BACKGROUND TO THE INVENTION Protein kinases are important components of intracellular signalling pathways and kinases are involved in the regulation of a variety of cellular functions. The MAP kinase signalling pathways are activated by engagement of a number of cell surface receptors. One of these pathways, the JNK pathway is activated specifically by stress or pro-inflammatory cytokines. Activators include LPS, the cytokines tumor necrosis factor (TNF-a) and Interleukin-1 (IL-1), osmotic shock, chemical stress and UV radiation (Cohen, P. Trends in Cell Biol. 7: 353-361 1997). Targets of the JNK pathway include a number of transcription factors, such as but not exclusively c-jun and ATF-2 (Whitmarsh, A. and Davis, R. J. Mol.

Med. 74: 589-607 1998).

Three different genes: JNK1, JNK2 and JNK3; encode the JNK family of enzymes.

Alternatively spliced forms of these genes can give rise to 10 distinct isoforms: four for JNK1, four for JNK2 and two for JNK3. (Gupta, S. et al EMBO J. 15: 2760-2770 1996).

JNK1 and JNK2 are ubiquitously expressed in human tissues whereas JNK3 is selectively expressed in the brain, heart and testis (Dong, C. et al. Science 270: 1-4 1998).

JNKs 1,2 and 3 have been selectively knocked out in mice both singularly and in combination by both gene deletion and/or transgenic expression of dominant negative forms of the kinases (Dong, C. et al Science 282: 2092-2095,1998 ; Yang, D. et al Immunity 9: 575-585 1998; Dong, C. , et al Nature 405: 91-94 2000; Yang, D. et al Nature 389: 865-870 1997). Mice with targeted disruption of the JNK3 gene develop

normally and are protected from excitotoxin-induced apoptosis of neurons. This finding suggests that specific inhibitors of JNK 3 could be effective in the treatment of neurological disorders characterized by cell death such as Alzheimer's disease and stroke.

Mice disrupted in either JNK 1 or 2 also develop normally. Peripheral T cells from either type of mice can be activated to make IL2, but in both cases, there is a defect in Thl cell development. In the case of JNK1-/-mice, this is due to an inability to make gamma interferon (a key cytokine essential for the differentiation of Thl cells). In contrast, JNK2 -/- mice produce interferon gamma but are unable to respond to the cytokine. Similar defects in T cell biology (normal IL2 production but a block in Thl cell differentiation) are seen in T cells disrupted in the MKK7 gene confirming this role for the JNK pathway in T cell differentiation (Dong, C. , et al Nature 405: 91-94 2000).

JNK also plays a major role in apoptosis of cells (Davis RJ. Cell. 103: 239-252,2000).

JNK is essential for UV induced apoptosis through the cytochrome C mediated pathway (Tournier, C. et al Science 288 : 870-874 2000). Ischemia and ischemia coupled with re- perfusion as well as restricted blood flow itself have been shown to be accompanied by activation of JNK. Cell death can be prevented with dominant negative forms of JNK transfected into cells demonstrating a potential utility for JNK in conditions characterized by stress-induced apoptosis.

Activation of the JNK pathway has been observed in a number of human tumors and transformed cell lines (Davis RJ. Cell. 103: 239-252,2000). Indeed, one of the major targets of JNK, cjun, was originally identified as an oncogene indicating the potential of this pathway to participate in unregulated cell growth. JNK also regulates phosphorylation of p53 and thus modulates cell cycle progression (Chen T. et al Mol. Carcinogenesis 15: 215-226,1996). Inhibition of JNK may therefore be beneficial in some human cancers.

Based on current knowledge JNK signalling, especially JNK3, has been implicated in areas of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, traumatic brain injury, as well as ischernic and haemorrhaging stroke.

Thus there is a high unmet medical need for JNK specific inhibitors useful in treating the various conditions associated with JNK activation.

DISCLOSURE OF THE INVENTION It has been found that compounds of the Formula I, which are substituted pyridine compounds, are particularly effective and thereby suitable in the treatment of the various conditions.

In one aspect, the invention relates to compounds of the general Formula I wherein: R is R3, R5, R6, COR', COR6, CON3, CONHOR', CON', CONHR6, CON (R6)2, COUR', COOR6, SO2R5, SO2R6, OR3, ODOR', COOR3, COR3, CONR3R4, NHCOR3, NR3R4, NHSO2R3, SO2R3, SO2NR3R4, SR3, CN, halogeno or NO2 ; R1 is aryl or heteroaryl each of which is optionally substituted with one or more of fluoro or chloro; R2 is R5, R6, COR5, COR6, CONHR5, CONHR6, CON (R6) 2, COOR5, or COOR6 ; R3 and R4 are each independently hydrogen, halogeno, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, (C3-8 cycloalkyl) C, 6 alkyl, heterocycle, hetrocycleC1-6 alkyl, C1-6 fluoroalkyl, C1-6 trifluoroalkoxyl, wherein any C1-6 alkyl, 2-6 alkenyl, heterocycle, hetrocycleCl-6 alkyl is optionally substituted by one or more NR3R4, hydroxyl, OR6, heterocycle or, alternatively NR3R4 can form a ring having 3 to 7 atoms, said ring optionally including one or more additional heteroatoms selected from N, O or S optionally substituted with one or more A;

R5 is aryl or heteroaryl each of which is optionally substituted with one or more of R7, oR7, COR7, COOk7, CoR7, CON', NHCOR7, NR7R8, NHSO2R7, SO2R7, SO2NR7R8 SR7, C1-6 alkyl-SR7, CN, halogeno and N02 ; R6 is hydrogen, NH2, C1-6 alkyl, C3-8 cyloalkyl, heterocycle, hetrocycleC1-6 alkyl, C1-6 alkoxyl, or 2-6 alkenyl, wherein any of C1-6 alkyl, C3-8 cycloalkyl, hetrocycle, hetrocycleC 6 alkyl and 2-6 alkenyl is optionally substituted with one or more B; R7 and R8 are each independently hydrogen, halogeno, C16 alkyl, C1-6 alkyl optionally substituted by NR3R4, C3-8 cycloalkyl, C2-6 alkenyl, 2-6 alkenyl optionally substituted by NR3R4, (C3-8 cycloalkyl) C1-6 alkyl, hetrocycle, hetrocycleCl-6 alkyl, aryl, C1-6 fluoroalkyl, C1-6 chloroalkyl, or alternatively NR3R4 can form a ring having 3 to 7 atoms, said ring optionally including one or more additional heteroatoms selected from N, O or S being optionally substituted with one or more A; R9 is Cl-6 alkyl ; A is C1-6 alkyl, or halogeno; B is C,-6 alkoxyl, Ci-6 alkyl, COR7, NCOR6, NR3R4, hydroxyl, S02NH2, SO2 R9, SO2NHR9, S02N (R9) 2, halogeno, heteroaryl or aryl, said SO2 R9, S02NHR9, SO2N (R9) 2, heteroaryl or aryl optionally substituted with one or more C; C is C16 alkyl, hetrocycle, hetrocycleC1-6 alkyl, C1-6 alkoxyl, heteroaryl, aryl, halogeno, hydroxyl or oxo; as a free base or a salt thereof.

Listed below are definitions of various terms used in the specification and claims to describe the present invention.

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

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

For the avoidance of doubt it is to be understood that in this specification'Co-6'means a carbon group having 0, 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. Cl 6alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, and hexyl.

In this specification, unless stated otherwise, the term"C3-8 cycloalkyl"includes a non- aromatic, completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms.

Examples of said cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term"alkoxyl"as used herein, unless stated otherwise includes"alkyl"O groups in which"alkyl"is as hereinbefore defined. Ci-ealkoxyl may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, hexyloxy. C16 trifluoroalkoxyl represents a Ci. 6 alkoxyl substituted with three fluorine atoms.

In this specification, unless stated otherwise, the term"alkenyl"includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl is specific for the straight chain version only. Unless otherwise stated, the term "alkenyl"advantageously refers to chains with 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms. C2-6alkenyl may be ethenyl, propenyl, 2-methylpropenyl, butenyl and 2- butenyl.

In this specification, unless stated otherwise, the term"alkynyl"includes both straight and branched chain alkynyl groups but references to individual alkynyl groups such as 2-butynyl is specific for the straight chain version only. Unless otherwise stated, the term "alkynyl"advantageously refers to chains with 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms.

In this specification, unless stated otherwise, the term"heterocycle"includes a 3-to 10- membered non-aromatic partially or completely saturated hydrocarbon group, which contains one or two rings and at least one heteroatom. Examples of said heterocycle include, but are not limited to pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, oxazolyl, 2-oxazolidonyl or tetrahydrofuranyl.

In this specification, unless stated otherwise, the expression"NR3R4 can form a ring having 3 to 7 atoms, said ring optionally including one or more additional heteroatoms selected from N, O or S"include, but are not limited to piperidinyl, piperazinyl and morpholinyl.

In this specification, unless stated otherwise, the term"aryl"may be a C6-C14 aromatic hydrocarbon and includes, but is not limited to, benzene, naphthalene, indene, anthracene, phenanthrene.

In this specification, unless stated otherwise, the term"heteroaryl"may be a monocyclic heteroaromatic, or a bicyclic fused-ring heteroaromatic group. Examples of said heteroaryl include, but are not limited to, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, benzofuryl, indolyl, isoindolyl, benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl or triazolyl.

In this specification, unless stated otherwise, the term halogeno may be fluor, chlorine, bromine or iodine.

In this specification, unless stated otherwise, the term"C16 fluoroalkyl"may be an alkyl substituted with one or more fluorine atoms. Examples of said fluoroalkyl include, but are not limited to, monofluoromethyl, trifluoromethyl, difluoromethyl and trifluoroethyl.

In this specification, unless stated otherwise, the term"Cl-6 chloroalkyl"may be an alkyl substituted with one or more chlorine atoms. Examples of said chloroalkyl include, but are not limited to, monochloromethyl, trichloromethyl, dichloromethyl and trichloroethyl.

In one aspect of the invention there is provided compounds of formula I wherein R'is aryl.

In one embodiment of this aspect there is provided compounds of formula I wherein said aryl is phenyl.

In one embodiment of this aspect there is provided compounds of formula I wherein R2 is selected from CoR5, COR6, CONHR, CONHR6, CON (R6) 2, COOR5 and COOR6.

In yet another aspect of the invention there is provided compounds of formula I wherein: R is R3, CON3, CON (R6) 2, COUR', or CONR3R4, R2 is COR6 ; R3 and R4 are each independently hydrogen or C1-6 alkyl, C1-6 alkyl optionally substituted by hydroxyl, or a heterocycle, alternatively NR3R4 can form a ring having 3 to 7 atoms, said ring optionally including one additional heteroatom selected from N or O optionally substituted with one or more A; R6 is a heterocycle, optionally substituted with one or more B; R7 is C1-6 alkyl ; A is C1-6 alkyl ; and B is COR7.

In yet another aspect of the invention there is provided compounds of formula I wherein R2 is COR6. In one embodiment of this aspect there is provided compounds of formula I wherein said R6 is a heterocycle. In one class of this embodiment aspect there is provided compounds wherein said heterocycle is substituted with one B, wherein said B is CoR7 and R7 is Cl-6 alkyl, preferably methyl.

In yet another aspect of the invention there is provided compounds of formula I wherein R is R3, and R3 is hydrogen or Cl-6 alkyl, said C1-6 alkyl optionally substituted by hydroxyl.

In yet another aspect of the invention there is provided compounds of formula I wherein R is COOR3, and R3 is hydrogen or C1-6 alkyl.

In yet another aspect of the invention there is provided compounds of formula I wherein R is CONHR3, and R3 is C16 alkyl, said C1-6 alkyl optionally substituted by hydroxyl or a heterocycle.

In yet another aspect of the invention there is provided compounds of formula I wherein R is CON (R6) 2 and R6 is hydrogen.

In yet another aspect of the invention there is provided compounds of formula I wherein R is CONR3R4 and NR3R4 can form a ring having 3 to 7 atoms, said ring optionally including one additional heteroatom selected from N or O optionally substituted with one A. In one embodiment of this aspect there is provided compounds of formula I wherein said ring has 6 atoms, including one additional N heteroatom and is substituted with one A, said A being methyl.

In yet another aspect of the invention there is provided compounds said compounds being: Methyl 3-anilino-5-{2-[(tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl}benzoate ; N-{4-[3-Anilino-5-(hydroxymethyl)phenyl]pyridin-2-yl}tetrahy drofuran-3- carboxamidecarboxamide; 3-anilino-5- {2-[(Tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl lbenzoic acid; N- [4- (3-Anilino-5- { [ (2-hydroxyethyl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydrofuran-3-carboxamide ; N- {4- [3- (Aminocarbonyl)-5-anilinophenyl] pyridin-2-yl} tetrahydrofuran-3-carboxamide ; N-(4-{3-Anilino-5-[(methylamino) carbonyl] phenyl lpyridin-2-yl) tetrahydrofuran-3- carboxamide; N-(4-{3-Anilino-5-[(4-methylpiperazin-1-yl) carbonyl] phenyl} pyridin-2- yl) tetrahydrofuran-3-carboxamide; N-[4-(3-Anilino-5-{[(2-morpholin-4-ylethyl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydrofuran-3-carboxamide ; N [4- (3-Anilinophenyl) pyridin-2-yl] tetrahydrofuran-3-carboxamide; 1-Acetyl-N- [4- (3-anilinophenyl) pyridin-2-yl] piperidine-4-carboxamide ; Methyl 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl lbenzoate ; 3-Anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid;

N-[4-(3-anilino-5-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide ; N- [4- (3-anilino-5- { [ (2-oxotetrahydrofuran-3-yl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide ; (R)-N-[4-(3-anilino-5- { [2-(methoxymethyl) pyrrolidin-1-yl] carbonyl lphenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide ; (S)-N-[4-(3-anilino-5-{[2-(methoxymethyl)pyrrolidin-1-yl]car bonyl}phenyl)pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide ; N- {4- [3-anilino-5- (morpholin-4-ylcarbonyl) phenyl] pyridin-2-yl} tetrahydro-2H-pyran-4- carboxamide; (R)-N- [4-(3-anilino-5-{[(tetrahydrofuran-2-ylmethyl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide ; (S)-N-[4-(3-anilino-5-{[(tetrahydrofuran-2-ylmethyl)amino]ca rbonyl}phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide ; N-{4-[3-anilino-5-(1, 4-dioxa-8-azaspiro [4.5] dec-8-ylcarbonyl) phenyl] pyridin-2- yl ltetrahydro-2H-pyran-4-carboxamide ; N-(4- {3-anilino-5-[(2, 6-dimethylmorpholin-4-yl) carbonyl] phenyl lpyridin-2-yl) tetrahydro- 2H-pyran-4-carboxamide ; N-{4-[3-anilino-5-({[2-(1, 3-dioxolan-2-yl) ethyl] amino} carbonyl) phenyl] pyridin-2- yl} tetrahydro-2H-pyran-4-carboxamide ; N [4- (3-anilino-5- { [bis (2-methoxyethyl) amino] carbonyl} phenyl) pyridin-2-yl] tetrahydro- 2H-pyran-4-carboxamide ; N [4- (3-anilino-5- { [ (1, 3-dioxolan-2-ylmethyl) (methyl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide ; Ethyl 4-[(3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4- yl} benzoyl) amino] piperidine-1-carboxylate ; N-(4-{3-anilino-5-[(tetrahydro-2H-pyran-4-ylamino) carbonyl] phenyl} pyridin-2- yl) tetrahydro-2H-pyran-4-carboxamide ; N-(4-{3-anilino-5-[(hydroxyamino)carbonyl]phenyl}pyridin-2-y l)tetrahydro-2H-pyran-4- carboxamide ; N-(4-{3-anilino-5-[(methoxyamino) carbonyl] phenyl} pyridin-2-yl) tetrahydro-2H-pyran-4- carboxamide ;

N- {4- [3- ( { [2- (acetylamino) ethyl] amino} carbonyl) -5-anilinophenyl] pyridin-2- yl} tetrahydrofuran-3-carboxamide; N-{4-[3-({[3-(acetylamino)propyl]amino} carbonyl) -5-anilinophenyl] pyridin-2- yl} tetrahydrofuran-3-carboxamide ; N- 4- [3-anilino-5- ( { [2- (dimethylamino) ethyl] amino} carbonyl) phenyl] pyridin-2- yl tetrahydrofuran-3-carboxamide ; N-{4- [3-anilino-5- ( { [3- (dimethylamino) propyl] amino} carbonyl) phenyl] 3yridine-2- yl} tetrahydrofuran-3-carboxamide ; N-[4-(3-{[(2-amino-2-oxoethyl) amino] carbonyl}-5-anilinophenyl) pyridin-2- yl] tetrahydrofuran-3-carboxamide ; tert-butyl [4- (3-amino-5-nitrophenyl) pyridin-2-yl] carbamate; tert-butyl [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] carbamate; N [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] tetrahydrofuran-3-carboxamide ; N [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide ; N [4- (3-amino-5-anilinophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide ; N-14- [3- (acetylamino)-5-anilinophenyl] pyridin-2-ylltetrahydro-2H-pyran-4-carboxarnide ; N- 4- [3-anilino-5- (dimethylamino) phenyl] pyridin-2-yl} tetrahydro-2H-pyran-4- carboxamide; N-[4-(3-anilino-5-{[2-(dimethylamino) ethyl] amino} phenyl) pyridin-2-yl] tetrahydro-2H- pyran-4-carboxamide ; N-(4-{3-anilino-5-[(pyridin-3-ylmethyl) amino] phenyl lpyridin-2-yl) tetrahydro-2H-pyran- 4-carboxamide; N-{4- [3-anilino-5- (tetrahydro-2H-pyran-4-ylamino) phenyl] pyridin-2-yl} tetrahydro-2H- pyran-4-carboxamide ; N-{4-[3-(cyclohexylamino) phenyl] pyridin-2-yl}tetrahydro-2H-pyran-4-carboxamide ; as a free base or a salt thereof.

In yet another aspect of the invention there is provided compounds of Formula I as a pharmaceutically acceptable salt.

The present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I. Such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically-acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric; or, for example a salt of a compound of Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt, or a salt with an organic base.

Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E-and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.

Certain compounds of the present invention may exist as tautomers. It is to be understood that the present invention encompasses all such tautomers.

The present invention relates to novel pyridine derivatives, which are inhibitors of c-Jun N- terminal kinases (JNKs). JNKs have been implicated in mediating a number of disorders.

The invention relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing these compositions in the treatment of various disorders.

Pharmaceutical compositions According to one aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula I, as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, for use in the prevention and/or treatment of conditions associated with c-Jun N-terminal kinases (JNKs).

The composition may be in a form suitable for oral administration, for example as a tablet, for parenteral injection as a sterile solution or suspension. In general the above

compositions may be prepared in a conventional manner using pharmaceutically carriers or diluents. Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man, are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.

A compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, can be used on its own but will usually be administered in the form of a pharmaceutical composition in which the formula I compound/salt (active ingredient) is in association with a pharmaceutically acceptable diluent or carrier. Dependent on the mode of administration, the pharmaceutical composition may comprise from 0.05 to 99 % w (per cent by weight), for example from 0.10 to 50 % w, of active ingredient, all percentages by weight being based on total composition.

A diluent or carrier includes water, aqueous polyethylene glycol, magnesium carbonate, magnesium stearate, talc, a sugar (such as lactose), pectin, dextrin, starch, tragacanth, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose or cocoa butter.

A composition of the invention can be in tablet or injectable form. The tablet may additionally comprise a disintegrant and/or may be coated (for example with an enteric coating or coated with a coating agentsuch as hydroxypropyl methylcellulose).

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, a hereinbefore defined, with a pharmaceutically acceptable diluent or carrier.

An example of a pharmaceuticall composition of the invention is an injectable solution containing a compound of the invention, or a a pharmaceutically acceptable salt, solvate or

solvate of salt thereof, as hereinbefore defined, and sterile water, and, if necessary, either sodium hydroxide or hydrochloric acid to bring the pH of the final composition to about pH 5, and optionally a surfactant to aid dissolution.

Liquid solution comprising a compound of formula I, or a salt thereof, dissolved in water. Solution mg/ml Compound X 5.0% w/v Pure water To 100% Medical use The compounds of Formula I have activity as medicaments. In particular the compounds of formula I are potent JNK inhibitors and preferred compounds are selective JNK3 inhibitors. The present invention provides a compound of Formula I for use as a medicament. In particular the present invention provides a compound of Formula I for use in the prevention or treatment of conditions associated with JNK activation.

The present invention provides a method of treating or preventing conditions associated with JNK activation comprising the administration of a therapeutically effective amount of a compound of Formula I to a mammal (particularly a human including a patient) in need thereof.

In a further aspect the present invention provides the use of a compound of Formula I in the manufacture of a medicament for the treatment of conditions associated with JNK activation.

Conditions that may be treated by the compounds of this invention, according to Formula I, or a pharmaceutical composition containing the same, include any condition associated with JNK activation. Conditions associated with JNK activation include but are not limited to:

central or peripheral neurological degenerative disorders including Alzheimer's disease, cognitive disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Gaum, HIV dementia, corticobasal degeneration, dementia pugilistica, Down's syndrome, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann- Pick's Disease, epilepsy, a peripheral neuropathy, spinal cord injury, head trauma; autoimmune diseases including Multiple Sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, asthma, septic shock, transplant rejection; cardiovascular diseases including stroke, arterosclerosis, myocardial infarction, myocardial reperfusion injury ; cancer including breast-, colorectal, pancreatic, prostate cancer.

In addition, JNK inhibitors of the instant invention may be capable of inhibiting the expression of inducible pro-inflammatory proteins. Therefore other conditions, which may be treated by the compounds of this invention, include edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.

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

The term"condition", unless stated otherwise, means any disorder and disease associated with JNK activity.

Non-medical use In addition to their use in therapeutic medicine, the compounds of formula I or salt thereof, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of JNK inhibitor related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.

Methods of preparation The compounds of this invention may be prepared by methods known to those skilled in the art for analogous compounds, as illustrated by the general schemes and procedures below and by the preparative examples that follow. The starting material compounds are commercially available, unless otherwise stated.

Method 1.

An aryl bromide (A) like tert-Butyl 4-bromopyridin-2-ylcarbamate is reacted with an arylboronic acid (B) in an ether solvent like DME with a palladium catalyst like Pd (dppf) 2Cl2 in the presence of a base such as Na2C03 to give the biaryl compound C. The reaction is carried out under nitrogen atmosphere at elevated temperature such as 80 °C for an extended time such as 12 to 24 hrs.

The aniline compound (C) is reacted with an aryl halide (R1X) such as iodobenzene in an ether solvent or solvent mixture like dioxane/tert-butanol with a palladium catalyst like Pd2 (dba) 3/xantphos in the presence of a base such as Cs2CO3 to give an N-aryl compound D. The reaction is carried out under nitrogen atmosphere at elevated temperature such as 90-100 °C for an extended time such as 12 to 24 hrs.

Compound D is N-boc deprotected with an acid such as TFA followed by amide coupling with an acid such as tetrahydrofuran-3-carboxylic acid using an amide coupling reagent such as HATU or TBTU + HOBt, and a base such as DIPEA in a solvent such as DMF to give compound E (equal to a compound according to formula I). The reaction is carried out under nitrogen atmosphere at ambient temperature for an extended time such as 12 hrs to 5 days. Method 1 Br H Br H2N \ R Ri N R Palladium catalyst Palladium catalyst N NHBoc R'X H N R A 2 X= halide 9 NHBoc N NHBoc B B (OH) 2 C D H H Formula 11 Ri, N R Ri R 1) tua 1) TFA 2) carboxylic acid, R 2 R2 ) y N H N N coupling reagent E

Formula I Formula I In conjunction with this process there is provided an embodiment of the present invention to a process for the preparation of a compound of formula E (equal to a compound according to formula 1), wherein R, Ri and R are as defined for formula I, comprising the steps: reacting an aryl bromide (A) with an arylboronic acid (B) in an ether solvent with a palladium catalyst in the presence of a base to give a biaryl compound C; reacting compound (C) with an aryl halide (RIX) in an ether solvent with a palladium catalyst in the presence of a base to give an N-aryl compound D followed by N-boc deprotection of Compound D with an acid followed by amide coupling with an acid using an amide coupling reagent and a base in a solvent to give compound E, equal to a compound according to formula I. Alternatively, the substitiuent R in compound E can be reacted to yield another substituent R in formula I as described in more detail in method 2-6.

Method 2.

Compound F is reduced with a hydride reducing agent such as DIBAL-H in a solvent such as THF to give compound G. The reaction is carried out under nitrogen atmosphere at lowered to ambient temperature for an extended time such as 6 hrs.

Method 2 H ? H O H OU / hydride/ reducing agent Il in2 NA H N H H F G

Method 3.

Compound D is hydrolyzed with a basic reagent such as LiOH in a solvent mixture such as water/MeOH/DMF. The reaction is carried out at ambient temperature for an extended time such as 1 to 3 days and is followed by N-boc cleavage and amide coupling as described above to give compound H.

Compound H is coupled with an amine using an amide coupling reagent such as HATU as described above to give a compound such as compound 1. The reaction is carried out under nitrogen atmosphere at ambient temperature for an extended time such as 2 hrs. Method 3 H 0 H 0 H Ohi R1 iN IVR3R4 I 1) basic hydrolysis R3-N \ D R4 2) TFA coupling reagent 3) Carboxylic acid, coupling reagent N s N z R2 N s N/R2 H H H H H

Method 4.

Compound F is reacted with an amine in a solvent such as MeOH with a catalyst such as sodium cyanide to give compound J. The reaction is carried out at elevated temperature such as 50 °C for an extended time such as 12 hrs to 3 days. Method 4 H H R"-'N I NHR3 R3-NH2 F NaCN, MeOH NA H H H J

Method 5.

Compound D is reacted with an amine in a solvent such as MeOH with a catalyst such as sodium cyanide. The reaction is carried out at elevated temperature such as 50 °C for an extended time such as 12 hrs to 3 days and is followed by N-boc cleavage and amide coupling as described above to give compound K. Method 5 H 0 N NHR3 R3 NH NaCN, MeOH D 2) TFA 1 A w R2 3) Carboxylic acid N N coupling reagent K

Method 6 Compound E can be reduced by hydrogenation with Put02 as catalyst at atmospheric pressure for 20 h to yield the amino compound L. Alkylation with an alkyl halide R3-X or reductive amination with an aldehyde R3CHo or a ketone R3COR4 under standard conditions will yield compound M. Compound L can be reacted with an acid R3COOH and amide coupling reagents, acid chloride or acid anhydride under standard conditions to yield the amide derivative N.

Method 6

0 H H RiO-NH, H. NR. R, N N, 0 Rl NH2 R3-X RI NR 3R4 hydrogenation R3CHO. R3y 0 R3 O I I N. N i R N N i R2 N N i R2 H H E L OH M , N N R3 R1 I E L COOH H H 0 R2 N N H N

Another aspect of the present invention provides a process for the preparation of a compound of Formula I comprising the reaction of a compound of Formula II :

Wherein R1 and R are as previously defined and PG represent an amino protecting group, for example t-butoxycarbonyl or 2- (trimethylsilyl) ethoxymethyl.

Compounds of Formula II may be prepared as described in Method 1.

Compounds of Formula II are novel, useful intermediates and are claimed as a further aspect of the present invention.

Another aspect of the present invention thus is a compound according to Formula II wherein Rl and R are as defined above for Formula I and PG represent an amino protecting group, for example t-butoxycarbonyl or 2- (trimethylsilyl) ethoxymethyl.

Working Examples The invention will now be described in more detail with the following examples that are not to be construed as limiting the invention. All chemicals and reagents were used as received from suppliers.'H and 13C nuclear magnetic resonance (NMR) spectra were recorded for the free base if not stated otherwise, on a BRUKER DPX 400 (400 MHz) spectrometer using the following solvents and references.

CDCl3 : 1H NMR TMS (0.0 ppm) and 13C the central peak of CDC13 (77.0).

CD30D :'H NMR 3.31 ppm (central peak) and 13C 49.0 ppm (central peak).

DMSO-d6 :'H NNM 2.50 ppm (central peak) and 13C 39.51 ppm (central peak).

Mass spectra (TSP) were recorded on a Finigan MAT SSQ 7000 spectrometer.

Mass spectra (EI) were recorded on a Finigan MAT SSQ 710 spectrometer.

LC-MS were recorded on a Waters Alliance 2790 + ZMD spectrometer equipped with software Mass Lynx 3.5.

Purification by flash chromatography was done on silica gel 60 (70-230 mesh), eluting with gradients of EtOAc in heptane. Reverse phase chromatography was done on a X- Terra MS C-8 (10 AM) l9x300 mm preparative column, eluting with gradients of acetonitrile in water containing 0.1 M ammonium acetate, followed by lyophilization.

Example 1 Methyl 3-anilino-5-{2-[(tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl} benzoate (i) Methyl 3-amino-5-{2-[(tert-butoxycarbonyl) amino] pyridin-4-ylybenzoate Tert-Butyl 4-bromopyridin-2-ylcarbamate (Deady, L. W. et al. , Aust. J. Chem. , 1982,35, 2025-34), (1.6 g, 6.0 mmol) was mixed with 3-amino-5- (methoxycarbonyl) phenylboronic acid, (1.3 g, 6.6 mmol) in 30 mL of dimethoxyethane and 6.6 mL 2 M Na2C03 (aq. ) (13 mmol). The solution was degassed (vacuum/nitrogen), [1, 1'- bis (diphenylphosphino) ferrocene] palladium (II) chloride (Pd (dppf) 2Cl2, 1 : 1 complex with CH2C12, 0.22 g, 0.30 mmol) was added and the solution was stirred 12 h under nitrogen at

80 °C. The reaction mixture was concentrated in vacuo, evaporated onto silica gel and purified by chromatography on silica (0 to 80% EtOAc in heptane) to yield the title compound (1.7 g, 84%). 1H NMR (DMSO-d6) : 8 9.84 (s, 1H), 8.28 (dd, J = 5.0, 0.5 Hz, 1H), 8.02 (m, 1H), 7. 35 (m, 1H), 7.27 (m, 1H), 7.22 (dd, J = 5.5, 1.5 Hz, 1H), 7.11 (m, 1H), 5.66 (s, 2H), 3.83 (s, 3H), 3.31 (s, 9H).

MS (ES) m/z 344 (M+1).

(ii) Methyl 3-anilino-5-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}benz oate Methyl 3-amino-5- {2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} benzoate, (0.60 g, 1.7 mmol) was mixed with iodobenzene (0.20 mL, 1.7 mmol) in dry dioxane (4 mL) and tert- butanol (2 mL). The solution was degassed (vacuum/nitrogen).

Tris (dibenzylideneacetone) dipalladium (0) (Pd2 (dba) 3,73 mg, 0.08 mmol) and 9,9- dimethyl-4,5-bis (diphenylphosphino) xanthene (xantphos, 98 mg, 0.17 mmol) was added followed by Cs2CO3 (0.80 g, 2.4 mmol) and the solution was stirred 12 h under nitrogen at 100 °C. The reaction mixture was concentrated in vacuo, evaporated onto silica gel and purified by chromatography on silica (0 to 80% EtOAc in heptane) to yield the title compound (0.48 g, 65%). 1H NMR (CDCl3) : 8 8.36 (s, 1H), 8.22 (d, J = 5.5 Hz, 1H), 7.82 (m, 2H), 7.47 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.15 (m, 2H), 7.04 (m, 1H), 5.98 (s, 1H), 3.93 (s, 3H), 1.55 (s, 9H).

MS (ES) m/z 420 (M+1).

(iii) Methyl 3-anilino-5- (2- [ (tetrahydrofuran-3-ylcarbonyl) aminolpyridin-4-yljbenzoate Methyl 3-anilino-5- {2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} benzoate (0.36 g, 0.85 mmol) was treated with TFA in CH2C12 (1: 1,5 mL) for 3 h at 25 °C followed by evaporation in vacuo. Extraction (CH2C12/K2CO3 (aq. ) ) followed by drying of the organic phase (K2CO3) and evaporation gave the Boc-deprotected free amine.

Ethyldiisopropylamine (0.31 mL, 1.8 mmol) was slowly added to a solution of0- (7- azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluroniumhexafluorophosphat (HATU, 0.34 g, 0.89 mmol) and tetrahydrofuran-3-carboxylic acid (85 uL, 0.89 mmol) in 1 mL of dry DMF under nitrogen at 25 °C. After 5min, the boc deprotected free amine (approx. 0.85 mmol) was added dissolved in 1 mL of dry DMF and the solution was stirred 12 h under nitrogen

at 25 °C. The reaction mixture was concentrated in vacuo, evaporated onto silica gel and purified by chromatography on silica (0 to 100% EtOAc in heptane) to yield the title compound (0.26 g, 71%). 1H NMR (CDCl3) : 8 8.58 (s, 1H), 8. 48 (s, 1H), 8.30 (d, J = 5.5 Hz, 1H), 7.81 (m, 2H), 7.46 (m, 1H), 7. 33 (m, 2H), 7.27 (m, 1H), 7.14 (m, 2H), 7.02 (m, 1H), 6.14 (s, 1H), 4.10-4. 00 (m, 3H), 3.92 (s, 3H), 3.88 (m, 1H), 3.14 (m, 1H), 2.28 (m, 2H).

MS (ES) m/z 418 (M+1).

Example 2 N- {4- [3-anilino-5- (hydroxymethyl) phenyl] pyridin-2-yl} tetrahydrofuran-3- carboxamidecarboxamide Methyl 3-anilino-5- {2- [ (tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl} benzoate from Example 1 (23 mg, 55 µmol) was dissolved in dry THF (2 mL) and DIBAL-H (165, uL, 0.16 mmol, 1M solution in hexane) was added at-78 °C. After 3 h, another portion DIBAL-H was added and the temperature was then allowed to slowly reach 25 °C. After another 3 h, the reaction was quenched with NH4C1 (aq) and the solvent evaporated in vacuo. Purification by reverse phase chromatography gave 7 mg (33%) of the title compound. Hydrochloride salt was made with one eq. HCl (aq.). lH NMR (CD30D) : 5 8.36 (s, 1H), 8.30 (d, J = 5. 5 Hz, 1H), 7.34 (dd, J = 5. 5,2. 0 Hz, 1H), 7.29-7. 22 (m, 4H), 7.20 (m, 1H), 7.15 (m, 2H), 7.13 (m, 1H), 6.88 (m, 1H), 4.03 (m, 1H), 3.94 (m, 2H), 3. 83 (m, 1H), 3.33 (s, 2H), 2.23 (m, 2H).

MS (ES) m/z 390 (M+1).

Example 3 3-anilino-5-{2-[(tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl} benzoic acid Methyl 3-anilino-5-{2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} benzoate (0.22 g, 0.53 mmol) was dissolved in MeOH/DMF (10/5 mL). LiOH (1 M (aq. ), 2.6 mL, 2.6 mmol) was added and stirring was continued for 3 d. The solvent was concentrated in vacuo.

Extraction with CH2Cl2 / 0. 2 M citric acid, drying (MgS04) and evaporation of the solvent gave the acid (0.26 g, quant.).

The acid (0.18 g, 0.43 mmol) was subjected to boc deprotection and amide coupling as described in example 1, but after the TFA treatment the solvent was evaporated in vacuo.

The product was dissolved in DMF (1 mL), ethyldiisopropylamine (0.21 mL, 1.2 mmol) was subsequently added and this solution was used in the amide coupling with tetrahydrofuran-3-carboxylic acid. Purification by reverse phase chromatography gave 25 mg (14%) of the title compound. Hydrochloride salt made with one eq. HCl (aq. ).

IH NMR (HCl salt, DMSO-d6): 8 10.86 (s, 1H), 8.34 (m, 2H), 7.70 (m, 1H), 7.61 (m, 1H), 7.51 (m, 1H), 7. 38 (m, 1H), 7.27 (m, 2H), 7.12 (m, 2H), 6.90 (m, 1H), 3.90 (m, 1H), 3.71 (m, 3H), 3.29 (m, 1H), 2.05 (m, 2H).

MS (ES) m/z 404 (M+1).

Example 4 N- [4- (3-anilino-5-1 [ (2-hydroxyethyl) amino] carbonyllphenyl) pyridin-2- yl] tetrahydrofuran-3-carboxamide Methyl 3-anilino-5- {2-[(tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl} benzoate from Example 1 (35 mg, 84 umol) and ethanolamine (1.2 g, 20 mmol) was dissolved in methanol (1 mL), sodium cyanide (5 mg, 0.10 mmol) was added and the mixture heated at 50 °C in a capped vial for 12 h. Evaporation of solvent and purification by HPLC gave the title compound. The product was treated with 1 eq. HC1 (aq. ) and freeze dried to give 8 mg (20%) of the HCl salt. 1H NMR (CD30D) : 8 8.39 (s, 1H), 8.34 (d, J = 5 Hz, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 7.40 (m, 1H), 7.28 (m, 2H), 7.17 (m, 2H), 6.93 (m, 1H), 4.55 (s, 2H), 4.03 (m, 1H), 3.95 (m, 2H), 3.83 (m, 1H), 3.72 (m, 2H), 3.51 (m, 2H), 2.22 (m, 2H).

MS (ES) m/z 447 (M+1).

Example 5 N- {4- [3- (aminocarbonyl)-5-anilinophenyl] pyridin-2-yl} tetrahydrofuran-3- carboxamide Methyl 3-anilino-5- {2- [ (tert-butoxycarbonyl) amino] pyridin-4-yl} benzoate (50 mg, 0.10 mmol) was reacted with ammonia (2 mL, 7 N in MeOH) for 6 d as described in example 4. Purification by reverse phase chromatography was followed by boc deprotection and amide coupling with HATU as described in example 3. Purification by reverse phase chromatography gave 5 mg (10%) the title compound. Hydrochloride salt made with one eq. HCl (aq.). lH NMR (CD30D) : 8 8.39 (s, 1H), 8.34 (d, J = 5.5 Hz, 1H), 7.65 (m, 1H),

7.60 (m, 1H), 7.51 (m, 1H), 7.39 (dd, J = 5.5, 2 Hz, 1H), 7.28 (m, 2H), 7.18 (m, 2H), 6.93 (m, 1H), 4.03 (m, 1H), 3.95 (m, 2H), 3.83 (m, 1H), 2.23 (m, 2H).

MS (TSP) m/z 403 (M+1).

Example 6 N-(4-{3-anilino-5-[(methylamino)carbonyl]phenyl}pyridin-2-yl )tetrahydrofuran-3- carboxamide Methyl 3-anilino-5-{2-[(tert-butoxycarbonyl) amino] pyridin-4-yl lbenzoate (42 mg, 0.10 mmol) was reacted with methylamine (2 mL, 33 % in MeOH) for 12 h as described in example 4. Boc deprotection and amide coupling with HATU as described in example 3.

Purification by reverse phase chromatography gave the title compound. Hydrochloride salt made with one eq. HCl (aq. ) to give 9 mg (20%). 1H NMR (CD30D): # 8.38 (s, 1H), 8.32 (d, J = 5. 5 Hz, 1H), 7. 59 (m, 1H), 7. 51 (m, 1H), 7.47 (m, 1H), 7. 36 (dd, J = 5. 5, 1. 5 Hz, 1H), 7.27 (m, 2H), 7.16 (m, 2H), 6.93 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3.83 (m, 1H), 2.92 (s, 3H), 2.23 (m, 2H).

MS (ES) m/z 417 (M+1).

Example 7 N- (4- {3-anilino-5- [ (4-methylpiperazin-1-yl) carbonyl] phenyl} pyridin-2- yl) tetrahydrofuran-3-carboxamide Ethyldiisopropylamine was slowly added to a solution of 0- (7-azabenzotriazol-1-yl)- N, N, N', N'-tetramethyluroniumhexafluorophosphat (HATU) and 3-anilino-5- {2- [(tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (18 mg, 44 pool) in 1 mL of dry DMF under nitrogen at 25 °C. After 5min, methylpiperazine (20 uL, 0.18 mmol) was added dissolved in 1 mL of dry DMF and the solution was stirred under nitrogen at 25 °C. After 2 h the reaction was complete and the product purified by reverse phase chromatography to give 7 mg (32%) of the title compound. Hydrochloride salt made with one eq. HC1 (aq.). lH NMR (CD30D) : 8 8.37 (s, 1H), 8.32 (d, J = 5.5 Hz, 1H), 7.32 (m, 1H), 7.42 (m, 1H), 7.32 (dd, J = 5.0, 1.5 Hz, 1H), 7.31-7. 25 (m, 2H), 7.17 (m, 2H), 7.12 (m, 2H), 6.95 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3. 82 (m, 1H), 3.77, 3.54 (2m, 4H), 2.52, 2.44 (2m, 4H), 2.32 (s, 3H), 2.22 (m, 2H).

MS (TSP) m/z 486 (M+1).

Example 8 N- [4-(3-anilino-5-{ [(2-morpholin-4-ylethyl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydrofuran-3-carboxamide 3-anilino-5- {2- [(tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl lbenzoic acid (18 mg, 44 Rmol) was reacted with 2-morpholin-4-ylethanamine (23 RL, 0. 18 mmol) using HATU as described in example 7. After 2 h the reaction was complete and the product purified by reverse phase chromatography to give 9 mg (39%) of the title compound. Hydrochloride salt made with one eq. HC1 (aq.).'H NMR (CD30D) : 8 8.40 (s, 1H), 8.32 (d, J = 6.0 Hz, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.53 (m, 1H), 7.36 (dd, J = 5.0, 2.0 Hz, 1H), 7.28 (m, 2H), 7.17 (m, 2H), 6.93 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3.82 (m, 1H), 3.69 (m, 4H), 3.54 (m, 2H), 2.61 (m, 4H), 2.54 (m, 4H), 2.22 (m, 2H).

MS (TSP) nez 516 (M+1).

Example 9 N- [4- (3-anilinophenyl) pyridin-2-yl] tetrahydrofuran-3-carboxamide (i) tert-butyl 4- (3-aminophenyl) pyridin-2-ylcarbamate Using the same procedure as described in example 1 (i). tert-Butyl 4-bromopyridin-2- ylcarbamate, (1.4 g, 5.1 mmol) and 3-aminophenylboronic acid hydrochloride (0.98 g, 5.6 mmol) gave the title compound (1.1 g, 73%). 1H NMR (CDC13) : 8 8. 36 (s, 1H), 8.25 (m, 1H), 7.23 (d, J = 8 Hz, 1H), 7.18 (m, 1H), 7.06 (d, J = 8 Hz, 1H), 6.99 (m, 1H), 6.75 (dd, J = 8, 1. 5 Hz, 1H), 1. 55 (s, 9H).

MS (ES) 77z/Z 286 (M+1).

(ii) tert-butyl 4- (3-anilinophenyl) pyridin-2-ylcarbamate Using the same procedure as described in example 1 (ii). tert-Butyl 4- (3- aminophenyl) pyridin-2-ylcarbamate (100 mg, 0.35 mmol) and iodobenzene gave the title compound (70 mg, 47%). %).'H NMR (CD30D) : 8 8.21 (d, J = 5 Hz, 1H), 8.10 (s, 1H), 7.45 (m, 1H), 7.38 (m, 1H), 7.33 (m, 1H), 7.27-7. 21 (m, 3H), 7.18-7. 10 (m, 3H), 6. 87 (m, 1H), 1.54 (s, 9H).

(iii) N-[4-(3-anilinophenyl)pyridin-2-yl]tetrahydrofuran-3-carboxa mide

Using the same procedure as in example 1 (iii). tert-Butyl 4- (3-anilinophenyl) pyridin-2- ylcarbamate (compound 12) (70 mg, 0.19 mmol) was Boc deprotected and reacted with tetrahydrofuran-3-carboxylic acid to give 22 mg (32%) of the title compound.

Hydrochloride salt made with one eq. HC1 (aq.). lH NMR (CD30D) : 8 8.35 (d, J = 6.5 Hz, 1H), 7.82 (dd, J = 6. 5,2. 0 Hz, 1H), 7.65 (d, J = 2 Hz, 1H), 7.49 (m, 1H), 7.43 (m, 1H), 7.31-7. 24 (m, 4H), 7.19-7. 14 (m, 2H), 6.94 (m, 1H), 4.04 (m, 2H), 3.94 (m, 1H), 3.85 (m, 1H), 3.36 (m, 1H), 2.29 (m, 2H).

MS (ES) m/z 360 (M+1).

Example 10 1-Acetyl-N-[4-(3-anilinophenyl)pyridin-2-yl]piperidine-4-car boxamide tert-Butyl 4- (3-anilinophenyl) pyridin-2-ylcarbamate (4 mg, 15 jimol) was boc deprotected with TFA and then reacted with 1-acetylpiperidine-4-carboxylic acid (3 mg, 15 Fmol) as described in example 1 (iii) but using TBTU (5 mg, 15 Rmol) and HOBt (2 mg, 15, umol) instead of HATU as coupling reagent. The reaction was stopped after 5 days and the product purified by reverse phase chromatography to give 2 mg (32%) of the title compound. Hydrochloride salt made with one eq. HC1 (aq.). lH NMR (CD30D): 8 8.35 (s, 1H), 8.30 (dd, J = 5.5, 1 Hz, 1H), 7.37 (m, 1H), 7.35-7. 30 (m, 2H), 7.27-7. 21 (m, 2H), 7.18-7. 10 (m, 4H), 6.87 (m, 1H), 3.21 (m, 2H), 2.75 (m, 2H), 2.11 (s, 3H), 2.07-1. 90 (m, 4H), 1.78 (m, 1H), 1.67 (m, 2H).

MS (ES) nalz 415 (M+1).

Example 11 Methyl 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4- yl} benzoate Methyl 3-anilino-5- {2-[(tert-butoxycarbonyl) amino] pyridin-4-yl lbenzoate (from examplel) (1.28 g, 3.05 mmol) was treated with trifluoroacetic acid (5 mL) in dichloromethane (10 mL) for 3h at room temperature. The solvent was evaporated under vacuum. The resulting material was dissolved in an aqueous solution of potassium carbonate (20 mL) and extracted with dichloromethane. The organic layer was dried over potassium carbonate, filtered and evaporated under vacuum to give the deprotected 2- aminopyridine derivative.

Tetrahydro-2H-pyran-4-carboxylic acid (390 mg, 3.0 mmol) was dissolved in 15 mL thionyl chloride and this solution was stirred for 1h. After evaporation of the solvent the resulting oil was dissolved in dichloromethane (2 mL). This solution was added dropwise to a solution of the deprotected 2-aminopyridine derivative in pyridine (30 mL) at 0°C under nitrogen atmosphere. After lh stirring, the solvent were removed under vacuum and the crude compound purified by flash chromatography (ethyl acetate/DME: 2/1). Yield: 64% (850 mg).

1H NMR (400 MHz, CDCl3) : b 8.49 (s, 1 H), 8.29 (d, J=6. 1 Hz, 1 H), 8.10 (s, 1 H), 7.80 (s, 2 H), 7.46 (m, 1 H), 7.34 (m, 3 H), 7.29-7. 25 (m, 1 H), 7.13 (d, J=7. 6 Hz, 3 H), 7.02 (t, J=7. 6 Hz, 2 H), 5.92 (s, 1H), 4.06 (m, 2H), 3.92 (s, 3H), 3.47 (td, J= 11.1/3. 1 Hz, 2H), 2.55 (m, 1H), 1.96-1. 85 (m, 4H).

MS (TSP) m/z (M+1) : 432.

Example 12 3-Anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid Methyl 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl lbenzoate (850 mg, 1.97 mmol) was dissolved in a mixture of THF (50 mL) and lithium hydroxide 1M aqueous solution (10 mL). The reaction was stirred for 3 days at 20°C. The solution was concentrated in vacuo. The aqueous solution was extracted with ethyl acetate (3x20 mL) and concentrated again in vacuo. The resulting material was mixed with a 0.2M citric acid aqueous solution until pH 4. After extraction with dichloromethane, the organic layer was filtered and concentrated to afford a crude material, which was purified by HPLC.

Yield: 70 % (580 mg).

1H NMR (400 MHz, DMSO-D6) : 6 10.57 (s, 1 H), 8.60 (s, 1 H), 8.42 (d, J=1. 0 Hz, 1 H), 8.37 (d, J=5. 3 Hz, 1 H), 7.73 (dd, J=2. 1,1. 4 Hz, 1 H), 7.64 (t, J=1. 6 Hz, 1 H), 7.55-7. 48 (m, 1 H), 7.36 (dd, J=5. 3,1. 8 Hz, 1 H), 7.30 (ddd, J=9. 6,6. 3,2. 1 Hz, 2 H), 7.15 (dd, J=8. 6,1. 2 Hz, 2 H), 6.94-6. 90 (m, 1 H), 3.93-3. 83 (m, 2 H), 2.78 (s, 1 H), 1.74-1. 63 (m, J=6. 8,6. 7,6. 6,6. 6 Hz, 4 H).

MS (TSP) m/z (M+1): 418.

Example 13 N- [4- (3-anilino-5-1 [ (tetrahydro-2H-pyran-4- ylmethyl) amino] carbonyl} phenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide 3-Anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl lbenzoic acid (42 mg, 0.10 mmol) and N [ (dimethylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35mL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of (tetrahydro-2H-pyran-4-ylmethyl) amine (11.5 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 63% (32 mg).

1H NMR (400 MHz, CDCl3) : 8 8. 66 (s, 1 H), 8.48 (s, 1 H), 8.25 (d, J=4. 5 Hz, 1 H), 7.55 (s, 2 H), 7.40 (d, J=25. 3Hz, 3H), 7.31 (t, J=7. 8 Hz, 3 H), 7.27-7. 21 (m, 2 H), 7.13 (d, J=7. 1 Hz, 3 H), 7.01 (t, J=7. 3 Hz, 2 H), 6.55 (t, J=6. 1 Hz, 1 H), 6.14 (s, 1 H), 4.06 (dd, J=7. 8,3. 3 Hz, 2 H), 3.97 (dd, J=11. 4,2. 8 Hz, 2 H), 3.50-3. 44 (m, 2 H), 3.41-3. 37 (m, 4 H), 2.63- 2.53 (m, 1 H), 1.94-1. 84 (m, 5 H), 1.66 (dd, J=13. 1,2. 0 Hz, 2 H), 1.42-1. 31 (m, 2 H).

MS (ES) m/z (M+1) : 515.

Example 14 N- [4- (3-anilino-5- { [ (2-oxotetrahydrofuran-3-yl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide 3-Anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyri din-4-yl}benzoic acid (42 mg, 0.10 mmol) and N-[(dimethylamino) (3H-[1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (53mL, 0.30 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of () 3-aminodihydrofuran-2 (3H)-one hydrobromide (18 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl

acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 20% (10 mg).

'H NMR (400 MHz, CDC13) : 8 8.80 (s, 1 H), 8.37 (s, 1 H), 8.16 (d, J=5. 6 Hz, 1 H), 7.59 (d, J=7. 1 Hz, 1 H), 7.53 (s, 1 H), 7.39 (s, 1 H), 7.28 (m, 3 H), 7.08 (m, 3 H), 6.98 (t, J=7. 6 Hz, 1 H), 6.15 (s, 1 H), 4.88-4. 79 (m, 1 H), 4.53 (t, J=8. 3 Hz, 1 H), 4.40-4. 29 (m, 1 H), 4. 07-4. 00 (m, 2 H), 3.52-3. 42 (m, 2 H), 2.89-2. 85 (m, 1 H), 2.83 (dd, J=8. 8/4. 8 Hz, 1 H), 2.65-2. 55 (m, 1 H), 2.42-2. 31 (m, 1 H), 1.93-1. 82 (m, 5 H).

MS (ES) m/z (M+1) : 501.

Example 15 (R)-N- [4- (3-anilino-5- { [2- (methoxymethyl) pyrrolidin-1-yl] carbonyl} phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide 3-Anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (42 mg, 0.10 mmol) and N- [ (di'methylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 µL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of (R) 2- (methoxymethyl) pyrrolidine (11 mg, 0.10 mmol) in DMF (0. 5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 39% (20 mg).

'H NMR (400 MHz, CDC13) : 8 9.20 (s, 1 H), 8.52 (s, 1 H), 8.19 (d, J=5. 6 Hz, 1 H), 7.29 (m, 3 H), 7. 25- 7. 21 (m, 3 H), 7.11 (d, J=7. 6 Hz, 2 H), 6.99 (t, J=7. 3 Hz, 1 H), 6.01 (s, 1 H), 4.41 (d, J=2. 0 Hz, 1 H), 4.11 (d, J=7. 6 Hz, 1 H), 4.05 (ddd, J=8. 7/4.5/4. 4 Hz, 2 H), 3.70-3. 64 (m, 1 H), 3.62-3. 56 (m, 1 H), 3.51-3. 46 (m, 4 H), 3. 38 (s, 3 H), 3.13 (s, 1 H), 2.60 (m, 1 H), 2.11 (s, 2 H), 2.04 (s, 2 H), 1.95 (dd, J=12. 9/4.3 Hz, 3 H), 1.90-1. 76 (m, 6 H).

MS (ES) m/z (M+1) : 515.

Example 16 <BR> <BR> <BR> (S)-N- [4- (3-anilino-5-1 [2- (methoxymethyl) pyrrolidin-1-yl] carbonyllphenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide 3-anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyridin-4-yl}ben zoic acid (42 mg, 0.10 mmol) and N-[(dimethylamino) (3H-[1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 pLL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of (S)-2- (methoxymethyl) pyrrolidine (11 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 39% (20 mg).

1H NMR (400 MHz, CDC13) : 8 9.20 (s, 1 H), 8. 52 (s, 1 H), 8.19 (d, J=5. 6 Hz, 1 H), 7.29 (m, 3 H), 7.21-7. 25 (m, 3 H), 7.11 (d, J=7. 6 Hz, 2 H), 6.99 (t, J=7. 3 Hz, 1 H), 6.01 (s, 1 H), 4.41 (d, J=2. 0 Hz, 1 H), 4.11 (d, J=7. 6 Hz, 1 H), 4.05 (ddd, J=8. 7/4. 5/4. 4 Hz, 2 H), 3.70-3. 64 (m, 1 H), 3.59 (m, 1 H), 3.51-3. 46 (m, 4 H), 3. 38 (s, 3 H), 3.13 (s, 1 H), 2.63- 2.57 (m, 1 H), 2.11 (s, 2 H), 2.04 (s, 2 H), 1.95 (dd, J=12. 9/4.3 Hz, 3 H), 1.90-1. 76 (m, 6 H).

MS (ES) m/z (M+1) : 515.

Example 17 <BR> <BR> <BR> N- {4- [3-anilino-5- (morpholin-4-ylcarbonyl) phenyl] pyridin-2-yl} tetrahydro-2H-<BR> <BR> <BR> <BR> pyran-4-carboxamide 3-anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (42 mg, 0.10 mmol) and N- [ (dimethylamino) (3H- [ 1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 uL, 0.20 mmol) was added dropwise and the solution stirred for 1h at room temperature under nitrogen atmosphere.

Then a solution of morpholine (8.7 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous

solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 57% (28 mg).

'H NMR (400 MHz, DMSO-d6): 8 10.55 (s, 1 H), 8.56 (s, 1 H), 8.37 (m, 2 H), 7.37 (m, 2 H), 7.30 (m, 2 H), 7.13 (m, 3 H), 7.09 (s, 1 H), 6.92 (s, 1 H), 3.88 (d, J=4. 0 Hz, 2 H), 3.60 (s, 7 H), 2.77 (t, J=10. 9 Hz, 1 H), 1.90 (s, 2H), 1.71-1. 63 (m, 5 H).

MS (ES) m/z (M+1) : 487.

Example 18 (R)-N- [4- (3-anilino-5-1 [ (tetrahydrofuran-2-ylmethyl) amino] carbonyl} phenyl) pyridin- 2-yl] tetrahydro-2H-pyran-4-carboxamide 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl lbenzoic acid (42 mg, 0. 10 mmol) and N- [ (dimethylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 I1L, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of [(2R)-tetrahydrofuran-2-ylmethyl] amine (10 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 40% (20 mg).

IH NMR (400 MHz, CDC13) : 8 9.17 (s, 1 H), 8.50 (s, 1 H), 8.19 (d, J=6. 1 Hz, 1 H), 7.54 (m, 1 H), 7.48 (m, 1 H), 7.37 (m, 1 H), 7.30 (m, 2 H), 7.21 (dd, J=8.0/4. 0 Hz, 1 H), 7.12 (m, 2 H), 6.99 (m, 1 H), 6. 84 (m, 1 H), 6.07 (s, 1 H), 4.10 (m, 1H), 4.06 (m, 2 H), 3. 88 (q, J=6. 7 Hz, 1 H), 3.83 (m,, 4 H), 3.50 (td, J=8. 0/4.0 Hz, 2 H), 3.47 (m, 1 H), 2.60 (m, 1 H), 1.93-1. 82 (m, 7 H), 1.60 (m, 1 H).

3C NMR (101 MHz, CDC13) : 8 173.63 (s, 1 C), 167.31 (s, 1 C), 152.11 (s, 1 C), 150.81 (s, 1 C), 147.35 (s, 1 C), 144.71 (s, 1 C), 141.96 (s, 1 C), 139.51 (s, 1 C), 136.77 (s, 1 C), 129.60 (s, 2 C), 122.23 (s, 1 C), 118.99 (s, 2 C), 118.09 (s, 1 C), 118.00 (s, 1 C), 117.31 (s, 1 C), 116.15 (s, 1 C), 112.24 (s, 1 C), 77.93 (s, 1 C), 68.18 (s, 1 C), 67.13 (s, 2 C), 43.88 (s, 1 C), 42. 98 (s, 1 C), 29.00 (s, 2 C), 28.80 (s, 1 C), 25.90 (s, 1 C).

MS (ES) m/z (M+1) : 501.

Example 19 (S)-N- [4- (3-anilino-5-1 [ (tetrahydrofuran-2-ylmethyl) amino] carbonyl} phenyl) pyridin- 2-yl] tetrahydro-2H-pyran-4-carboxamide 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyri din-4-yl}benzoic acid (42 mg, 0.10 mmol) and N [ (dimethylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 µL, 0.20 mmol) was added dropwise and the solution stirred for 1 h at room temperature under nitrogen atmosphere.

Then a solution of [(25)-tetrahydrofuran-2-ylmethyl] amine (10 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 48% (24 mg).

1H NMR (400 MHz, CDCl3) : # 9.17 (s, 1 H), 8.50 (s, 1 H), 8.19 (d, J=6. 1 Hz, 1 H), 7.54 (m, 1 H), 7.48 (m, 1 H), 7.37 (m, 1 H), 7.30 (m, 2 H), . 7.21 (dd, J=8.0/4. 0 Hz, 1 H), 7.12 (m, 2 H), 6.99 (m, 1 H), 6.84 (m, 1 H), 6.07 (s, 1 H), 4.10 (m, 1H), 4.05 (m, 2 H), 3. 88 (q, J=6. 7 Hz, 1 H), 3.78 (m, 4 H), 3.50 (td, J=8. 0/4.0 Hz, 2 H), 3.47 (m, 1 H), 2.60 (m, 1 H), 1.93-1. 82 (m, 7 H), 1.61 (m, 1 H).

3C NMR (101 MHz, CDC13) : 8 173.63 (s, 1 C), 167.31 (s, 1 C), 152.11 (s, 1 C), 150. 81 (s, 1 C), 147.35 (s, 1 C), 144.71 (s, 1 C), 141.96 (s, 1 C), 139.51 (s, 1 C), 136.77 (s, 1 C), 129.60 (s, 2 C), 122.23 (s, 1 C), 118.99 (s, 2 C), 118. 09 (s, 1 C), 118.00 (s, 1 C), 117.31 (s, 1 C), 116.15 (s, 1 C), 112.24 (s, 1 C), 77.93 (s, 1 C), 68.18 (s, 1 C), 67.13 (s, 2 C), 43.88 (s, 1 C), 42.98 (s, 1 C), 29.00 (s, 2 C), 28. 80 (s, 1 C), 25.90 (s, 1 C).

MS (ES) m/z (M+1) : 501.

Example 20 N- {4- [3-anilino-5- (1, 4-dioxa-8-azaspiro [4.5] dec-8-ylcarbonyl) phenyl] pyridin-2- yl} tetrahydro-2H-pyran-4-carboxamide 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyri din-4-yl}benzoic acid (42 mg, 0.10 mmol) andN-[(dimethylamino) (3H-[1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 p, L, 0.20 mmol) was added

dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of 1, 4-dioxa-8-azaspiro [4.5] decane (14.3 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 50% (27 mg).

'H NMR (400 MHz, CDC13) : 8 8.90 (s, 1H), 8.49 (d, J= 0.6 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.32-7. 28 (m, 3H), 7.21 (dd, J= 8.0/1. 5 Hz, 1H), 7.15-7. 10 (m, 4H), 7.00 (t, J= 7.3 Hz, 1H), 6.11 (s, 1H), 4.08-4. 03 (m, 2H), 3.98 (m, 4H), 3.84 (bs, 2H), 3.53 (bs, 2H), 3.47 (td, J=11. 5/2.6 Hz, 2H), 2.59 (m, 1H), 1.97-1. 80 (m, 6H), 1.66 (bs, 2H).

MS (ES) m/z (M+1) : 543.

Example 21 N- (4- {3-anilino-5- [ (2, 6-dimethylmorpholin-4-yl) carbonyl] phenyl} pyridin-2- yl) tetrahydro-2N-pyran-4-carboxamide 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (42 mg, 0.10 mmol) and N-[(dimethylamino) (3H-[1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35, uL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of 2,6-dimethylmorpholine (11.5 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 37% (19 mg).

1H NMR (400 MHz, CDC13) : 8 8.56 (s, 1H), 8.49 (d, J= 0.6 Hz, 1H), 8.23 (d, J=6.1 Hz, 1H), 7.31 (m, 3H), 7.21 (dd, J= 8.0/1. 5 Hz, 1H), 7.12 (m, 4H), 7.00 (m, 1H), 6.00 (s, 1H), 4.06 (m, 2H), 3.69-3. 43 (m, 5H), 2.81 (m, 1H), 2.61-2. 49 (m, 2H), 1.93-1. 84 (m, 4H), 1.24 (bs, 3H), l. 11 (bs, 3H).

MS (ES) m/z (M+1) : 515.

Example 22 N-14- [3-anilino-5- (1 [2- (1, 3-dioxolan-2-yl) ethyl] amino} carbonyl) phenyl] pyridin-2- yl} tetrahydro-2H-pyran-4-carboxamide 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyri din-4-yl}benzoic acid (42 mg, 0.10 mmol) and N [ (dimethylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 µL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of [2- (1, 3-dioxolan-2-yl) ethyl] amine (11.7 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 52% (27 mg).

1H NMR (400 MHz, CDC13) : 8 8.79 (s, 1H), 8. 50 (s, 1H), 8. 24 (d, J=5.5 Hz, 1H), 7.56 (t, J= 1.7 Hz, 1H), 7.49 (t, J= 1.3 Hz, 1H), 7.37 (t, J= 1./ Hz, 1H), 7.28 (m, 3H), 7.13 (m, 2H), 7.07 (m, 1H), 7.01 (m, 1H), 6.16 (s, 1H), 5.00 (t, J = 4.2 Hz, 1H), 4.02 (m, 4H), 3.87 (m, 2H), 3.63 (m, 2H), 3. 48 (td, J= 11.4/2. 6 Hz, 2H), 2.57 (m, 1H), 2.02 (m, 2H), 1.93-1. 85 (m, 4H).

13C NMR (101 MHz, CDC13) : 8 173.31 (s, 1 C), 166.71 (s, 1 C), 152.05 (s, 1 C), 150.59 (s, 1 C), 147.62 (s, 1 C), 144.63 (s, 1 C), 141.92 (s, 1 C), 139.56 (s, 1 C), 136.87 (s, 1 C), 129.51 (s, 2 C), 122.11 (s, 1 C), 118.93 (s, 2 C), 118.07 (s, 1 C), 117.98 (s, 1 C), 117.18 (s, 1 C), 115.65 (s, 1 C), 111.97 (s, 1 C), 103.91 (s, 1 C), 67.03 (s, 2 C), 64.96 (s, 2 C), 42.97 (s, 1 C), 35.29 (s, 1 C), 32.31 (s, 1 C), 28.95 (s, 2 C).

MS (ES) m/z (M+1) : 517.

Example 23 N- [4- (3-anilino-5-1 [bis (2-methoxyethyl) amino] carbonyl} phenyl) pyridin-2- yl] tetrahydro-2H-pyran-4-carboxamide 3-anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} lbenzoic acid (42 mg, 0.10 mmol) and N-[(dimethylamino) (3H-[1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 pL, 0.20 mmol) was added

dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of 2-methoxy-N (2-methoxyethyl) ethanamine (13.3 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 53% (28 mg).

'H NMR (400 MHz, CDC13) : 6 9.48 (s, 1H), 8.54 (s, 1H), 8. 18 (d, J= 5.3 Hz, 1H), 7.28 (m, 3H), 7.21 (m, 3H), 7.12 (dd, J= 8.4/0. 8 Hz, 2H), 6.99 (m, 1H), 6.09 (s, 1H), 4.07 (m, 2H), 3.75 (bs, 2H), 3.67 (bs, 2H), 3.56 (bs, 2H), 3.49 (m, 4H), 3.37 (s, 3H), 3.25 (s, 3H), 2.61 (m, 1H), 1.93-1. 82 (m, 4H).

3C NMR (101 MHz, CDCl3) : 6 176.49 (s, 1 C), 173.67 (s, 1 C), 171.65 (s, 1 C), 152.17 (s, 1 C), 151.04 (s, 1 C), 146.79 (s, 1 C), 144.41 (s, 1 C), 141.87 (s, 1 C), 139.27 (s, 1 C), 138.63 (s, 1 C), 129.46 (s, 1 C), 122.07 (s, 1 C), 118.97 (s, 1 C), 117.78 (s, 1 C), 117.44 (s, 1 C), 116.30 (s, 1 C), 115.37 (s, 1 C), 112.24 (s, 1 C), 77.31 (s, 1 C), 76.68 (s, 1 C), 67.06 (s, 1 C), 58.83 (s, 1 C), 42.80 (s, 1 C), 28.91 (s, 1 C), 21.24 (s, 1 C).

MS (ES) m/z (M+1) : 533.

Example 24 N- [4- (3-anilino-5-1 [ (1, 3-dioxolan-2-ylmethyl) (methyl) amino] carbonyl} phenyl) pyridin- 2-yl] tetrahydro-2H-pyran-4-carboxamide 3-anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (42 mg, 0.10 mmol) and N-[(dimethylamino) (3H-[1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35, uL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of (1, 3-dioxolan-2-ylmethyl) methylamine (11 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 44% (23 mg).

IH NMR (400 MHz, CDCl3) : 8 9.50 (s, 1H), 8.56 (s, 1H), 8.18 (d, J= 5.5 Hz, 1H), 7.33- 7.12 (m, 7H), 7.00 (t, J= 7.4 Hz, 1H), 6.02 (s, 1H), 5.17-4. 98 (m, 1H), 4.06 (m, 3H), 4.02

(m, 2H), 3.93 (m, 1H), 3.50 (td, J= 8.5/1. 5 Hz, 3H), 3.17 (s, 1H), 3.10 (s, 1H), 2.63 (m, 1H), 2.13 (s, 2H), 1.95-1. 86 (m, 4H).

MS (ES) m/z (M+1) : 517.

Example 25 Ethyl 4-[(3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4- yl} benzoyl) amino] piperidine-1-carboxylate 3-anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcalbonyl) amino] pyridin-4-yl} benzoic acid (42 mg, 0.10 mmol) and N [ (dimethylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 1L, 0.20 mmol) was added dropwise and the solution stirred for 1h at room temperature under nitrogen atmosphere.

Then a solution of ethyl 4-aminopiperidine-1-carboxylate (17 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 44% (25 mg).

1H NMR (400 MHz, DMSO-d6): 8 10.57 (s, 1 H), 8.56 (s, 1 H), 8.33-8. 43 (m, 2 H), 7.64 (m, 1 H), 7.56 (s, 1 H), 7.42 (m, 2 H), 7.29 (m, 2 H), 7.13 (m, 2 H), 6.91 (m, 1 H), 4.02 (m, 5 H), 3.89 (dt, J=9. 3,2. 1 Hz, 2 H), 2.90 (m, 2 H), 2.78 (m, 1 H), 1.81 (m, 2 H), 1.68 (m, 4 H), 1.42 (m, 2 H), 1.17 (t, J=7. 0 Hz, 3 H).

3C NMR (101 MHz, DMSO-d6) : 8 174.16 (s, 1 C), 165.44 (s, 1 C), 154.67 (s, 1 C), 152.93 (s, 1 C), 149. 10 (s, 1 C), 148.57 (s, 1 C), 144.52 (s, 1 C), 142.58 (s, 1 C), 138.82 (s, 1 C), 136.65 (s, 1 C), 129.36 (s, 2 C), 120.67 (s, 1 C), 117.61 (s, 2 C), 117.26 (s, 1 C), 116.87 (s, 1 C), 116.30 (s, 1 C), 115.34 (s, 1 C), 110.74 (s, 1 C), 66.37 (s, 2 C), 60.67 (s, 2C), 46.55 (s, 1 C), 42.68 (s, 1 C), 41.28 (s, 1 C), 28.75 (s, 2 C), 14.64 (s, 1 C).

MS (ES) m/z (M+1) : 572.

Example 26 N-(4-{3-anilino-5-[(tetrahydro-2H-pyran-4-ylamino) carbonyl] phenyl} pyridin-2- yl) tetrahydro-2H-pyran-4-carboxamide

3-anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (42 mg, 0.10 mmol) and N- [ (dimethylamino) (3H- [1, 2, 3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 uL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then a solution of tetrahydro-2H-pyran-4-amine (9.2 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHCO3 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC.

Yield: 48% (24 mg).

1H NMR (400 MHz, DMSO-d6): b 8.62 (s, 1H), 8. 46 (m, 3H), 8.01 (s, 1H), 7.71 (m, 1H), 7.64 (m, 1H), 7.52-7. 48 (m, 2H), 7.35 (m, 2H), 7.22 (m, 2H), 6.97 (m, 1H), 4.09 (m, 3H), 3.96 (m, 3H), 2.95 (s, 2H), 2.85 (m, 1H), 2.79 (s, 2H), 1.86-1. 60 (m, 7H).

MS (TSP) m/z (M+1) : 501.

Example 27 <BR> <BR> <BR> <BR> <BR> N-(4-43-anilino-5-[(hydroxyamino) carbonyl] phenyl} pyridin-2-yl) tetrahydro-2H-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> pyran-4-carboxamide 3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl) arnino] pyridin-4-yl lbenzoic acid (100 mg, 0.24 mmol) and N- [ (dimethylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (182 mg, 0.48 mmol) were dissolved in 5 mL of DMF. Diisopropylethylamine (167 gel, 0.96 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then hydroxylamine hydrochloride (25 mg, 0.36 mmol) was added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 32% (33 mg).

1H NMR (400 MHz, DMSO-d6): 8 11.30 (s, 1H), 10.55 (s, 1H), 9.06 (s, 1H), 8. 55 (s, 1H), 8.43 (s, 1H), 8.38 (d, J= 5.2 Hz, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 7.38 (d, J=1 Hz, 1H), 7.29 (t, J= 7.9 Hz, 2H), 7.15 (d, J= 7.9 Hz, 2H), 6.91 (t, J= 7.3 Hz, 1H), 3.91 (m, 2H), 3.42 (m, 2H), 2.78 (m, 1H), 1.75-1. 60 (m, 4H).

MS (ES) m/z (M+1) : 433.

Example 28 N-(4-{3-anilino-5-[(methoxyamino) carbonyl] phenyl} pyridin-2-yl) tetrahydro-2H- pyran-4-carboxamide 3-anilino-5- {2- [(tetrahydro-2H-pyran-4-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (100 mg, 0.24 mmol) and N- [ (dimethylamino) (3H- [1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) methylene]-N-methylmethanaminium hexafluorophosphate (182 mg, 0.48 mmol) were dissolved in 5 mL of DMF. Diisopropylethylamine (167 uL, 0.96 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere.

Then O-methylhydroxylamine hydrochloride (25 mg, 0.36 mmol) was added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution of NaHCO3 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 35% (37 mg).

IH NMR (400 MHz, MeOD-d4): 8 8.43 (s, 1H), 8.38 (d, J= 5.3 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.41 (dd, J= 5. 5/1. 6 Hz, 1H), 7.35 (t, J= 7.8 Hz, 2H), 7.24 (d, J= 7.8 Hz, 2H), 7.01 (t, J= 7.8 Hz, 1H), 4.00 (m, 2H), 3.82 (s, 3H), 3.49 (td, J= 11.4/2. 9 Hz, 2H), 2.74 (m, 1H), 1.90-1. 75 (m, 4H).

13C NMR (101 MHz, MeOD-d4): # 176.30 (s, 1 C), 167.73 (s, 1C), 153.82 (s, 1 C), 151.41 (s, 1 C), 149.65 (s, 1 C), 147.09 (s, 1 C), 143.74 (s, 1 C), 141.04 (s, 1 C), 135. 10 (s, 1 C), 130.41 (s, 2 C), 122. 68 (s, 1 C), 119.85 (s, 2 C), 118.93 (s, 1 C), 118. 84 (s, 1 C), 117.22 (s, 1 C), 115.96 (s, 1 C), 113.18 (s, 1 C), 68.17 (s, 2 C), 64.42 (s, 1 C), 43.62 (s, 1 C), 30.19 (s, 2C).

MS (ES) m/z (M+1) : 447.

Example 29 N-{4-[3-({[2-(acetylamino) ethyl] amino} carbonyl)-5-anilinophenyl] pyridin-2- yl} tetrahydrofuran-3-carboxamide Methyl 3-anilino-5- {2-[(tert-butoxycarbonyl) amino] pyridin-4-yl lbenzoate (from examplel) (42 mg, 0.10 mmol) was reacted with ethylenediamine (0.67 mL, 10 mmol) in MeOH (0.5 mL) for 12 h as described in example 4. After evaporation of solvent and aqueous workup (EtOAc/K2C03 (aq. ) ), the product was dissolved in pyridine (1 mL) and acetic anhydride (9 RL, 0.1 mmol) was added. After 1 h, evaporation of the solvent and

aqueous workup gave the N-acetyl compound. Boc deprotection and amide coupling with HATU and tetrahydrofuran-3-carboxylic acid as described in example 1. Purification by reverse phase chromatography gave the title compound. Hydrochloride salt made with one eq. HCl (aq. ) to give 20 mg (41%). %).'H NMR (CD30D) : 8 8.39 (s, 1H), 8. 33 (d, J = 5.5 Hz, 1H), 7.59 (m, 1H), 7.54 (m, 1H), 7.48 (m, 1H), 7.37 (dd, J = 5.5, 1.5 Hz, 1H), 7.31-7. 25 (m, 2H), 7.19-7. 15 (m, 2H), 6.93 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3.83 (m, 1H), 3.49 (m, 2H), 3.40 (m, 2H), 2.23 (m, 2H), 1.94 (s, 3H).

MS (ES) m/z 488 (M+1).

Example 30 N- {4- [3- ( f [3- (acetylamino) propyl] amino} carbonyl)-5-anilinophenyl] pyridin-2- yl} tetrahydrofuran-3-carboxamide Methyl 3-anilino-5- {2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} benzoate (42 mg, 0.10 mmol) was reacted with propane-1,3-diamine (0.84 mL, 10 mmol) in MeOH (0.5 mL) for 12h according to the procedure described in example 29. Purification by reverse phase chromatography gave the title compound. Hydrochloride salt made with one eq. HCl (aq. ) to give 19 mg (38%). 1H NMR (CD30D) : 8 8.38 (s, 1H), 8.32 (d, J = 5.5 Hz, 1H), 7.60 (m, 1H), 7. 53 (m, 1H), 7.48 (m, 1H), 7.37 (dd, J = 5.5, 1.5 Hz, 1H), 7.31-7. 25 (m, 2H), 7.19- 7.15 (m, 2H), 6.93 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3.83 (m, 1H), 3.41 (m, 2H), 3.25 (m, 2H), 2.22 (m, 2H), 1.94 (s, 3H), 1.79 (m, 2H).

MS (ES) m/z 502 (M+1).

Example 31 <BR> <BR> <BR> <BR> N- {4- [3-anilino-5- (f [2- (dimethylamino) ethyl] amino} carbonyl) phenyl] pyridin-2-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> yl} tetrahydrofuran-3-carboxamide Methyl 3-anilino-5-{2-[(tert-butoxycarbonyl) amino] pyridin-4-yl} benzoate (42 mg, 0.10 mmol) was reacted with NN-dimethylethane-1, 2-diamine (1.0 mL, 10 mmol) in MeOH (0.5 mL) for 12 h according to the procedure described in example 29. Purification by reverse phase chromatography gave the title compound. Hydrochloride salt made with one eq. HC1 (aq. ) to give 6 mg (11%). g H NMR (CD30D) : 8 8. 39 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7.62 (m, 1H), 7.56 (m, 1H), 7.48 (m, 1H), 7.37 (dd, J = 5.5, 1.5 Hz, 1H), 7.31-7. 25 (m,

2H), 7.19-7. 15 (m, 2H), 6.93 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3.83 (m, 2H), 3.55 (m, 2H), 2.64 (m, 2H), 2.36 (s, 6H), 2.23 (m, 2H).

MS (ES) nilz 474 (M+1).

Example 32 N-{4-[3-anilino-5-({[3-(dimethylamino) propyl] amino} carbonyl) phenyl] 0 yridine-2- yl} tetrahydrofuran-3-carboxamide Methyl 3-anilino-5-{2-[(tert-butoxycarbonyl) amino] pyridine-4-yl} benzoate (42 mg, 0.10 mmol) was reacted with NN-dimethylpropane-1, 3-diamine (1.0 mL, 10 mmol) in MeOH (0.5 mL) for 12 h according to the procedure described in example 29. Purification by reverse phase chromatography gave the title compound. Hydrochloride salt made with one eq. HCl (aq. ) to give 7 mg (13%). 1H NMR (CD30D) : 8 8.40 (s, 1H), 8. 33 (d, J = 5.5 Hz, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.48 (m, 1H), 7.37 (dd, J = 5.5, 1.5 Hz, 1H), 7.32-7. 24 (m, 2H), 7.21-7. 14 (m, 2H), 6.94 (m, 1H), 4.02 (m, 1H), 3.94 (m, 2H), 3.83 (m, 1H), 3.43 (m, 2H), 2.62 (m, 2H), 2.42 (s, 6H), 2.23 (m, 2H), 1.88 (m, 2H).

MS (ES) m/z 488 (M+1).

Example 33 N-[4-(3-{[(2-amino-2-oxoethyl)amino]carbonyl}-5-anilinopheny l)pyridin-2- yl] tetrahydrofuran-3-carboxamide 3-Anilino-5- {2-[(tetrahydrofuran-3-ylcarbonyl) amino] pyridin-4-yl} benzoic acid (0.30 g, 0.74 mmol) was reacted with glycinamide hydrochloride (0.24 g, 2.2 mmol) by amide coupling using HATU as described in example 7. Hydrochloride salt made with one eq.

HC1 (aq. ) to give 75 mg (20%). 1H NMR (CD30D) : 8 8.36 (s, 1H), 8.30 (d, J = 5 Hz, 1H), 7.64 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.34 (dd, J = 5.5, 1.5 Hz, 1H), 7.26 (m, 2H), 7.16 (m, 2H), 6.92 (m, 1H), 4.06-3-99 (m, 3H), 3.97-3. 90 (m, 2H), 3. 85-3. 78 (m, 2H), 2.22 (m, 2H), 1.24 (m, 3H).

MS (ES) m/z 460 (M+1).

Example 34 tert-butyl [4- (3-amino-5-nitrophenyl) pyridin-2-yl] carbamate

tert-Butyl 4-bromopyridin-2-ylcarbamate, (0.27 g, 1.0 mmol) and (3-amino-5- nitrophenyl) boronic acid hydrochloride (0.24 g, 1. 1 mmol) was reacted as described in example li to give the title compound (0.28 g, 84%) after purification by chromatography on silica (0 to 10% MeOH in CH2Cl2). lH NMR (DMSO-d6) : 8 9.90 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 8.06 (m, 1H), 7.54 (m, 1H), 7.46 (m, 1H), 7.29 (dd, J = 5.0, 1.5 Hz, 1H), 7.27 (m, 1H), 6.07 (s, 2H), 1.48 (s, 9H).

MS (ES) 331 (M+1).

Example 35 tert-butyl [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] carbamate tert-Butyl [4- (3-amino-5-nitrophenyl) pyridin-2-yl] carbamate (1.3 g, 3.8 mmol) was reacted with iodobenzene as described in example lii to give the title compound (1.4 g, 87%) after purification by chromatography on silica (0 to 10% MeOH in CH2Cl2). lH NMR (DMSO- d6): 8 9.93 (s, 1H), 8.95 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 8.09 (m, 1H), 7.86 (m, 1H), 7.80 (m, 1H), 7.65 (m, 1H), 7.39-7. 33 (m, 3H), 7.23 (m, 2H), 7.02 (m, 1H), 1.48 (s, 9H).

Example 36 N- [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] tetrahydrofuran-3-carboxamide tert-Butyl [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] carbamate (35 mg, 86, umol) was deprotected and reacted with terahydrofuran-3-carboxylic acid as described in example liii, but a threefold excess of carboxylic acid and coupling reagent was used, to give 16 mg (46%) of the title compound. Hydrochloride salt made with one eq. HC1 (aq. ).

IH NMR (CD30D) : 8 8.42 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.90 (m, 1H), 7. 88 (m, 1H), 7.63 (m, 1H), 7.40-7. 32 (m, 3H), 7.22 (m, 2H), 7.04 (m, 1H), 4.03 (m, 1H), 3.94 (m, 2H), 3.83 (m, 1H), 2.23 (m, 2H).

MS (ES) m/z 405 (M+1).

Example 37 N- [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide tert-Butyl [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] carbamate (0.38 g, 0.93 mmol) was deprotected and reacted with terahydropyran-4-carboxylic acid as described in example

liii, but a threefold excess of carboxylic acid and coupling reagent was used to give 0.36 g (92%) of the title compound. Hydrochloride salt made with, one eq. HC1 (aq. ).

'H NMR (CD30D) : 5 8. 41 (d, J = 6. 5 Hz, 1H), 7.99 (d, J = 2 Hz, 1H), 7.84 (d, J = 2 Hz, 1H), 7.75 (s, 1H), 7.72 (m, 1H), 7. 38 (m, 2H), 7.25 (m, 2H), 7.09 (m, 1H), 4.03 (m, 2H), 3.52 (m, 2H), 2.83 (m, 1H), 1. 88 (m, 4H).

MS (ES) m/z 419 (M+1).

Example 38 N- [4- (3-amino-5-anilinophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide N [4- (3-anilino-5-nitrophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide (0.55 g, 1.3 mmol) was hydrogenated in EtOH/EtOAc (1 : 1, 20 mL) with Put02 (25 mg, 0.11 mmol) and hydrogen at atmospheric pressure for 20 h. Filtering and evaporation of solvent gave the title compound (0.46 g, 92%) which was reacted further without further purification.

Purification on a sample was done by reverse phase chromatography. Hydrochloride salt made with one eq. HC1 (aq. ).

IH NMR (CD30D) : 8 8. 40 (d, J = 6.5 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J = 6.5 Hz, 1H), 7.42 (m, 1H), 7.35 (m, 2H), 7.26-7. 18 (m, 3H), 7.12 (m, 1H), 7.05 (m, 1H), 4.02 (m, 2H), 3.52 (m, 2H), 2.87 (m, 1H), 1.88 (m, 4H).

MS (ES) m/z 389 (M+1).

Example 39 N-14- [3- (acetylamino)-5-anilinophenyl] pyridin-2-ylltetrahydro-2H-pyran-4- carboxamide N-[4-(3-amino-5-anilinophenyl)pyridin-2-yl]tetrahydro-2H-pyr an-4-carboxamide (10 mg, 26 imol) was dissolved in pyridine (1 mL) and treated with acetic anhydride (2.5 u, L, 26 µmol) for 5 h. Purification by reverse phase chromatography gave 6 mg (53%) of the title compound. Hydrochloride salt made with one eq. HC1 (aq. ).

'H NMR (CDCl3) : 8 8. 38 (s, 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.96 (s, 1H), 7.55 (s, 1H), 7.31- 7.19 (m, 2H), 7.09 (d, J = 7.5 Hz, 2H), 6.95 (m, 2H), 6.07 (s, 1H), 4.06 (m, 2H), 3.49 (m, 2H), 2.70 (m, 1H), 2.20 (s, 3H), 1.90 (m, 4H).

MS (ES) m/z 431 (M+1).

Example 40 N- {4- [3-anilino-5- (dimethylamino) phenyl] pyridin-2-yl} tetrahydro-2H-pyran-4- carboxamide N [4- (3-amino-5-anilinophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide (10 mg, 26 p, mol), NaBHsCN (3.2 mg, 52 µmol) and formaldehyde (4 RL, 37% solution in water, 52 µmol) was dissolved in MeCN (1 mL). The pH was adjusted to 7 with acetic acid and the solution was stirred for 30 min. Purification by reverse phase chromatography gave 4 mg (20%) of the title compound. Hydrochloride salt made with one eq. HCl (aq. ).

1H NMR (CDC13) : 8 9.18 (s, 1H), 8.59 (s, 1H), 8. 20 (d, J = 5.5 Hz, 1H), 7.34-7. 25 (m, 3H), 7.13 (d, J = 7.5 Hz, 2H), 6.95 (m, 1H), 6.71 (m, 1H), 6.57 (m, 2H), 5. 82 (s, 1H), 4.06 (m, 2H), 3. 48 (m, 2H), 3.00 (s, 6H), 2.65 (m, 1H), 1.92 (m, 4H).

MS (ES) m/z 417 (M+1).

Example 41 N- [4- (3-anilino-5-1 [2- (dimethylaniino) ethyl] amino} phenyl) pyridin-2-yl] tetrahydro- 2H-pyran-4-carboxamide N [4- (3-amino-5-anilinophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide (5 mg, 13) imol), (2-chloroethyl) dimethylamine hydrochloride (2 mg, 13 jimol) was dissolved in MeCN (1 mL) and diisopropylethylamine (7 uL, 38 u. mol). The solution was stirred for 1 h at 150°C. Purification by reverse phase chromatography gave 1 mg (15%) of the title compound. Hydrochloride salt made with one eq. HC1 (aq. ).

'H NMR (CD30D) : # 8.32 (s, 1H), 8.26 (d, J = 5.5 Hz, 1H), 7.30 (dd, J = 5.5, 1.5 Hz, 1H), 7.22 (m, 2H), 7.12 (d, J = 8 Hz, 2H), 6.84 (m, 1H), 6.69 (m, 1H), 6.48 (m, 2H), 4.01 (m, 2H), 3.50 (m, 2H), 3.27 (m, 2H), 2.74 (m, 1H), 2.60 (m, 1H), 2.31 (s, 6H), 1.82 (m, 4H).

MS (ES) m/z 460 (M+1).

Example 42 N-(4-{3-anilino-5-[(pyridin-3-ylmethyl)amino]phenyl}pyridin- 2-yl)tetrahydro-2H- pyran-4-carboxamide N [4- (3-amino-5-anilinophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide (12 mg, 31 µmol) and 3-pyridinecarboxaldehyde (3 µL, 31 Rmol) was dissolved in 1,2-

dichloroethane (1 mL) and triacetoxyborohydride (13 mg, 60 jimol) was added. The solution was stirred for 12 h at 25°C. Purification by reverse phase chromatography gave 11 mg (74%) of the title compound. Hydrochloride salt made with one eq. HC1 (aq. ).

'H NMR (CD30D): # 8.55 (s, 1H), 8.41 (m, 1H), 8.28 (s, 1H), 8. 24 (d, J = 5.5 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 7.40 (m, 1H), 7.24 (m, 1H), 7.15 (m, 2H), 6.96 (d, J = 7. 5 Hz, 2H), 6.81 (m, 1H), 6.64 (m, 1H), 6.50 (m, 1H), 6.41 (m, 1H), 4.41 (s, 1H), 4.00 (m, 2H), 3.49 (m, 2H) o 2.74 (m, 1H), 1.82 (m, 4H).

MS (ES) m/z 480 (M+1).

Example 43 N-14- [3-anilino-5- (tetrahydro-2H-pyran-4-ylamino) phenyllpyridin-2-yIltetrahydro-<BR> 2H-pyran-4-carboxamide N [4- (3-amino-5-anilinophenyl) pyridin-2-yl] tetrahydro-2H-pyran-4-carboxamide (70 mg, 0.18 mmol) was reacted with tetrahydro-4H-pyran-4-one as described in example 42 to give 31 mg (36%) of the title compound. Hydrochloride salt made with one eq. HCl (aq. ).

IH NMR (CD30D) : 8 8.31 (s, 1H), 8.26 (d, J = 5 Hz, 1H), 7.28 (dd, J = 5.5, 1.5 Hz, 1H), 7.22 (m, 2H), 7.11 (m, 2H), 6.84 (m, 1H), 6.68 (m, 1H), 6.51 (m, 2H), 3.98 (m, 4H), 3.51 (m, 5H), 2.73 (m, 1H), 2.01 (m, 2H), 1.82 (m, 4H), 1.49 (m, 2H).

MS (ES) m/z 473 (M+1).

Example 44 N- {4- [3- (cyclohexylamino) phenyl] pyridin-2-yl} tetrahydro-2H-pyran-4-carboxamide tert-Butyl 4- (3-aminophenyl) pyridine-2-yl carbamate (0.10 g, 0.35 mmol) was reacted with cyclohexanone (36 mL, 0.35 mmol) as described in example 42. Boc cleavage and amide coupling with terahydropyran-4-carboxylic acid as described in example liii, but three fold excess coupling reagent was used, to give 50 mg (39%) of the title compound.

Hydrochloride salt made with one eq. HCl (aq. ).

1H NMR (CD30D) : 8 8.33 (s, 1H), 8.27 (d, J = 5 Hz, 1H), 7.30 (dd, J = 5.5, 1.5 Hz, 1H), 7.20 (m, 1H), 6.94-6. 87 (m, 2H), 6.70 (m, 1H), 4.00 (m, 2H), 3.48 (m, 2H), 2.73 (m, 1H), 2.04 (m, 2H), 1.91-1. 73 (m, 6H), 1.66 (m, 1H), 1.41 (m, 2H), 1.23 (m, 3H).

MS (ES) m/z 380 (M+1).

List of abbreviations SPA scintillation proximity assay ATP adenosine triphosphate ATF Activating transcription factor MOPS 3-[N-Morpholino]-propanesultonic acid EGTA Ethylene glycol-bis (ß-aminoethylether)-N, N, N', N'-tetraacetic acid DTT dithiothreitol JNK c-Jun N-terminal kinases MAP mitogen-activated protein Biological evaluation The compounds of this invention may be assayed for their activity according to the following procedure: A scintillation proximity assay (SPA) based on the inhibition of JNK3 catalyzed transfer of the y-phosphate group of [γ-33P] ATP to biotinylated ATF2, has been set up to identify inhibitory compounds. The resulting 33P-labeled biotinylated ATF2 is trapped on SPA beads surface coated with streptavidin.

The assay is performed in 96-well plates. Test compounds made up at 10 mM in DMSO and 1: 3 serial dilutions are made in 100% DMSO. These serial dilutions are then diluted 1: 10 in assay buffer (50 mM MOPS pH 7.2, 150 mM, NaCl, 0.1 mM EGTA, 1 mM DTT, 6.25 mM p-glycerolphosphate) and 10 ul are transferred to assay plates (results in 2% DMSO final concentration in assay). To each well with test compound a 2.4 pl JNK3/ATP

enzyme solution (1.18 U/ml JNK3, 20 uM ATP, 2 mM Mg (Ac) 2, 0. 01 % Brij-35 in assay buffer) was added. The mixture was pre-incubated for 10 minutes at ambient temperature.

After this, 3.6 p1 of a [7-33P] ATP-solution (0.20 µCi/µl [γ-33P]ATP, 66.6 mM Mg (Ac) 2, 1 mM DTT, 50 mM MOPS pH 7.2, 150 mM NaCl, 0.1 mM EGTA) was added to each well followed by 10 pl a ATF2 solution (60 llg/ml biotinylated ATF2 in assay buffer) to start the reaction. The reaction was allowed to proceed for 10 minutes at ambient temperature.

After this, the reaction was terminated by the addition of 200 RI per well of stop buffer/bead mix (0.4 mg/ml streptavidin coated SPA-beads in 50 mM EDTA, pH 7.6).

Plates were sealed with a plastic cover and centrifuged (2000 rpm, 5 minutes) to settle the beads followed by counting in a Wallac 1450 microbeta.

The IC50 values were calculated as the concentration of test compound at which the ATF2 phosphorylation is reduced to 50% of the control value.

Results Typical Ki values for the compounds of the present invention are in the range of about 0.001 to about 10,000 nM. Other values for Ki are in the range of about 0.001 to about 1000 nM. Further values for K ; are in the range of about 0.001 nM to about 300 nM.