 0 ⁰ C, for 5 min, thereafter adding an alkylating reagent such as iodomethane. The compound of formula Ib, when BOC-protected, can also be deprotected to the secondary amine which then can be treated with a suitable amine and a coupling reagent such as N,N'-carbonyldiimidazole to give a compound of formula Ib.

Method C whereby a compound of formula Ib is obtained from the amine of formula III wherein each substituent is as defined for formula I above, by treatment with an amine R ⁷ MLNH ₂ in the presence of a carbonylated reagent, for example, N,N'-carbonyldiimidazole.

III Ib

Compounds of formula III can be readily synthesized by procedures descibed in the literature, for example as depicted in Scheme 2, wherein each substituent is as defined for formula I above.

MeI

NaH

THF

Pharmaceutical compositions

According to one embodiment of the present invention there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

The pharmaceutical composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream or for rectal administration e.g. as a suppository.

In general the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.

A suitable daily dose of a compound of the invention in the treatment of a mammal, in- eluding man, is approximately from 0.1 to 100 mg/kg bodyweight at peroral administration and from about 0.01 to 250 mg/kg bodyweight at parenteral administration.

The typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.

Medical Use

Compounds according to the present invention are contemplated to be useful in therapy. Compounds of formula I as herein described and claimed, or a pharmaceutically acceptable salt thereof, as well as their corresponding active metabolites, exhibit a high degree of potency at the sodium channel NaVl .7 and also selectivity for this channel compared with other essential sodium channels. Accordingly, compounds of the present invention are expected to be useful in the treatment of conditions associated with upregulation of NaV 1.7 and other sodium channels present in C-fibers.

Compounds of the invention may be used to produce an inhibitory effect of sodium channels in mammals, including man.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in the manufacture of a medicament for the treatment of NaVl .7 mediated disorders.

Compounds of formula I according to the invention are expected to be useful for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is the use of a compound of formula I, for the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of a compound of formula I, for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of a compound of formula I, for the treatment of epilepsy.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the treatment of pain conditions related to arthritis, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis or ischeamic pain.

One embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, in therapy.

Still an embodiment of the invention relates to the use of a compound of formula I as hereinbefore defined, for the manufacture of a medicament for the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is the use of a compound of formula I, for the manufacture of a medicament for use in the treatment of of epilepsy.

Still an embodiment of the invention relates to a method for the treatment of any one of the following pain disorders such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout; whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.

Still an aspect of the invention is a method for the treatment of a vascular headache such as migraine, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.

Yet an aspect of the invention is a method for the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder, whereby a compound of formula I as hereinbefore defined, is administered to a subject in need of such treatment.

Still an embodiment of the present invention is a method for the treatment of epilepsy, whereby a compound of formula I as hereinbefore defined is administered to a subject in need of such treatment.

Yet an embodiment of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a pain disorder such as: acute pain; chronic pain; neuropathic pain such as diabetic neuropathies; inflammatory pain associated with arthritis and rheumatoid diseases; low back pain; post-operative pain; pain associated with various conditions including cancer, angina, renal or billiary colic, menstruation, fibromyalgia, low back pain, post-operative pain, cancer

pain, visceral pains such as chronic pelvic pain, cystitis, IBS, pancreatitis, ischeamic pain, or gout.

Still an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of a vascular headache such as migraine.

Yet an aspect of the invention is a compound of formula I as hereinbefore defined, for use in the treatment of pain conditions related to erythermalgia, psoriasis, emesis, urinary incontinence and hyperactive bladder.

Still an embodiment of the present invention is a compound of formula I as hereinbefore defined, for use in the treatment of epilepsy.

Still an embodiment of the invention is any one compound selected from:

• 3-[[2,6-bis(dimethylamino)phenyl]methyl]- 1 -[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2- oxazol-4-yl]urea;

• l-[(2,6-dichlorophenyl)methyl]-3-[3-(2,6-dichlorophenyl)-5-m ethyl-l,2-oxazol-4- yl]urea; • 1 - [3 -(2,6-dichlorophenyl)-5 -methyl- 1 ,2-oxazol-4-yl] -3 - [3 ,3 ,3 -trifluoro-2-( 1 H-pyrrol-2- yl)propyl]urea;

• 1 - [3 -(2,6-dichlorophenyl)-5 -methyl- 1 ,2-oxazol-4-yl]-3-(3-imidazol- 1 -ylpropyl)urea;

• [3-(2,5-dimethylpyrrol- 1 -yl)thiophen-2-yl]methyl N-[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yl] carbamate; • [3-(2,5-dimethylpyrrol-l-yl)thiophen-2-yl]methyl N-[3-(2-chloro-6-fiuoro-phenyl)-5- methyl- 1 ,2-oxazol-4-yl] carbamate;

• (2,3,4,5,6-pentamethylphenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol- 4-yl]carbamate;

• (2-chloro-6-fluoro-phenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4- yl] carbamate;

• (3,5-dichlorophenyl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l ,2-oxazol-4- yljcarbamate; and

• (2,6-dichloropyridin-4-yl)methyl N-[3-(2,6-dichlorophenyl)-5-methyl-l ,2-oxazol-4- yl] carbamate; for use in therapy, such as for use in the treatment of a pain disorder, including each disorder disclosed above for a compound of formula I.

In the context of the present specification, the term "therapy" and "treatment" includes prevention and prophylaxis, unless there are specific indications to the contrary. The terms "treat", "therapeutic" and "therapeutically" should be construed accordingly.

In this specification, unless stated otherwise, the term "inhibitor" and "antagonist" mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the ligand.

The term "disorder", unless stated otherwise, means any condition and/or disease associated with NaVl .7 activity.

Combinations

Pain treatment as defined herein may be applied as a sole therapy or may involve, in addition to a compound according to the invention, administration of other analgesics or adjuvant therapy. Such therapy may for example include in combination with a compound of the present invention, one or more of the following categories of pain-relieving ingredients:

a) opioid analgesics, for example morphine, ketobemidone or fentanyl; b) analgesics of the NSAID or COX- 1/2 class, for example ibuprofene, naproxene, celecoxib or acetylsalicylic acid, and their analogues containing nitric oxide- donating groups; c) analgesic adjuvants such as amitriptyline, imipramine, duloxetine or mexiletine; d) NMDA antagonists for example ketamine or dextrometorfan; e) sodium channel blocking agents, for example lidocaine; f) anticonvulsants, for example carbamazepine, topiramate or lamotrigine; g) anticonvulsant/analgesic amino acids such as gabapentin or pregabalin; h) cannabinoids.

Each active compound of such a combination may be administered simultaneously, separately or sequentiallly.

Examples

General methods

All starting materials are commercially available or described in the literature.

NMR spectra were recorded on a Varian Mercury Plus 400 NMR Spectrometer, operating at 400 MHz and equipped with a Varian 400 ATB PFG probe; or on a Varian Unity+ 400 NMR Spectrometer, operating at 400 MHz for proton and 100 MHz for carbon- 13, and equipped with a 5 mm BBO probe with Z-gradients; or on a Bruker av400 NMR spectrometer operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 3 mm flow injection SEI ¹ HZD- ¹³ C probe head with Z-gradients, using a BEST 215 liquid handler for sample injection; or on a Bruker DPX400 NMR spectrometer, operating at 400 MHz for proton and 100 MHz for carbon-13, and equipped with a 4-nucleus probe with Z-gradients. The following reference signals were used: TMS δ 0.00, or the residual solvent signal of DMSOd ₆ δ 2.49, CD ₃ OD δ 3.31 or CDCl ₃ δ 7.25 (unless otherwise indicated). Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broad, respectively.

Mass spectra were recorded on one of the following instruments:

A) A LC-MS system consisting of a Waters Alliance 2795 HPLC, a Waters PDA 2996 diode array detector, a Sedex 75 or 85 ELS detector and a ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode. The capillary voltage was set to 3.2 kV and the cone voltage to 30 V, respectively. The mass spectrometer scanned between m/z 100-700 with a scan time of 0.3s. The diode array detector scanned from 200-400 nm. The temperature of the ELS detector was adjusted to 40 ⁰ C and the pressure was set to 1.9 bar. Separation was performed on an X-Terra MS C8, 3.0 mm x 50 mm, 3.5 μm (Waters) run at a flow rate of 1 ml/min. A linear gradient was applied starting at 100% A (A: 1OmM

NH ₄ OAc in 5% CH3CN, or 8 mM HCOOH in 5% CH ₃ CN) ending at 100% B (B: CH ₃ CN). The column oven temperature was set to 40 ⁰ C.

B) A LC-MS consisting of a Waters sample manager 2111 C, a Waters 1525 μ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative ion mode. The mass spectrometer scanned between m/z 100-700 with a scan time of 0.3s. The capillary voltage was set to 3.4 kV and the cone voltage was set to 30 V, respectively. The diode array detector scanned from 200-400 nm. The temperature of the ELS detector was adjusted to 40 ⁰ C and the pressure was set to 1.9 bar. For separation a linear gradient was applied starting at 100 % A (A: 10 mM NH4OAc in 5 % CH ₃ CN or 8 mM HCOOH in 5% CH ₃ CN) and ending at 100 % B (B: CH ₃ CN). The column used was a Gemini C 18, 3.0 mm x 50 mm, 3 μm, (Phenomenex) which was run at a flow rate of 1 ml/min. The column oven temperature was set to 40 ⁰ C.

C) A LC-MS consisting of a Waters sample manager 2111 C, a Waters 1525 μ binary pump, a Waters 1500 column oven, a Waters ZQ single quadrupole mass spectrometer, a Waters PDA2996 diode array detector and a Sedex 85 ELS detector. The mass spectrometer was configured with an atmospheric pressure chemical ionisation (APCI) ion source which was further equipped with atmospheric pressure photo ionisation (APPI) device. The mass spectrometer scanned in the positive mode, switching between APCI and APPI mode. The mass range was set to m/z 120-800 using a scan time of 0.3 s. The APPI repeller and the APCI corona were set to 0.86 kV and 0.80 μA, respectively. In addition, the desolvation temperature (300 ⁰ C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) were constant for both APCI and APPI mode. Separation was performed using a Gemini column C 18, 3.0 mm x 50 mm, 3 μm, (Phenomenex) and run at a flow rate of 1 ml/min. A linear gradient was used starting at 100 % A (A: 10 mM NH ₄ OAc in 5% MeOH) and ending at 100% B (MeOH). The column oven temperature was set to 40 ⁰ C.

Preparative chromatography was run on Waters auto purification HPLC with a diode array detector. Column: XTerra MS C8, 19 x 300 mm, 10 μm. Gradient with CH ₃ CNA). IM NH ₄ OAc in 5 % CH ₃ CN in MiIIiQ Water, run from 20% to 60% CH ₃ CN, in 13 min. Flow

rate: 20 ml/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a Shimadzu SPD-IOA UV- vis. -detector equipped with a Waters Symmetry ^® column (C 18, 5 μm, 100 mm x 19 mm). Gradient with CH ₃ CNA).1% trifluoroacetic acid in MiIIiQ Water, run from 35% to 60% CH ₃ CN in 20 min. Flow rate: 10 ml/min. Alternatively, another column was used; Atlantis C18 19 x 100 mm, 5 μm column. Gradient with CH ₃ CN/0.1M NH ₄ OAc in 5% CH ₃ CN in MiIIiQ Water, run from 0% to 35-50% CH ₃ CN, in 15 min. Flow rate: 15 ml/min.

Microwave irradiation was performed in a Creator ^™ , Initiator ^™ or Smith Synthesizer ^™ Single -mode microwave cavity producing continuous irradiation at 2450 MHz.

Column chromatography was performed using Merck Silica gel 60 (0.040-0.063 mm), or employing a Combi Flash ^® Companion ^™ system using RediSep ^™ normal-phase flash columns.

Method 1: General procedure for the preparation of examples 1-8, 11-18 and 22-28 via Curtius rearrangement.

The corresponding carboxylic acid (0.4 mmol), diphenyl phosphorylazide (110 mg, 0.4 mmol), triethylamine (0.4 mmol) and the alcohol or amine (0.8 mmol) were mixed in dioxane (ImL) and heated in a microwave oven for 5 min at 180 ⁰ C. The reaction mixture was purified by preparative HPLC affording the carbamate or urea.

Method 2: General procedure for the preparation of examples 19-21 and 29-31 via urea formation with N,N'-carbonyldiimidazole.

The corresponding primary amine (33.7 mg, 0.19 mmol) was dissolved in DMF (0.5 mL) and N,N'-carbonyldiimidazole (31.5 mg, 0.19 mmol) was added. The mixture was stirred for 20 min at room temperature a then the secondary amine (50 mg, 0.19 mmol) was added and the mixture was stirred at 8O ⁰ C for 16 h. The product urea was obtained by preparative HPLC purification.

Intermediates

Intermediate 1

methyl 3-(2,6-dimethylphenyl)l ,2-oxazole-4-carboxylate

(NZ)-N-[chloro-(2,6-dimethylphenyl)methylidene]hydroxylamine (1.62 g, 8.8 mmol, prepared according to the method described in Journal of Organic Chemistry 1980, 45, 3916) and [(E)-2-methoxycarbonylethenyl] 4-nitrobenzoate (1.85 g, 7.3 mmol, prepared according to the method described in Journal of Heterocyclic Chemistry 2000, 37, 75) were mixed in dry dichloromethane (12 mL) and triethylamine (3.0 mL, 22.0 mmol) was slowly added via a syringe. The mixture was stirred at room temperature for 16 h then diluted by water and the phases were separated. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude was purified by column chromatography using (heptane : ethyl acetate= 100:0 to 50:50 gradient) affording the methyl ester as a yellowish brown solid (0.79 g, 39% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.08 (s, 1 H), 7.27 (s, 1 H), 7.12 (d, 2 H), 3.73 (s, 3 H), 2.10 (s, 6 H); MS (ESI) m/z 232 [M+H].

Intermediate 2

3-(2,6-dimethylphenyl) 1 ,2-oxazole-4-carboxylic acid

The ester intermediate 1 (0.416 g, 1.8 mmol) was refiuxed in a mixture of concentrated acetic acid (1.8 mL) and concentrated hydrochloric acid (1.5 mL) for 3 h. The solvents were removed in vacuo and the residue was treated with water. The resulted pink solid was collected by filtration (0.347 g, 89% yield). ¹ U NMR (400 MHz, DMSO-J ₆ ) δ (ppm) 9.72 (s, 1 H), 7.26 (t, 1 H), 7.13 (d, 2 H), 2.00 (s, 6 H); MS (ESI) m/z 218 [M+H].

Intermediate 3

3-(2,6-dichlorophenyl)l ,2-oxazole-4-carboxylic acid

The title compound was prepared by the same method as described for the syntesis of intermediates 1 and 2; MS (ESI) m/z 258 [M+H].

Intermediate 4

methyl 3-(2,6-dimethylphenyl)-5-methyl- 1 ,2-oxazole-4-carboxylate (NZ)-N-[chloro-(2,6-dimethylphenyl)methylidene]hydroxylamine (1.34 g, 7.3 mmol, prepared according to the method described in Journal of Organic Chemistry 1980, 45, 3916) and methyl but-2-ynoate (0.72 g, 7.3 mmol) were mixed in dry tetrahydrofuran (15 mL), cooled down to 0 ⁰ C and set under N ₂ atmosphere. Triethylamine (2.0 mL, 14.6 mmol) was added slowly via a syringe and the resulted slurry was refluxed for 5 days. Thereafter the cold mixture was filtered through celite and the solvent was removed in vacuo. The residual oil was purified by column chromatography (heptane: ethyl acetate= 100:0 to 90:10 gradient) furnishing the product as a colorless oil (1.6 g, 88% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.24 (s, 1 H), 7.10 (d, 2 H), 3.66 (s, 3 H), 2.79 (s, 3 H), 2.10 (s, 6 H); MS (ESI) m/z 246 [M+H].

Intermediate 5

3-(2,6-dimethylphenyl)-5-methyl- 1 ,2-oxazole-4-carboxylic acid

The title compound was prepared from intermediate 4 by the same method as described for the syntesis of intermediate 2. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.24 (d, 1 H), 7.10 (d, 2 H), 2.79 (s, 3 H), 2.10 (s, 6 H); MS (ESI) m/z 232 [M+H].

Intermediate 6

methyl 3-(2,6-dichlorophenyl)-5-(methoxymethyl)l,2-oxazole-4-carbox ylate The title compound was prepared by the method described for the synthesis of intermediate 4 using (NZ)-N-[chloro-(2,6-dichlorophenyl)methylidene]hydroxylamine (prepared according to the method described in Journal of Organic Chemistry 1980, 45, 3916) and methyl 4-methoxybut-2-ynoate (prepared according to the method described in Journal of American Chemical Society 1988, 110, 860). ¹ U NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.43 - 7.45 (m, 1 H), 7.42 (br. s., 1 H), 7.34 - 7.39 (m, 1 H), 4.96 (s, 2 H), 3.72 (s, 3 H), 3.55 (s, 3 H); MS (ESI) m/z 316 [M+H].

3-(2,6-dichlorophenyl)-5-(methoxymethyl) 1 ,2-oxazole-4-carboxylic acid The title compound was prepared from intermediate 6 by the same method as described for the syntesis of intermediate 2; MS (ESI) m/z 302 [M+H].

Intermediate 8

6-cvclopentyloxypyridine-3-carboxylic acid

To the tetrahydrofuran (10 mL) solution of potassium tert-butoxide (0.864g, 7.7 mmol) cyclopentanol (0.662g, 7.7 mmol) was added at 0 ⁰ C. After 5 min the commercially available 6-chloropyridine-3-carbonitrile (0.97 g, 7.0 mmol) was added. The mixture was allowed to warm up room temperature and stirred for 16 h, thereafter brine was added to the reaction mixture and extracted by ethylacetate. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulted cherry red oil (0.94g, 5.0 mmol) was stirred in 4 M aqueous NaOH solution for 16 h at 100 ⁰ C. The cold mixture was treated with 4 M aqueous HCl solution and the resulted precipitates were collected by filtration, washed with water and dried in vacuo affording the acid as a white solid (0.793 g, 54 % yield). ¹ U NMR (400 MHz, DMSO-J ₆ ) δ (ppm) 8.70 (d, 1 H), 8.10 (dd, 1 H), 6.82 (d, 1 H), 5.43 (m, IH), 1.90 - 2.00 (m, 2 H), 1.65 - 1.74 (m, 4 H), 1.55 - 1.65 (m, 2H); MS (ESI) m/z 208 [M+H].

Intermediate 9

(ό-cvclopentyloxypyridin-S-vDmethanol

Lithium aluminium hydride (31.3 mg, 0.83 mmol) was suspended in dry tetrahydrofuran (1.5 mL) and cooled down to 0 ⁰ C. The acid intermediate 8 (0.114 g, 0.55 mmol) was added portionwise and the mixture was stirred for 2 h at room temperature then cooled back to 0 ⁰ C and water was added (0.017 mL) then 15 % aqueous NaOH solution (0.017 mL) followed by water (0.053 mL). The resulted white precipitates were filtered off and washed with ethyl acetate. The solvent was removed in vacuo affording the alcohol as colorless oil (0.059 g, 64% yield); ¹ U NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.13 (d, 1 H), 7.60 (dd, 1 H), 6.70 (d, 1 H), 5.36 - 5.42 (m, 1 H), 4.62 (d, 2 H), 1.92 - 2.02 (m, 2 H), 1.75 - 1.85 (m, 4 H), 1.52 - 1.72 (m, 3 H); MS (ESI) m/z 194 [M+H].

Intermediate 10

(6-propan-2-yloxypyridin-3-yl)methanol The title compound was prepared via the corresponding acid using the methods described for the synthesis of intermediates 8 and 9. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.11 (d, 1

H), 7.60 (dd, 1 H), 6.69 (d, 1 H), 5.30 (s, 1 H), 4.62 (s, 2 H), 1.70 (br. s., 1 H), 1.35 (d, 6 H). MS (ESI) m/z 168 [M+H].

Intermediate 11

3-(2.6-dichlorophenvπ-N.5-dimethyl-1.2-oxazol-4-amine

Step 1 :

Equimolar mixtures of the commercially available 3-(2,6-dichloro-phenyl)-5-methyl- isoxazole-4-carboxylic acid (5.0 g, 18.3 mmol), triethylamine (2.54 mL, 18.3 mmol) and diphenyl phosphorylazide (5.03 g, 18.3 mmol) in t-butanol was heated under reflux for 6 h.

After this time the reaction mixture showed the formation of single product. The solvent was evaporated and the crude residue was purified by column chromatography eluting with

10 to 30% of ethyl acetate in hexane gave the desired product (4.5 g, 82.7% yield). ¹ H NMR (400 MHz, CDCl ₁ ) δ (ppm) 7.3-7.45 (m, 3H), 6.8 (bs, IH), 2.42 (s, 3H), 1.35 (s,

9H); MS (ESI) m/z 344 [M+H].

Step 2:

To a solution of BOC-protected amine from step 1(4.5 g, 13.6 mmol) in THF (50.0 mL) was added sodium hydride (60% suspension in mineral oil, 0.614 g, 15.4 mmol). After 30 min, iodomethane (1.5 mL, 17.6 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and then water (10.0 mL) was added. The mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the tertiary amine (4.6 g, quantitive yield). ¹ H NMR (400 MHz, CDCl _3. ) δ (ppm) 7.3-7.45 (m, 3H), 2.93 (s, 3H), 2.40 (s, 3H), 1.39 (s, 9H); MS (ESI) m/z 358 [M+H].

Step 3:

The obtained carbamate from step 2 (1.0 g, 2.80 mmol) was dissolved in dichloromethane (14.0 mL) and set under N atmosphere then cooled down to 0 ⁰ C. Trifiuoroacetic acid

(1.51 mL, 19.6 mmol) was added via syringe then the mixture was allowed to warm up to room temperature and stirred for 2 days. The mixture was diluted by water and the phases were separated. The organic layer was washed with water and dried over anhydrous sodium sulfate, filtered and concentrated to afford the title product as an orange oil (0.72 g, 99% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.45 (s, 2 H), 7.37 (s, 1 H), 2.68 (s, 3 H), 2.53 (s, 3 H); MS (ESI) m/z 257 [M+H].

Intermediate 12 r6-(oxan-4-yloxy)pyridin-3-vHmethanamine

The commercially available 6-(tetrahydro-2H-pyran-4-yloxy)nicotinonitrile (1.47 g, 7.20 mmol) was dissolved in methanol (50.0 mL) and hydrogenated in a continuous flow hydrogenating apparatus (H-Cube) using Pd/C (10 % standard cartridge) with 1.3 mL/min flow at 50 ⁰ C. The title product was obtained as yellow oil (1.3 g, 87 % yield) after evaporation of the solvent; MS (ESI) m/z 209 [M+H] .

3-(2.6-dimethylphenvπ-N.5-dimethylisoxazol-4-amine The title compound was prepared from intermediate 5 by the same method as described for the syntesis of intermediate 11.

¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.28 - 7.32 (m, 1 H), 7.15 (d, 2 H), 2.71 (s, 3 H), 2.61 (s, 3 H), 2.15 (s, 6 H); MS (ESI) m/z 217 [M+H].

Example 1

(2-chloro-6-fluoro-phenyl)methyl N-r3-(2,6-dichlorophenyl)-5-ethyl-l,2-oxazol-4- yll carbamate

The titel compound was prepared by general method 1 using the commercially available 3-

(2,6-dichlorophenyl)-5-ethyl-l,2-oxazole-4-carboxylic acid and (2-chloro-6-fluoro- phenyl)methanol; ¹ U NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.32 (d, 1 H), 7.30 (s, 1 H), 7.20 -

7.26 (m, 1 H), 7.16 - 7.20 (m, 1 H), 7.11 (s, 1 H), 6.91 (t, 1 H), 5.68 (s, 1 H), 5.18 (br. s., 2

H), 2.78 (br. s., 2 H), 1.28 (br. s., 3 H); MS (ESI) m/z 443 [M+H].

(2-chlorophenyl)methyl N-r3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4-yllcarbamate The titel compound was prepared by general method 1 using the commercially available 3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (2- chlorophenyl)methanol. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.33 (d, 1 H), 7.31 (s, 1 H), 7.22 - 7.29 (m, 3 H), 7.10 - 7.20 (m, 2 H), 5.82 (br. s., 1 H), 5.11 (s, 2 H), 2.39 (br. s., 3 H); MS (ESI) m/z 411 [M+H].

Example 3

(2,5-dichlorophenyl)methyl N-r3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4- yll carbamate

The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (2,5- dichlorophenyl)methanol. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.36 (s, 2 H), 7.30 (s, 1 H), 7.23 (s, 2 H), 7.17 (s, 1 H), 5.88 (br. s., 1 H), 5.10 (s, 2 H), 2.44 (br. s., 3 H); MS (ESI) m/z 440 [M+H].

Example 4

(3-dimethylaminophenvπmethyl N-[3-(2.6-dichlorophenvπ-5-methyl-1.2-oxazol-4- yl] carbamate

The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (3- dimethylaminophenyl)methanol. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.41 (s, 2 H), 7.34 (s, 1 H), 7.21 (t, 1 H), 6.68 (s, 3 H), 5.82 (br. s., 1 H), 5.06 (s, 2 H), 2.94 (s, 6 H), 2.51 (br. s., 3 H); MS (ESI) m/z 420 [M+H].

Example 5

(6-propan-2-yloxypyridin-3-yl)methyl N-r3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4- yl] carbamate

The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and intermediate 10. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.08 (br. s., 1 H), 7.50 (br. s., 1 H), 7.30 - 7.44 (m, 3 H), 6.63 (d, 1 H), 5.76 (s, 1 H), 5.24 - 5.35 (m, 1 H), 5.01 (br. s., 2 H), 2.49 (br. s., 3 H), 1.35 (d, 6 H); MS (ESI) m/z 436 [M+H].

Example 6

(ό-cvclopentyloxypyridin-S-vDmethyl N-[3-(2.6-dichlorophenvD-5-methyl- 1 ,2-oxazol-4- yl] carbamate

The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and intermediate 9. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.09 (br. s., 1 H), 7.53 (br. s., 1 H), 7.35 (s, 3 H), 6.64 (d, 1 H), 5.72 (br. s., 1 H), 5.35 - 5.43 (m, 1 H), 5.01 (br. s., 2 H), 2.47 (br. s., 3 H), 1.90 - 2.04 (m, 2 H), 1.73 - 1.86 (m, 4 H), 1.54 - 1.70 (m, 2 H); MS (ESI) m/z 462 [M+H].

Example 7

(3-methylimidazol-4-vπmethyl N-[3-(2.6-dichlorophenvπ-5-methyl-1.2-oxazol-4- yll carbamate

The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (3-methylimidazol-4- yl)methanol. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.16 - 7.52 (m, 5 H), 6.12 (br. s., 1 H), 5.11 (br. s., 2 H), 3.58 (br. s., 3 H), 2.50 (s, 3 H); MS (ESI) m/z 381 [M+H].

Example 8

(2-chloro-6-fluoro-phenvDmethyl N-[3-(2-chloro-6-fluoro-phenviy5-methyl- 1 ,2-oxazol- 4-vH carbamate

The titel compound was prepared by general method 1 using the commercially available 3- (2-chloro-6-fluoro-phenyl)-5 -methyl- 1 ,2-oxazole-4-carboxylic acid and (2-chloro-6-fluoro- phenyl)methanol. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.37 - 7.44 (m, 1 H), 7.28 - 7.34 (m, 2 H), 7.19 - 7.24 (m, 1 H), 7.11 (t, 1 H), 7.02 (t, 1 H), 5.89 (br. s., 1 H), 5.28 (br. s., 2 H), 2.50 (br. s., 3 H); MS (ESI) m/z 413 [M+H].

Example 9

(2-chloro-6-fluoro-phenyl)methyl N-r3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4-yll-N- methyl-carbamate

In a 2 mL microwave vial commercially available (2-chloro-6-fluoro-phenyl)methyl N-[3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4-yl]carbamate (43 mg, 0.1 mmol) was stirred in DMF (0.6 mL) at room temperature and sodium hydride (2.5 mg, 0.105 mmol) was added. The mixture was set under N ₂ atmosphere and after 5 min iodomethane (10 μL, 0.15 mmol) was added via a syringe. The mixture was allowed to stir for 1.5 h at room temperature and then 0.1 mL water was added and purified by preparative HPLC furnishing the product (31 mg, 70% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.25 - 7.42 (m, 4 H), 7.20 (s, 1 H), 7.00 (t, 1 H), 5.25 (s, 2 H), 3.01 (s, 3 H), 2.34 (s, 3 H); MS (ESI) m/z 443 [M+H].

Example 10

(6-propan-2-yloxypyridin-3-yl)methyl N-r3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4- yll-N-methyl-carbamate The title compound (17 mg, 63% yield, colorless oil) was prepared from example 5 (26 mg, 0.06 mmol) employing the same method as for the synthesis of example 9. ¹ H NMR

(400 MHz, CDCl ₃ ) δ (ppm) 8.04 (d, 1 H), 7.45 (dd, 1 H), 7.28 - 7.40 (m, 3 H), 6.60 (d, 1 H), 5.24 - 5.35 (m, 1 H), 4.95 (s, 2 H), 3.05 (s, 3 H), 2.35 (s, 3 H), 1.36 (d, 6 H); MS (ESI) m/z 450 [M+H].

Example 11

(2-chlorophenyl)methyl N-r3-(2,6-dichlorophenyl)-5-(methoxymethyl)l,2-oxazol-4- yll carbamate

The titel compound was prepared by general method 1 using intermediate 7 and the commercially available (2-chlorophenyl)methanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.44 (d, 1 H), 7.42 (s, 1 H), 7.34 - 7.40 (m, 2 H), 7.21 - 7.31 (m, 3 H), 6.00 (br. s., 1 H), 5.21 (s, 2 H), 4.69 (br. s., 2 H), 3.45 (s, 3 H); MS (ESI) m/z 442 [M+H].

Example 12

(2-chloro-6-fluoro-phenyl)methyl N-[3-(2,,6-dichlorophenvD 1 ,2-oxazol-4-yll carbamate The titel compound was prepared by general method 1 using the acid intermediate 3 and the commercially available (2-chloro-6-fluoro-phenyl)methanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 9.06 (s, 1 H), 7.38 - 7.48 (m, 3 H), 7.30 (s, 1 H), 7.24 (s, 1 H), 7.04 (t, 1 H), 6.01 (br. s., 1 H), 5.40 (s, 2 H); MS (ESI) m/z 415 [M+H].

Example 13

1 -[3-(2.6-dichlorophenyl)-5-methyl- 1.2-oxazol-4-yll-3-[(3-fluorophenyl)methyl ^" |urea

The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (3- fluorophenyl)methanamine. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.39 (s, 3 H), 7.20 - 7.26 (m, 1 H), 6.95 (s, 1 H), 6.91 (d, 1 H), 6.80 (d, 1 H), 5.43 (s, 1 H), 4.90 (br. s., 1 H), 4.31 (d,

2 H), 2.51 (s, 3 H); MS (ESI) m/z 394 [M+H].

Example 14

3-[(2-chloro-6-fluoro-phenvπmethyll-l-[3-(2.6-dichloroph envπ-5-methyl-1.2-oxazol-4- yllurea

The titel compound was prepared by general method 1 using the commercially available 3-

(2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (2-chloro-6-fluoro- phenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.36 (s, 3 H), 7.19 - 7.25 (m, 1

H), 7.16 (s, 1 H), 6.94 - 7.00 (m, 1 H), 5.59 (s, 1 H), 4.87 (t, 1 H), 4.49 (dd, 2 H), 2.43 (s, 3

H); MS (ESI) m/z 428 [M+H].

Example 15

3-r(2,4-dichlorophenyl)methvH- 1 -[3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yllurea

The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (2,4- dichlorophenyl)methanamine. ¹ R NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.39 (s, 3 H), 7.35 (d, 1 H), 7.12 (d, 1 H), 7.11 (s, 1 H), 5.50 (s, 1 H), 5.01 (t, 1 H), 4.35 (d, 2 H), 2.48 (s, 3 H); MS (ESI) m/z 445 [M+H].

Example 16

1 -[3-(2.6-dichlorophenvD-5-methyl- 1.2-oxazol-4-yl]-3-[(4-propan-2-ylphenv0methyl]urea The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (4-propan-2- ylphenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.34 - 7.40 (m, 3 H), 7.14 (s,

2 H), 7.07 (s, 2 H), 5.57 (s, 1 H), 4.86 (t, 1 H), 4.26 (d, 2 H), 2.88 (s, 1 H), 2.47 (s, 3 H), 1.24 (d, 6 H); MS (ESI) m/z 418 [M+H].

Example 17

l-[3-(2.6-dichlorophenvπ-5-methyl-1.2-oxazol-4-yll-3-[(2-me thoxypyridin-3- vDmethyllurea

The titel compound was prepared by general method 1 using the commercially available 3-

(2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (2-methoxypyridin-3- yl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.07 (dd, 1 H), 7.34 - 7.43 (m, 4 H),

6.80 (dd, 1 H), 5.41 (br. s., 1 H), 5.16 (t, 1 H), 4.27 (d, 2 H), 3.91 (s, 3 H), 2.45 (s, 3 H);

MS (ESI) m/z 407 [M+H].

l-[3-(2.6-dichlorophenvπ-5-methyl-1.2-oxazol-4-yll-3-[(4-py razol-l-ylphenvπmethyllurea The titel compound was prepared by general method 1 using the commercially available 3- (2,6-dichlorophenyl)-5-methyl-l,2-oxazole-4-carboxylic acid and (4-pyrazol-l- ylphenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.90 (d, 1 H), 7.73 (d, 1 H), 7.54 - 7.59 (m, 2 H), 7.30 - 7.39 (m, 3 H), 7.20 (d, 2 H), 6.48 (s, 1 H), 6.15 (br. s., 1 H), 5.07 (br. s., 1 H), 4.32 (d, 2 H), 2.48 (s, 3 H); MS (ESI) m/z 442 [M+H].

l-r3-(2,6-dichlorophenyl)-5-methyl-l,2-oxazol-4-yll-l-methyl -3-r(4-pyrazol-l- ylphenvDmethyllurea

The titel compound was prepared by general method 2 using intermediate 11 and the commercially available (4-pyrazol-l-ylphenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.91 (d, 1 H), 7.73 (d, 1 H), 7.57 - 7.62 (m, 2 H), 7.37 (br. s., 3 H), 7.26 (s, 2 H), 6.47 (s, 1 H), 5.01 (t, 1 H), 4.34 (d, 2 H), 3.13 (s, 3 H), 2.46 (s, 3 H); MS (ESI) m/z 456 [M+H].

Example 20

1 -r3-(2,6-dichlorophenyl)-5-methyl- 1 ,2-oxazol-4-yll-3-r(2-methoxypyridin-3-yl)methyll- 1 -methyl-urea

The titel compound was prepared by general method 2 using intermediate 11 and the commercially available (2-methoxypyridin-3-yl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 8.07 (dd, 1 H), 7.44 (dd, 1 H), 7.39 (s, 3 H), 6.81 (dd, 1 H), 5.27 (t, 1 H), 4.26 (d, 2 H), 3.90 (s, 3 H), 3.04 (s, 3 H), 2.38 (s, 3 H); MS (ESI) m/z 421 [M+H].

Example 21

1 - [3 -(2.6-dichlorophenvO-5 -methyl- 1.2-oxazol-4-yl] - 1 -methyl-3 - [ [6-(oxan-4- yloxy)pyridin-3 -yllmethyllurea

The titel compound was prepared by general method 2 using intermediates 11 and 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.93 (d, 1 H), 7.42 (dd, 1 H), 7.36 (s, 3 H), 6.63 (d, 1 H), 5.18 - 5.26 (m, 1 H), 4.89 (t, 1 H), 4.22 (d, 2 H), 3.95 - 4.03 (m, 2 H), 3.57 - 3.66 (m, 2 H), 3.10 (s, 3 H), 2.45 (s, 3 H), 2.02 - 2.11 (m, 2 H), 1.73 - 1.85 (m, 2 H); MS (ESI) m/z 491 [M+H].

Example 22

(2-chloro-6-fluoro-phenvπmethyl N-[3-(2.6-dimethylphenvπ-5-methyl-1.2-oxazol-4- yll carbamate

The titel compound was prepared by general method 1 using the acid intermediate 5 and the commercially available (2-chloro-6-fluoro-phenyl)methanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.26 - 7.33 (m, 1 H), 7.22 (s, 2 H), 7.09 (d, 2 H), 6.99 - 7.05 (m, 1 H), 5.56 (br. s., 1 H), 5.29 (s, 2 H), 2.51 (br. s., 3 H), 2.10 (br. s., 6 H); MS (ESI) m/z 389 [M+H].

Example 23

3-[(2-chloro-6-fluoro-phenyl)methyl]-l-[3-(2,6-dimethylph enyl)-5-methyl-l,2-oxazol-4- yl]urea

The titel compound was prepared by general method 1 using intermediate 5 and the commercially available (2-chloro-6-fluoro-phenyl)methanamine.

¹ R NMR (400 MHz, CDCL ₃ ) δ (ppm) 7.16 - 7.26 (m, 3 H), 7.06 (d, 2 H), 6.96 - 7.02 (m, 1 H), 5.30 (s, 1 H), 4.77 (t, 1 H), 4.52 (dd, 2 H), 2.45 (s, 3 H), 2.06 (s, 6 H). MS (ESI) m/z 388 [M+H].

Example 24

1 -r3-(2,6-dimethylphenvD-5-methyl- 1 ,2-oxazol-4-yll-3-r(6-propan-2-yloxypyridin-3- vDmethyllurea

The titel compound was prepared by general method 1 using intermediate 5 and (6-propan- 2-yloxypyridin-3-yl)methanamine (prepared according to Nippon Noyaku Gakkaishi 1997, 22(3), 230-232). ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.93 (s, 1 H), 7.34 (dd, 1 H), 7.24 (t, 1 H), 7.07 (d, 2 H), 6.60 (d, 1 H), 5.23 - 5.32 (m, 2 H), 4.62 (br. s., 1 H), 4.23 (d, 2 H), 2.47 (s, 3 H), 2.07 (s, 6 H), 1.35 (d, 6 H); MS (ESI) m/z 395 [M+H].

Example 25

l-[3-(2.6-dimethylphenyl)-5-methyl-1.2-oxazol-4-yll-3-[(4-py razol-l- ylphenyl)methyllurea

The titel compound was prepared by general method 1 using intermediate 5 and the commercially available (4-pyrazol-l-ylphenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.89 (d, 1 H), 7.67 (d, 1 H), 7.51 - 7.56 (m, 2 H), 7.21 (t, 1 H), 7.15 (d, 2 H), 7.05

(d, 2 H), 6.47 (s, 1 H), 5.86 (s, 1 H), 5.06 (t, 1 H), 4.29 (d, 2 H), 2.46 (s, 3 H), 2.06 (s, 6 H);

MS (ESI) m/z 402 [M+H].

Example 26

(4-bromophenvDmethyl N-[3-(2.6-dimethylphenvD 1.2-oxazol-4-yl] carbamate

The titel compound was prepared by general method 1 using acid intermediate 2 and the commercially available (4-bromophenyl)methanol.

¹ R NMR (400 MHz, CDCL ₃ ) δ (ppm) 8.98 (s, 1 H), 7.50 (d, 2 H), 7.30 (s, 1 H), 7.24 (d, 2

H), 7.16 (d, 2 H), 5.94 (br. s., 1 H), 5.12 (s, 2 H), 2.12 (s, 6 H).

MS (ESI) m/z 401 [M+H].

Example 27

(3-dimethylaminophenvπmethyl N-[3-(2.6-dimethylphenvπi.2-oxazol-4-yllcarbamate The titel compound was prepared by general method 1 using intermediate 2 and the commercially available (3-dimethylaminophenyl)methanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ

(ppm) 9.00 (s, 1 H), 7.29 (s, 1 H), 7.24 (t, 1 H), 7.15 (d, 2 H), 6.71 (s, 3 H), 5.95 (br. s., 1 H), 5.12 (s, 2 H), 2.95 (s, 6 H), 2.12 (s, 6 H); MS (ESI) m/z 366 [M+H].

l-r3-(2,6-dichlorophenyl)-5-(methoxymethyl)isoxazol-4-yll-3- {r6-(tetrahvdro-2H-pyran-4- yloxy)p yridin-3 - yllmethyl } urea

The titel compound was prepared by general method 1 using intermediates 7 and 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.94 (d, 1 H), 7.35 - 7.45 (m, 4 H), 6.64 (d, 1 H), 5.61 (s, 1 H), 5.26 (t, 1 H), 5.18 - 5.24 (m, 1 H), 4.59 (s, 2 H), 4.23 (d, 2 H), 3.95 - 4.03 (m, 2 H), 3.57 - 3.65 (m, 2 H), 3.41 (s, 3 H), 2.01 - 2.10 (m, 2 H), 1.73 - 1.83 (m, 2 H); MS (APPI/APCI) m/z 507, 509 [M+H].

Example 29

143-(2,6-dimethylphenyl)-5-methylisoxazol-4-yl1- 1 -methyl-3-[4-(lH-pyrazol- 1 - vDbenzyl ^" |urea

The titel compound was prepared by general method 2 using intermediate 13 and the commercially available 4-(lH-pyrazol-l-yl)benzylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ _. (ppm) 7.93 (d, 1 H), 7.75 (d, 1 H), 7.64 (d, 2 H), 7.29 (d, 2 H), 7.24 (d, 1 H), 7.08 (d, 2 H), 6.48 - 6.50 (m, 1 H), 4.90 (t, 1 H), 4.38 (d, 2 H), 2.95 (s, 3 H), 2.41 (s, 3 H), 2.10 (br. s., 6 H); MS (ESI) m/z 416 [M+H].

Example 30

l-r3-(2,6-dimethylphenyl)-5-methylisoxazol-4-yll-3-r(6-isopr opoxypyridin-3-yl)methyll- 1-methylurea The titel compound was prepared by general method 2 using intermediate 13 and 6- propan-2-yloxypyridin-3-yl)methanamine (prepared according to Nippon Noyaku Gakkaishi 1997, 22(3), 230-232). ¹ U NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.97 (d, 1 H), 7.42 (dd, 1 H), 7.23 (t, 1 H), 7.06 (d, 2 H), 6.62 (d, 1 H), 5.22 - 5.32 (m, 1 H), 4.74 (t, 1 H), 4.26 (d, 2 H), 2.92 (s, 3 H), 2.40 (s, 3 H), 2.07 (br. s., 6 H), 1.35 (d, 6 H); MS (ESI) m/z 409 [M+H].

Example 31

1 -[3-(2.6-dimethylphenviy5-methvh ^' soxazol-4-yr|- 1 -methyl-3- ([6-(tetrahydro-2H-pyran-4- yloxy)p yridin-3 - yllmethyl } urea

The titel compound was prepared by general method 2 using intermediates 13 and 12. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.96 (d, 1 H), 7.44 (dd, 1 H), 7.24 (t, 1 H), 7.07 (d, 2 H), 6.67 (d, 1 H), 5.18 - 5.26 (m, 1 H), 4.75 (t, 1 H), 4.26 (d, 2 H), 3.95 - 4.04 (m, 2 H), 3.58 - 3.66 (m, 2 H), 2.92 (s, 3 H), 2.40 (s, 3 H), 2.07 (br. s., 8 H), 1.74 - 1.85 (m, 2 H); MS (ESI) m/z 451 [M+H].

Biological Tests

Expression of voltage-gated sodium channel in cell lines:

Gene(s) encoding the full-length protein of the voltage-gated sodium channel of interest are cloned and expressed under a suitable promoter in a suitable cell line, as well known in the art. The so constructed stable cell lines are used in screening assays to identify suitable compounds active on voltage-gated sodium channels. Suitable screening assays are as follows.

Li+ influx assay The cell line expressing the voltage-gated sodium channel of interest is plated in conventional 96 or 384 well tissue plates at a suitable cell density (for example 40000 cells/well in 96 well plate, or 20000 cells/well in 384 well plate). The cells are then repeatedly washed with a suitable Na free buffer using a suitable commercially available washer (for example EL-405 washer) until all tissue culture medium is removed from the wells. A suitable Na-free buffer could have the composition (mM) Choline chloride 137, KCl 5.4, MgSO ₄ 0.81, CaCl ₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. After completion of all wash steps, cells are incubated in the suitable Na free buffer for 15 min. Then, the Na free buffer is removed and cells are incubated with a buffer rich in LiCl for 60 min at 37 ⁰ C. The LiCl buffer is also enriched in potassium ions, causing a depolarizing stimulus to the cells. Such a buffer may have the composition (mM): LiCl 100, KCl 50, MgSO ₄ 0.81, CaCl ₂ 0.95, glucose 5.55 and HEPES 25 at pH 7.4, but may also have other suitable composition. To enhance signal-to-noise ratio, an effective concentration (for example 100 μM) of the voltage-gated sodium channel opener veratridine, or any other suitable voltage-gated sodium channel opener, may be added to the medium to enhance signal detection. Furthermore, and also to enhance signal-to-noise ratio, an effective concentration (for example 10 μg/ml) of suitable scorpion venom may also be added to the medium to delay channel inactivation. In order to find a modulator of the voltage-gated sodium channel of interest, the assay can be complemented with compounds from a compound library. Compounds of interest are added to the Li-rich solution, one in each well. At the end of the incubation period cells are repeatedly washed with Na free buffer until all extracellular LiCl is removed. Cell lysis is obtained through incubation of cells with triton (1%) for 15 min, or any other suitable method. The resulting cell lysate is then introduced into an atomic absorption

spectrophotometer, thus quantifying the amount of Li-influx during the procedure described above.

The described assay can be run with any atomic absorption spectrophotometer using plates of 96-well format, 384-well format, or any other conventional plate format. The described assay can be applied to cell lines expressing any given one or more of the voltage-gated sodium channel alpha subunits, as well as any given combination of one of the voltage- gated alpha subunits with any one or more beta subunit.

If needed the cell line of choice can be further hyperpolarised by expression of a suitable potassium leak ion channel, for example TREK-I, either by transient co-transfection or through establishment of a stable co-transfected cell line. The successful expression of a leak K current can be verified using traditional intracellular electrophysiology, either in whole cell patch-clamp, perforated patch-clamp or conventional two-electrode voltage- clamp. A cell line of choice modified to successfully express a voltage-gated sodium channel of interest together with a suitable potassium leak ion channel transfected can then be used for screening using atomic absorptions spectrometry, as described above.

Whole-cell voltage clamp electrophysiology assay Electrophysiological recordings of sodium currents in cells stably expressing the voltage- gated sodium channel of interest confirms activity and provides a functional measure of the potency of compounds that specifically affect such channels.

Electrophysiological studies can be performed using automated patch-clamp electrophysiology platforms, like Ion Works HT, Ion Works Quattro, PatchXpress, or any other suitable platform. The cell line expressing the voltage-gated sodium channel of interest is plated in appropriate well tissue plates, as provided by the manufacturer of the automated patch-clamp platforms. Suitable extracellular and intracellular buffer for such experiments are applied according to the instructions given by the manufacturer of the automated patch-clamp platforms. Cells that express the voltage-gated sodium channel protein of interest are exposed to drugs through the pipetting system integrated in the platforms. A suitable voltage stimulus protocol is used to activate the voltage-gated sodium channel proteins of interest. A suitable stimulus protocol may consist of eight voltage

pulses, each to -20 mV and 50 ms in length, and separated from each other by 330 ms intervals at a potential of -90 mV or -65 mV, but may also have other suitable parameters.

Electrophysiological studies can also be performed using the whole cell configuration of the standard patch clamp technique as described in the literature. In this assay, cells that express the human voltage-gated sodium channel protein of interest are exposed to the drugs by conventional microperfusion systems and a suitable voltage stimulus protocol is used to activate the voltage-gated sodium channels.

Examples

Title compounds of the above Examples were tested in the Whole-cell voltage clamp electrophysiology assay mentioned above and were found to exhibit IC ₅₀ values of less than 10 μm.

In vivo experiments

A compound of the invention when given by systemic injection to mice or rats, may specifically reduce pain behavior in the formalin test. This test is an accepted model of clinical pain in man, involving elements of nociceptor activation, inflammation, peripheral sensitization and central sensitization (A Tjølsen et al. Pain 1992, 51, 5). It can therefore be inferred that a compound of the present invention is usefulas a therapeutic agent to relieve pain of various origins.

Compounds of formula I may showin analgesic activity in the intraarticular FCA (Freund's complete adjuvant) test in the rat, a model of inflammatory pain (Iadarola et al. Brain Research 1988, 455, 205-12) and in the Chung nerve lesion test in the rat, a model for neuropathic pain (Kim and Chung. Pain 1992, 50, 355). The analgesic effects in the animal models may be obtained after doses that do not produce tissue concentrations leading to conduction block in nerve fibers. Thus, the analgesic effects can not be explained by the local anesthetic properties of the compounds mentioned in the publication by Kornet and Thio. Analgesic efficacy after systemic administration is not a general property of drugs with local anesthetic effects (Scott et al. British Journal of Anaesthesia 1988, 61, 165-8).