WO2007000337A1 - Bicyclic derivatives as p38 kinase inhibitors - Google Patents

Abstract

New bicyclic derivatives of formula (I); wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.

Description

BICYCLIC DERIVATIVES AS P38 KINASE INHIBITORS

Field of the invention

The present invention relates to a new series of bicyclic derivatives, to processes to prepare them, to pharmaceutical compositions comprising these compounds as well as to their use in therapy.

Background of the invention

Kinases are proteins involved in different cellular responses to external signals. In the Nineties, a new family of kinases called MAPK (mitogen-activated protein kinases) was discovered. MAPK activate their substrates by phosphorylation in serine and threonine residues. MAPK are activated by other kinases in response to a wide range of signals including growth factors, pro-inflammatory cytokines, UV radiation, endotoxins and osmotic stress. Once they are activated, MAPK activate by phosphorylation other kinases or proteins, such as transcription factors, which, ultimately, induce an increase or a decrease in expression of a specific gene or group of genes. The MAPK family includes kinases such as p38, ERK (extracellular- regulated protein kinase) and JNK (C-Jun N-terminal kinase). p38 kinase plays a crucial role in cellular response to stress and in the activation pathway in the synthesis of numerous cytokines, especially tumor necrosis factor (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8).

IL-1 and TNF-α are produced by macrophages and monocytes and are involved in the mediation of immunoregulation processes and other physiopathological conditions. For example, elevated levels of TNF-α are associated with inflammatory and autoimmune diseases and with processes that trigger the degradation of connective and bone tissue such as rheumatoid arthritis, osteoarthritis, diabetes, inflammatory bowel disease and sepsis.

Thus, it is believed that p38 kinase inhibitors can be useful to treat or prevent diseases mediated by cytokines such as IL-1 and TNF-α, such as the ones mentioned above.

On the other hand, it has also been found that p38 inhibitors inhibit other pro-inflammatory proteins such as IL-6, IL-8, interferon-γ and GM-CSF (granulocyte-macrophage colony-stimulating factor). Moreover, in recent studies it has been found that p38 inhibitors not only block cytokine synthesis but also the cascade of signals that these induce, such as induction of the cyclooxygenase-2 enzyme (COX-2).

Accordingly, it would be desirable to provide novel compounds which are capable of inhibiting the p38 kinase.

Description of the invention

One aspect of the present invention relates to the compounds of general formula I

I wherein:

A represents CRiR₂ or NR₃;

Ri and R₂ independently represent hydrogen or C_1-4 alkyl;

R₃ represents -(CH₂)_P-Cy¹, Ci_-4 alkyl or Ci_-4 hydroxyalkyl; m represents 1 or 2;

R₄ represents one or more groups selected from hydrogen, halogen, Ci_-4 alkyl,

Ci_-4 haloalkyl, NH₂ and C_1-4 hydroxyalkyl; p represents 0, 1 or 2;

Cy¹ represents phenyl, heteroaryl or C_3-7 cycloalkyl, which can all be optionally substituted with one or more R₅;

R₅ represents Ci_-4 alkyl, halogen, C_1-4 alkoxy, C_1-4 haloalkyl or C_1-4 haloalkoxy; R§ represents hydrogen or R₇;

R₇ represents Ci_-6 alkyl optionally substituted with one or more groups selected from halogen, -OR₈', -NO₂, -CN, -COR₈', -CO₂R₈', -CONR₉ R₉', -NR₉ R₉',

-NR₉COR₈', -NR₉ CONR₉ R₉', -NR₉CO₂R₈, -NR₉SO₂R₈, -SR₈', -SOR₈, -SO₂R₈,

-SO₂NR₉ R₉' and Cy²;

R₈ represents C_1-4 alkyl, Ci_-4 haloalkyl or Ci_-4 hydroxyalkyl;

R₈' represents hydrogen or R₈;

R₉ represents Ci_-4 alkyl or Ci_-4 hydroxyalkyl;

R₉' represents hydrogen or R₉; and

Cy² represents phenyl, heteroaryl, C_3-7 cycloalkyl or heterocyclyl, which can all be optionally substituted with one or more groups selected from Ci_-4 alkyl, halogen,

Ci_-4 alkoxy, Ci_-4 haloalkyl and Ci_-4 haloalkoxy.

The present invention also relates to the salts and solvates of the compounds of formula I.

Some compounds of formula I can have chiral centres that can give rise to various stereoisomers. The present invention relates to each of these stereoisomers and also mixtures thereof.

The compounds of formula I are p38 kinase inhibitors and also inhibit the production of cytokines such as TNF-α.

Thus, another aspect of the invention relates to a compound of general formula I

I wherein:

A represents CRiR₂ or NR₃;

Ri and R₂ independently represent hydrogen or Ci_-4 alkyl;

R₃ represents -(CH₂)_P-Cy¹, Ci_-4 alkyl or Ci_-4 hydroxyalkyl; m represents 1 or 2;

R₄ represents one or more groups selected from hydrogen, halogen, Ci_-4 alkyl,

C-_I-4 haloalkyl, NH₂ and Ci_-4 hydroxyalkyl; p represents 0, 1 or 2; Cy¹ represents phenyl, heteroaryl or C_3-7 cycloalkyl, which can all be optionally substituted with one or more R₅;

R₅ represents Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl or Ci_-4 haloalkoxy;

R₆ represents hydrogen or R₇;

R₇ represents Ci_-6 alkyl optionally substituted with one or more groups selected from halogen, -OR₈', -NO₂, -CN, -COR₈', -CO₂R₈', -CONR₉ R₉', -NR₉ R₉.,

-NR₉COR₈', -NR₉CONR₉ R₉', -NR₉CO₂R₈, -NR₉SO₂R₈, -SR₈-, -SOR₈, -SO₂R₈,

-SO₂NR₉ R₉' and Cy²;

R₈ represents Ci_-4 alkyl, Ci_-4 haloalkyl or Ci_-4 hydroxyalkyl;

R₈' represents hydrogen or R₈; R₉ represents Ci_-4 alkyl or Ci_-4 hydroxyalkyl;

R₉' represents hydrogen or Rg; and

Cy² represents phenyl, heteroaryl, C_3-7 cycloalkyl or heterocyclyl, which can all be optionally substituted with one or more groups selected from Ci_-4 alkyl, halogen,

Ci_-4 alkoxy, Ci_-4 haloalkyl and Ci_-4 haloalkoxy, for use in therapy.

Another aspect of this invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by p38.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cytokines. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by TNF-α, IL-1 ,

IL-6 and/or IL-8. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases mediated by p38. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases mediated by cytokines.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases mediated by TNF-α, IL-1 , IL-6 and/or IL-8.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by p38 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by cytokines in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by TNF-α, IL-1 , IL-6 and/or IL-8 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treating or preventing a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a process for the preparation of a compound of formula I as defined above, which comprises: (a) when in a compound of formula I R₆ = H, reacting a compound of formula Il with a compound of formula III

wherein A, R₄ and m have the meaning described above and Y represents halogen or trifluoromethanesulfonate, in the presence of a base and a palladium catalyst; or

(b) when in a compound of formula I R₆ = H and at least one group R₄= NH₂, reducing a nitro compound of formula XV

XV

wherein A, R₄ and m have the meaning described above; or (c) converting, in one or a plurality of steps, a compound of formula I into another compound of formula I.

In the above definitions, the term Ci_-n alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to n carbon atoms. When n is 4, it includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te/f-butyl. When n is 6, examples include among others the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, pentyl, isopentyl, neopentyl and hexyl.

A Ci_-4 haloalkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci^alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples include, among others, trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl and nonafluorobutyl.

A Ci_-4 alkoxy group means an alkoxy group having from 1 to 4 carbon atoms, the alkyl moiety having the same meaning as previously defined. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and ferf-butoxy.

A Ci_-4 haloalkoxy group means a group resulting from the replacement of one or more hydrogen atoms from a Ci_-4 alkoxy group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different.

Examples include, among others, trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy, 1 -fluoroethoxy , 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3- tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4- fluorobutoxy and nonafluorobutoxy. A Ci-₄ hydroxyalkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci_-4 alkyl group with one or more hydroxy groups. Examples include, among others, hydroxy methyl, 1-hydroxyethyl, 2- hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1- hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxy butyl, 3-hydroxybutyl, 2- hydroxybutyl and 1 -hydroxy butyl.

A halogen radical means fluoro, chloro, bromo or iodo. A C_3-7 cycloalkyl group means a saturated monocyclic hydrocarbon ring having 3 to 7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term heteroaryl means an aromatic 5- or 6-membered monocyclic or 8- to 12-membered bicyclic ring which contains from 1 to 4 heteroatoms selected from N, S and O. The heteroaryl group can be linked to the rest of the molecule through any available carbon or nitrogen atom. N atoms in the ring can be optionally oxidized forming N⁺O^*. The heteroaryl group can be optionally substituted as disclosed above in the definitions of Cy¹ and Cy²; if substituted, the substituents can be the same or different and can be placed on any available position in the ring. Examples of heteroaryl groups include among others 1,2,4- oxadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthiridinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, purinyl, quinazolinyl, quinolinyl and quinoxalinyl. A heterocyclyl group means a 3- to 7-membered monocyclic carbocyclic ring or an 8- to 12-membered bicyclic carbocyclic ring which can be saturated or partially unsaturated (i.e. non-aromatic) and which contains from 1 to 4 heteratoms selected from N, S and O, and wherein said ring can be linked to the rest of the molecule through any available carbon or nitrogen atom. Additionally, one or more C or S atoms in the ring can be optionally oxidized, forming CO, SO or SO₂ groups. The heterocyclyl group can be optionally substituted as disclosed above in the definition of Cy²; if substituted, the substituents can be the same or different and can be placed on any available position in the ring. Preferably, the heterocyclyl is a 3- to 7-membered monocyclic ring. More preferably, the heterocyclyl ring has 5 or 6 ring atoms. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, azepinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, tetrahydroisoquinolinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo- piperidinyl, 2-oxopiperazinyl, 2(1 H)-pyridonyl, 2(1H)-pyrazinonyl, 2(1 H)- pyrimidinonyl, 2(1H)-pyridazinonyl and phthalimidyl. In the previous definition of heteroaryl, when the specified examples refer to a bicycle in general terms, all possible dispositions of the atoms are included. For example, the term pyrazolopyridinyl is to be understood as including groups such as 1 /-/-pyrazolo[3,4-b]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, 1H-pyrazolo[3,4- φyridinyl, 1H-pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-b]pyridinyl; the term imidazopyrazinyl is to be understood as including groups such as 1/-/-imidazo[4,5- b]pyrazinyl, imidazo[1 ,2-a]pyrazinyl and imidazo[1 ,5-a]pyrazinyl and the term pyrazolopyrimidinyl is to be understood as including groups such as 1 H- pyrazolo[3,4-c/]pyrimidinyl, 1/-/-pyrazolo[4,3-d]pyrimidinyl, pyrazolo[1 ,5- a]pyhmidinyl and pyrazolo[1 ,5-c]pyrimidinyl. The expression "optionally substituted with one or more" means that a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, more preferably with 1 or 2 substituents, provided that said group has enough positions available susceptible of being substituted. When present, said substituents can be the same or different and can be placed on any available position.

In a compound of formula I₁ R₄ represents one or more, preferably one or two, groups selected from hydrogen, halogen, Ci_-4 alkyl, Ci_-4 haloalkyl, NH₂ and Ci_-4 hydroxyalkyl. The group or groups R₄ can be placed upon any available position of the phenyl ring and when there is more than one R₄ group, they can be the same or different.

When in a definition of a substituent two or more groups bearing the same numbering are shown (e.g. -NR₉R₉' Or -NR₉CONRgR₉-, etc), this does not mean that they have to be identical. Each of them is independently selected from the list of possible meanings provided for that group, and therefore they can be the same or different.

The invention thus relates to the compounds of formula I as defined here above. In another embodiment, the invention relates to compounds of formula I wherein A represents CR1R2.

In another embodiment, the invention relates to compounds of formula I wherein A represents NR₃.

In a further embodiment, the invention relates to compounds of formula I wherein m is 1.

In a further embodiment, the invention relates to compounds of formula I wherein m is 2.

In a further embodiment, the invention relates to compounds of formula I wherein A represents CRiR₂ and m is 1. In a further embodiment, the invention relates to compounds of formula I wherein A represents NR₃ and m is 1.

In a further embodiment, the invention relates to compounds of formula I wherein A represents CR1R2 and m is 2.

In a further embodiment, the invention relates to compounds of formula I wherein A represents NR₃ and m is 2.

In a further embodiment, the invention relates to compounds of formula I wherein Ri is identical to R₂.

In a further embodiment, the invention relates to compounds of formula I wherein p is 0 or 1. In a further embodiment, the invention relates to compounds of formula I wherein R₃ represents -(CH₂)_P-Cy¹. In a further embodiment, the invention relates to compounds of formula I wherein R₃ represents -(CH₂)_P-Cy¹ and Cy¹ represents phenyl or heteroaryl, which can all be optionally substituted with one or more R₅.

In a further embodiment, the invention relates to compounds of formula I wherein R₄ represents one or two groups selected from hydrogen, halogen, Ci_-4 alkyl, C_1-4 haloalkyl, NH₂ and Ci_-4 hydroxyalkyl.

In a further embodiment, the invention relates to compounds of formula I wherein R₄ represents one or two groups selected from halogen, C_1-4 alkyl, C_1-4 haloalkyl, NH₂ and C_1-4 hydroxyalkyl.

In a further embodiment, the invention relates to compounds of formula I wherein R₄ represents one or two groups selected from halogen, C_1-4 alkyl, NH₂ and C_1-4 hydroxyalkyl.

In a further embodiment, the invention relates to compounds of formula I wherein R₄ represents one or two groups selected from halogen, methyl, NH₂ and Ci_-4 hydroxyalkyl.

In a further embodiment, the invention relates to compounds of formula I wherein the phenyl ring bearing R₄ represents a ring selected from (a)-(h):

(a) (b) (C)

(g) (h) In groups (d) and (f) shown above, the CH₃ group can be placed on any available position in the phenyl ring.

In a further embodiment, the invention relates to compounds of formula I wherein R₆ represents hydrogen or Ci_-6 alkyl optionally substituted with one group selected from -OR₈', -NR₉ R₉' and Cy².

In a further embodiment, the invention relates to compounds of formula I wherein R₆ represents hydrogen.

Furthermore, the present invention covers all possible combinations of particular and preferred groups described hereinabove. In a further embodiment, the invention relates to compounds according to formula I above which provide more than 50% inhibition of p38 activity at 10 μM, more preferably at 1 μM and still more preferably at 0.1 μM, in a p38 assay such as the ones described in Example 13.

In a further embodiment, the invention relates to a compounds according to formula I selected from:

5-(2,4-Difluorophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one; 2-Benzyl-5-(2,4-difluorophenylamino)-2,3-dihydroisoindol-1-one; 5-(2,4-Difluorophenylamino)-2-methyl-2,3-dihydroisoindol-1-one; 5-(2,4-Difluorophenylamino)-2-(3-hydroxypropyl)-2,3-dihydroisoindol-1-one; 2-(2-Chlorophenyl)-6-(2,4-difluorophenylamino)-1 ,2,3,4-tetrahydroisoquinolin-1- one; 6-(2,4-Difluorophenylamino)-2-ethyl-1 ,2,3,4-tetrahydroisoquinolin-1-one;

2-Benzyl-6-(2,4-difluorophenylamino)-1 ,2,3,4-tetrahydroisoquinolin-1-one; 2-Benzyl-6-(2-(2-hydroxyethyl)phenylamino)-1 ,2,3,4-tetrahydroisoquinolin-1-one; 5-(2,4-Difluorophenylarnino)-2,2-dimethylindan-1 -one;

2,2-Dimethyl-5-(2-(2-hydroxyethyl)phenylamino)indan-1-one;

6-(2,4-Difluorophenylamino)-2,2-dimethyl-1 ,2,3,4-tetrahydronaphthalen-1-one;

2,2-Dimethyl-6-phenylamino-1,2,3,4-tetrahydronaphthalen-1-one;

2,2-Dimethyl-6-(2-(2-hydroxyethyl)phenylamino)-1 ,2,3,4-tetrahydronaphthalen-1- one; 2,2-Dimethyl-6-(2-hydroxymethylphenylamino)-1 ,2,3,4-tetrahydronaphthalen-1- one;

2,2-Diethyl-6-(2,4-difluorophenylamino)-1 ,2,3,4-tetrahydronaphthalen-1-one;

6-(2,4-Difluorophenylamino)-1 ,2,3,4-tetrahydronaphthalen-1-one; 5-(2-Amino-4-fluorophenylamino)-2,2-dimethylindan-1-one;

5-(2-Amino-6-methylphenylamino)-2,2-dimethylindan-1-one;

5-(2-Amino-5-methylphenylamino)-2,2-dimethylindan-1-one;

5-(5-Amino-2-methylphenylamino)-2,2-dimethylindan-1-one;

5-(3-Amino-2-methylphenylamino)-2,2-dimethylindan-1-one; 5-(3-Aminophenylamino)-2,2-dimethylindan-1-one;

5-(3-Amino-4-methylphenylamino)-2,2-dimethylindan-1-one;

5-(2-Aminophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one;

5-(2-Amino-4-fluorophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one;

5-(2-Aminophenylamino)-2-benzyl-2,3-dihydroisoindol-1-one; 6-(2-Aminophenylamino)-2,2-dimethyl-1 ,2,3,4-tetrahydronaphthalen-i -one;

6-(2-Aminophenylamino)-1 ,2,3,4-tetrahydronaphthalen-1 -one;

6-(2,4-Difluorophenylamino)-2-(3-pyridylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-1- one;

6-[Λ/-(2,4-Difluorophenyl)-Λ/-(3-hydroxypropyl)amino]-2,2-dimethyl-1, 2,3,4- tetrahydronaphthalen-1-one;

6-[Λ/-(2,4-Difluorophenyl)-/V-(2-hydroxyethyl)amino]-2,2-dimethyl-1 , 2,3,4- tetrahydronaphthalen-1-one; and

6-[Λ/-(2,4-Difluorophenyl)-Λ/-(2-(morpholin-4-yl)ethyl)amino]-2,2-dimethyl-1 , 2,3,4- tetrahydronaphthalen-1 -one. The compounds of the present invention may contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids. Examples of these salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others. Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases. Examples of these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, Λ/-methylglucamine, procaine and the like.

There is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when they are used for therapeutic purposes. The term pharmaceutically acceptable salt represents those salts which are, according to medical judgement, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art. The salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I with a sufficient amount of the desired acid or base to give the salt in the conventional manner. The salts of the compounds of formula I can be converted into other salts of the compounds of formula I by ion exchange using ionic exchange resins.

The compounds of formula I and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention. All salts of the compounds of formula I are included within the scope of the invention.

The compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as a hydrate. Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention.

Some of the compounds of the present invention may exist as several diastereoisomers and/or several optical isomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on products of general formula I. Optically pure isomers can also be individually obtained using enantiospecific synthesis. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.

The compounds of formula I can be obtained by following the processes described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups by conventional protective groups. Both the nature of these protective groups and the procedures for their introduction or removal are well known in the art (see for example Greene T.W. and Wuts P. G. M, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3^rd edition, 1999). As an example, as protective groups of an amino function tert- butoxycarbonyl (Boc) or benzyl (Bn) groups can be used. The carboxyl groups can be protected for example in the form of Ci_-4 alkyl esters or arylalkyl esters, such as benzyl, while the hydroxyl groups can be protected for example with tetrahydropyranyl (THP) or benzyl (Bn) groups. Whenever a protective group is present, a later deprotection step will be required, which can be performed under standard conditions in organic synthesis, such as those described in the above- mentioned reference. Unless otherwise stated, in the methods described below the meanings of the differents substituents are the meanings described above with regard to a compound of general formula I.

Most of the compounds of formula I wherein R₆ = H (Ia) can be obtained from a compound of formula Il and an amine of formula III, as shown in the following scheme:

III Ia

wherein A, R₄ and m have the meaning described above and Y represents halogen, preferably bromo, or trifluoromethanesulfonate. This reaction can be carried out in the presence of a base, such as CS₂CO₃ or sodium te/f-butoxide, in the presence of a palladium catalyst, such as palladium acetate (II) or tris(dibenzylideneacetone)dipalladium(0), and a phosphine such as 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl, in a solvent such as toluene or dioxane.

Compounds of formula Il wherein A= CR₁R₂ and Ri and/or R₂ represent Ci-₄ alkyl (lib) and Y represents halogen can be obtained by reacting a compound of formula Ha with an alkylating agent of formula IV, as shown in the following scheme:

Ma Mb

wherein R₁ and/or R₂ represent Ci_-4 alkyl, m has the meaning described above, Y represents halogen, preferably bromo, Rj represents Ci_-4 alkyl and W represents halogen or alkylsulfonate, preferably iodo. This reaction can be carried out in the presence of a base such as sodium hydride, in a suitable solvent such as toluene, tetrahydrofuran or dimethylformamide, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent. When both R₁ and R₂ represent Ci_-4 alkyl and Ri ≠ R2, this reaction is carried out in a two step sequence that involves alkylating a compound of formula Ha with an alkylating agent RiW to give a mono-alkylated intermediate and then reacting this intermediate with a second alkylating agent R2W to yield the compound of formula lib.

Compounds of formula Il wherein A= NR₃ and m= 1 (lie) can be obtained by reacting a compound of formula Va with an amine of formula Vl, as shown in the following scheme:

Va Mc

wherein R represents C₁-₄ alkyl, Y represents halogen, preferably bromo, and R₃ has the meaning described above. This reaction can be carried out in a suitable solvent such as methanol, ethanol or dimethylformamide, optionally in the presence of a base such as a tertiary amine (like triethylamine or N, N- diisopropylethylamine), sodium carbonate or potassium carbonate, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent. Alternatively, this reaction can be carried out in a two step sequence that involves bromo displacement from a compound of formula Va by the amine Vl, in a suitable solvent such as methanol, ethanol or dimethylformamide, to yield an intermediate aminoester, and final cyclization to the compound of formula Hc by heating in acetic acid or polyphosphoric acid.

Compounds of formula Il wherein Y represents trifluoromethanesulfonate can be obtained starting from a compound of formula VII, as shown in the following scheme:

VII Il

wherein A and m have the meaning described above and Y represents trifluoromethanesulfonate. This reaction can be carried out in the presence of a suitable sulfonylating agent, such as trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride, in a suitable solvent such as pyridine or dichloromethane, in the presence of a base such as pyridine or triethylamine, and at a suitable temperature comprised between 0 ⁰C and room temperature.

Compounds of formula VII can be obtained starting from a compound of formula VIII, as shown in the following scheme:

VIII VII

wherein A and m have the meaning described above. This reaction can be carried out in the presence of a strong acid, such as 48% HBr, and at a suitable temperature comprised between room temperature and the temperature of the boiling point of the solvent, or in the presence of a Lewis acid such as boron tribromide, in a suitable solvent such as dichloromethane, and at a temperature comprised preferably between -78 ⁰C and room temperature. Compounds of formula VIII wherein A= CRiR₂ and R₁ and/or R₂ represent

Ci-4 alkyl (VIIIb) can be obtained by reaction of compounds of formula Villa under the same conditions previously described for the conversion of a compound of formula Ua into a compound of formula lib, as shown in the following scheme:

Villa VIIIb

wherein Ri and/or R₂ represent C_1-4 alkyl, and m and Rj have the meaning described above.

Compounds of formula VIII wherein A= NR₃ and m= 1 (VIIIc) can be obtained by reacting a compound of formula Vb with an amine of formula Vl, as shown in the following scheme:

Vb VIIIc

wherein R and R₃ have the meaning described above. This reaction can be carried out under the same reaction conditions described above for the preparation of compounds Hc from Va.

Compounds of formula Va, b can be obtained starting from a compound of formula IX₁ as shown in the following scheme:

IX Va,b (Va: Y= halo; Vb: Y = OMe)

wherein R has the meaning described above and Y' represents halogen, preferably bromo, or methoxy. This reaction can be carried out in the presence of a suitable halogenating agent, such as Λ/-bromosuccinimide, optionally in the presence of a radical initiator such as 2,2'-azobis(2-methylbutyronitrile) or benzoyl peroxide, in a suitable solvent such as CCI₄, CHCI3, acetonitrile or chlorobenzene, and at a suitable temperature comprised between room temperature and the temperature of the boiling point of the solvent, optionally irradiating the mixture.

Compounds of formula IX can be obtained by reacting a carboxylic acid of formula X with an alcohol of formula Xl, as shown in the following scheme:

IX

wherein R and Y' have the meaning described above. This reaction can be carried out in the presence of an inorganic acid such as concentrated sulfuric acid, using the alcohol of formula Xl as the solvent, and at a suitable temperature comprised between room temperature and the temperature of the boiling point of the solvent. Alternatively, a compound of formula X can be converted into the corresponding acyl chloride by using standard conditions and then the latter can be converted into the corresponding ester of formula IX by reaction with an alcohol of formula Xl, in the presence of a base such as triethylamine, in a suitable solvent such as or example dichloromethane, and at a suitable temperature comprised between 0 ⁰C and room temperature.

Compounds of formula VIII wherein A= NR₃ (VIIIc: m= 1 ; VIIId: m= 2) can be obtained starting from a compound of formula XII₁ as shown in the following scheme:

XII Vlllc.d

wherein R₃ and m have the meaning described above. When R₃ is an alkyl-type group, this reaction can be carried out by treatment with an alkylating agent such as a halide or alkylsulfonate of formula XIII, preferably an alkyl iodide, in the presence of a base such as sodium hydride, in a suitable solvent such as toluene, tetrahydrofuran or dimethylformamide, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent. When R₃ is a phenyl or heteroaryl group, this reaction can be carried out by reaction with an halide of formula XIII, preferably a bromide, in the presence of a base, such as K₂CO₃, Na₂CO₃ or K₃PO₄, and a copper catalyst, such as copper(l) iodide, in a solvent such as Λ/-methylpyrrolidone and heating, preferably at reflux.

Compounds of formula Il wherein A= NR₃ (Hc: m= 1; Hd: m= 2) can alternatively be obtained in an analogous manner starting from a compound of formula XIV, as shown in the following scheme:

XIV llc,d

wherein R₃ and m have the meaning described above and Y represents halogen, preferably bromo. This reaction is carried out under the same reaction conditions described above for the preparation of compounds Vlllc.d from XII.

Alternatively, compounds of formula Ia wherein at least one group R₄= NH₂ (Ib) can be obtained by reduction of a nitro compound of formula XV, as shown in the following scheme:

XV Ib

wherein A, R₄ and m have the meaning described above. This reaction can be carried out in the presence of a suitable reducing agent such as tin (II) chloride or iron, in a suitable solvent such as ethanol or acetic acid, or alternatively in the presence of hydrogen gas and a palladium catalyst, such as palladium on carbon, in a suitable solvent such as methyl alcohol, ethyl alcohol or ethyl acetate.

Compounds of formula XV can be obtained from a compound of formula Il and an amine of formula XVI, as shown in the following scheme:

Il XVI XV

wherein A, R₄ and m have the meaning described above and Y represents halogen, preferably bromo, or trifluoromethanesulfonate. This reaction is carried out under the same reaction conditions described above for the preparation of compounds Ia from Il and III.

Alternatively, compounds of formula XV can be obtained starting from an amine of formula XVII and a fluoro compound of formula XVIII₁ as shown in the following scheme:

XVII XVIII XV

wherein A, R₄ and m have the meaning described above. This reaction can be carried out optionally in the presence of a base, such as potassium terf-butoxide, in a suitable solvent, such as dimethyl sulfoxide, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent. Compounds of formula Ha, III, IV, Vl, Villa, X, Xl, XII, XIII, XIV, XVI, XVII and XVIII are commercially available or can be prepared by methods widely described in the literature, and can be conveniently protected. Furthermore, some compounds of the present invention can also be obtained from other compounds of formula I by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the reported standard experimental conditions. Thus, a group R₃ can be converted into another group R₃, giving rise to new compounds of formula I. For example a group R₃ = benzyl can be converted into an intermediate wherein R₃ = H, in the presence of hydrogen gas and a palladium catalyst, such as palladium on carbon, in a suitable solvent such as methyl alcohol, ethyl alcohol, ethyl acetate or acetic acid, and at a suitable temperature, comprised between room temperature and the temperature of the boiling point of the solvent; and such intermediate wherein R₃ = H can be converted into a new compound of formula I wherein R₃ is a different group by alkylation or arylation with a suitable agent, under the same reaction conditions described above for the preparation of compounds of formula Vlllc,d from XII and XIII. A compound of formula I wherein R₆ = H can be converted into a compound of formula I wherein R₆ = R₇ by alkylation with a suitable alkylating agent such as a halide, preferably a iodide, or an alkyl- or arylsulfonate, in the presence of a base such as triethylamine, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydride or sodium bis(trimethylsilyl)amide, among others, in a suitable solvent such as dichloromethane, chloroform, dimethylformamide, tetrahydrofuran, acetonitrile or toluene, optionally in the presence of a crown ether, and at a temperature comprised between -78 ⁰C and the temperature of the boiling point of the solvent.

Some of these interconversion reactions are explained in greater detail in the examples.

As it will be obvious to those skilled in the art, these interconversion reactions can be carried out upon the compounds of formula I as well as upon any suitable synthesis intermediate thereof.

As mentioned previously, the compounds of the present invention act as p38 kinase inhibitors, inducing the reduction of proinflammatory cytokines. Therefore, the compounds of the invention are expected to be useful to treat or prevent diseases in which p38 plays a role in mammals, including human beings. This includes diseases caused by overproduction of cytokines such as TNF-α, IL- 1 , IL-6 or IL-8. These diseases include, but are not limited to, immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with cyclooxygenase-2 induction. Preferred diseases to be treated or prevented with the compounds of the invention are immune, autoimmune and inflammatory diseases.

As an example, immune, autoimmune and inflammatory diseases that can be treated or prevented with the compounds of the present invention include rheumatic diseases (e.g. rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis), glomerulonephritis (with or without nephrotic syndrome), autoimmune hematologic disorders (e.g. hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia and neutropenia), autoimmune gastritis and autoimmune inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), host versus graft disease, allograft rejection, chronic thyroiditis, Graves' disease, schleroderma, diabetes (type I and type II), active hepatitis (acute and chronic), primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, chronic renal insufficiency, Stevens-Johnson syndrome, idiopathic sprue, sarcoidosis, Guillain- Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease (e.g. chronic obstructive pulmonary disease) and other inflammatory or obstructive diseases of the airways.

Cardiovascular diseases that can be treated or prevented include, among others, myocardial infarction, cardiac hypertrophy, cardiac insufficiency, ischaemia-reperfusion disorders, thrombosis, thrombin-induced platelet aggregation, acute coronary syndromes, atherosclerosis and cerebrovascular accidents.

Infectious diseases that can be treated or prevented include, among others, sepsis, septic shock, endotoxic shock, sepsis by Gram-negative bacteria, shigellosis, meningitis, cerebral malaria, pneumonia, tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and hepatitis C), HIV infection, retinitis caused by cytomegalovirus, influenza, herpes, treatment of infections associated with severe bums, myalgias caused by infections, cachexia secondary to infections, and veterinary viral infections such as lentivirus, caprine arthritic virus, visna-maedi virus, feline immunodeficiency virus, bovine immunodeficiency virus or canine immunodeficiency virus.

Bone resorption disorders that can be treated or prevented include osteoporosis, osteoarthritis, traumatic arthritis and gouty arthritis, as well as bone disorders related with multiple myeloma, bone fracture and bone grafting and, in general, all these processes wherein it is necessary to induce osteoblastic activity and increase bone mass.

Neurodegenerative diseases that can be treated or prevented include Alzheimer's disease, Parkinson's disease, cerebral ischaemia and traumatic neurodegenerative disease, among others.

Proliferative diseases that can be treated or prevented include endometriosis, solid tumors, acute and chronic myeloid leukemia, Kaposi sarcoma, multiple myeloma, metastatic melanoma and angiogenic disorders such as ocular neovascularisation and infantile haemangioma. p38 kinase inhibitors also inhibit the expression of proinflammatory proteins such as cyclooxygenase-2 (COX-2), the enzyme responsible for prostaglandin production. Therefore, the compounds of the present invention can also be used to treat or prevent diseases mediated by COX-2 and especially to treat processes with edema, fever and neuromuscular pain such as cephalea, pain caused by cancer, tooth pain, arthritic pain, hyperalgesia and allodynia.

In vitro and in vivo assays to determine the ability of a compound to inhibit p38 activity are well known in the art. For example, a compound to be tested can be contacted with the purified p38 enzyme to determine whether inhibition of p38 activity occurs. Alternatively, cell-based assays can be used to measure the ability of a compound to inhibit the production of cytokines such as TNFalpha, e.g. in stimulated peripheral blood mononuclear cells (PBMCs) or other cell types. Detailed disclosure of assays that can be used to test the biological activity of the compounds of the invention as p38 inhibitors can be found below (see Example 13).

For selecting active compounds, testing at 10 μM must result in an activity of more than 50% inhibition in at least one of the tests provided in Example 13. More preferably, compounds should exhibit more than 50% inhibition at 1 μM, and still more preferably, they should exhibit more than 50% inhibition at 0.1 μM.

The present invention also relates to a pharmaceutical composition which comprises a compound of the present invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral, nasal, ocular, rectal and topical administration.

Solid compositions for oral administration include tablets, granulates and capsules. In any case the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients. These excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc. Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability. The active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents. Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.

Powders and granulates for the preparation of oral suspensions by the additon of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives. Other excipients can also be added, for example sweetening, flavouring and colouring agents.

Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly-used inert diluents, such as purified water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, flavouring agents, preservatives and buffers.

Injectable preparations, according to the present invention, for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process.

For the rectal administration, the active compound can be preferably formulated as a suppository on an oily base, such as for example vegetable oils or solid semisynthetic glycerides, or on a hydrophilic base such as polyethylene glycols (macrogol).

The compounds of the invention can also be formulated for their topical application for the treatment of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract.

Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.

For the nasal administration or for inhalation, the compound can be formulated as an aerosol and it can be conveniently released using suitable propellants.

The dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors. A representative example of a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.

The invention is illustrated by the following examples.

Examples

The following abbreviations have been used in the examples:

ACN: acetonitrile DMSO: dimethylsulfoxide

EtOAc: ethyl acetate

EtOH: ethanol

MeOH: methanol

TEA: triethylamine THF: tetrahydrofuran t_R: retention time

LC-MS: liquid chromatography-mass spectrometry

LC-MS spectra have been performed using the following chromatographic method:

Method 1: Column Tracer Excel 120, ODSB 5 μm (10 mm x 0.21 mm), temperature: 30 ⁰C, flow: 0.35 mL/min, eluent: A= ACN, B = 0.1 % HCOOH, gradient: 0 min 10% A - 10 min 90% A.

The MS spectra have been obtained with positive electrospray ionization mode over a scan range from 100 to 800 amu.

REFERENCE EXAMPLE 1 Methyl 4-bromo-2-methylbenzoate

To a solution of 4-bromo-2-methylbenzoic acid (6.17 g, 0.29 mol) in MeOH (170 mL), H₂SO₄ 95% (3 mL) was added. It was heated to reflux overnight and allowed to cool to room temperature. The solvent was evaporated and EtOAc was added. The organic phase was washed with saturated NaHCθ₃, aq Na₂CO₃ and water. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated, to afford 6.43 g of the title compound as an oil (yield: 98%). ¹H NMR (300 MHz, CDCI₃) δ (TMS): 2.58 (s, 3 H), 3.89 (s, 3 H), 7.36 (d, J = 1.8 Hz, 1 H)₁ 7.41 (dd, J = 8.1 Hz, J¹= 1.8 Hz, 1 H), 7.78 (d, J= 8.1 Hz, 1 H).

REFERENCE EXAMPLE 2 Methyl 4-bromo-2-(bromomethyl)benzoate

To a solution of methyl 4-bromo-2-methylbenzoate (9.60 g, 0.42 mol, obtained in reference example 1) in CCI₄ (150 mL), Λ/-bromosuccinimide (7.46g, 0.42mol) and benzoyl peroxide (0.19g, 0.79mmol) were added. The reaction mixture was stirred 4h at room temperature while irradiated with a 250 Watt lamp and it was then filtered to remove the precipitated solids. The filtrate was washed with 1 N NaOH and water and it was dried over Na₂SO₄. The solvent was evaporated to afford 11.87 g of the desired compound as an oil that solidified on standing (yield: 92%, uncorrected).

¹H NMR (300 MHz, CDCI₃) δ (TMS): 3.94 (s, 3 H), 4.90 (s, 2 H), 7.51 (dd, J = 8.4 Hz, J' = 2.1 Hz, 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H).

REFERENCE EXAMPLE 3 5-Bromo-2-phenyl-2,3-dihydroisoindol-1-one

To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (4.9 mmol, obtained in reference example 2) in MeOH (40 mL), aniline (0.93 g, 5.1 mmol) and TEA (1.05 mL, 7.6 mmol) were added. The mixture was heated to reflux for 24 h and then allowed to cool to room temperature. The solvent was evaporated and the crude product obtained was purified by chromatography on silica gel using hexane-

EtOAc mixtures of increasing polarity as eluent, to afford 1.07 g of the desired compound, impurified with starting aniline. The product was dissolved in CHCI₃ and the organic phase was washed with 1N HCI₁ dried over Na₂SO₄ and the solvent evaporated to afford 0.98 g of the title compound (yield: 67%). ¹H NMR (300 MHz, CDCI₃) δ (TMS): 4.85 (s, 2 H), 7.18 (m, 1 H), 7.46 (m, 2 H), 7.64-7.86 (complex signal, 5 H)

REFERENCE EXAMPLE 3A 5-Bromo-2-methyl-2,3-dihydroisoindol-1 -one

Following a similar procedure to that described in reference example 3, but starting from methyl 4-bromo-2-(bromomethyl)benzoate (obtained in reference example 2) and methylamine, the desired compound was obtained. ¹H NMR (300 MHz, CDCI₃) δ (TMS): 3.19 (s, 3 H), 4.36 (s, 2 H), 7.61 (m, 2 H), 7.70 (d, J = 8.7 Hz, 1 H).

REFERENCE EXAMPLE 3B 5-Bromo-2-(3-hydroxypropyl)-2,3-dihydroisoindol-1-one

Following a similar procedure to that described in reference example 3, but starting from methyl 4-bromo-2-(bromomethyl)benzoate (obtained in reference example 2) and 3-amino-1-propanol, the desired compound was obtained. LC-MS (method 1): t_R = 5.41 min; m/z = 270.1/272.1 [M+H]⁺.

REFERENCE EXAMPLE 4 5-Bromo-2,2-dimethylindan-1 -one

To a suspension of sodium hydride (55% in mineral oil, 1.37 g, 31.3 mmol) in toluene (8.5 mL), 5-bromo-1-indanone (3.00 g, 14.2 mmol) and methyl iodide (4.43 g, 31.3 mmol) were added. The mixture was heated at 90 ⁰C overnight and allowed to cool to room temperature. After adding some drops of MeOH to destroy the excess of hydride, EtOAc and water were added. The phases were separated and the aqueous phase was reextracted twice with EtOAc. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane- EtOAc mixtures of increasing polarity as eluent, to afford 2.43 g of the title compound (yield: 72 %). ¹H NMR (300 MHz, CDCI₃) δ (TMS): 1.25 (s, 6 H), 2.98 (s, 2 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.60-7.63 (complex signal, 2 H).

REFERENCE EXAMPLE 5 2,2-Dimethyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-one

To a suspension of sodium hydride (55% in mineral oil, 26.80 g, 0.55 mol) in benzene (159 ml_), 6-methoxy-1 ,2,3,4-tetrahydronaphthalen-1-one (50.00 g, 0.28 mol) and methyl iodide (99.10 g, 0.69 mol) were added. The mixture was heated to reflux overnight and allowed to cool to room temperature. After adding some drops of MeOH to destroy the excess of hydride, EtOAc and water were added. The phases were separated and the aqueous phase was reextracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated to afford the title compound (quantitative yield). 1H NMR (80 MHz, CDCI₃) δ (TMS): 1.19 (s, 6 H), 1.94 (t, J = 6.5 Hz, 2 H), 2.93 (t, J= 6.5 Hz, 2 H), 3.82 (s, 3 H), 6.67 (broad s, 1 H), 6.80 (dd, J = 9 Hz, J' =2 Hz, 1 H), 7.99 (d, J = 9 Hz, 1 H).

REFERENCE EXAMPLE 5A 2,2-Diethy l-6-methoxy-1 ,2,3,4-tetrahydronaphthalen-1 -one

Following a similar procedure to that described in reference example 5, but starting from 6-methoxy-1 ,2,3,4-tetrahydronaphthalen-1-one and ethyl iodide, the desired compound was obtained. 1H NMR (300 MHz, CDCI₃) δ (TMS): 0.85 (t, J = 7.5 Hz, 6 H), 1.52-1.77 (complex signal, 4 H), 2.00 (t, J = 6.3 Hz, 2 H), 2.93 (t, J= 6.3 Hz₁ 2 H), 3.84 (s, 3 H), 6.65 (d, J = 2.4 Hz, 1 H), ), 6.81 ( dd, J = 8.7 Hz, J¹ =2.4 Hz, 1 H), 7.99 (d, J = 9 Hz, 1 H).

REFERENCE EXAMPLE 6

2,2-Dimethy l-6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1 -one A mixture of 2,2-dimethyl-6-methoxy-1 ,2,3,4-tetrahydronaphthalen-1-one (20.0 g, 98 mmol, obtained in reference example 5) and 48% aq HBr (279 mL) was heated to reflux for 2h. Then HBr was distilled off and the reaction crude was allowed to cool to room temperature and diluted with water and ethyl ether. The phases were separated and the product was extracted from the organic phase with 1N NaOH. The basic aqueous phase was acidified with 2N HCI and the solid thus obatined was isolated by filtration and dried under vacuum, to afford 16.06 g of the desired compound as a tan solid (yield: 86%).

¹H NMR (300 MHz, CDCI₃) δ (TMS): 1.21 (s, 6 H), 1.96 (t, J = 6.3 Hz, 2 H), 2.92 (t, J = 6.3 Hz, 2 H), 5.62 (s, 1 H, OH), 6.65 (d, J = 2.4 Hz, 1 H), 6.76 (dd, J = 8.4 Hz, J' = 2.4 Hz₁ 1 H), 7.98 (d, J = 8.4 Hz, 1 H).

REFERENCE EXAMPLE 6A

2,2-Diethyl-6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1 -one

Following a similar procedure to that described in reference example 6, but starting from 2,2-diethyl-6-methoxy-1 ,2,3,4-tetrahydronaphthalen-1-one (obtained in reference example 5A), the desired compound was obtained. ¹H NMR (300 MHz, CDCI₃) δ (TMS): 0.85 (t, J = 7.5 Hz, 6 H), 1.53-1.78 (complex signal, 4 H), 2.00 (t, J = 6.3 Hz, 2 H), 2.91 (t, J = 6.3 Hz, 2 H), 6.66 (d, J = 2.1 Hz, 1 H), 6.78 (dd, J = 8.7 Hz, J¹ = 2.4 Hz, 1 H), 6.84 (broad s, 1 H, OH), 7.97 (d, J = 8.7 Hz, 1 H).

REFERENCE EXAMPLE 7

2,2-Dimethy 1-1 -oxo-1 ,2,3,4-tetrahydronaphthalen-6-yl trifluoromethanesulfonate

To a solution of 2,2-dimethyl-6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1-one (15.00 g, 78.8 mmol, obtained in reference example 6) in pyridine (40 mL), cooled at 0 ⁰C, trifluoromethanesulfonic anhydride (24.46 g, 86.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. After dilution with water and EtOAc, the phases were separated and the aqueous phase was reextracted 3 times with EtOAc. The combined organic phases were washed with water and twice with 10% HCI, dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 21.54 g of the desired compound (yield: 85%).

¹H NMR (300 MHz, CDCI₃) δ (TMS): 1.23 (s, 6 H), 2.02 (t, J = 6.3 Hz, 2 H), 3.03 (t, J = 6.3 Hz, 2 H), 7.15 (d, J = 2.4 Hz, 1 H), 7.20 (dd, J = 8.7 Hz, J' = 2.4 Hz, 1 H), 8.13 (d, J = 8.7 Hz, 1 H).

REFERENCE EXAMPLE 7A

2,2-Diethyl-1-oxo-1,2,3,4-tetrahydronaphthalen-6-yl trifluoromethanesulfonate

Following a similar procedure to that described in reference example 7, but starting from 2,2-diethyl-6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1-one (obtained in reference example 6A), the desired compound was obtained. ¹H NMR (300 MHz, CDCI₃) δ (TMS): 0.86 (t, J = 7.5 Hz, 6 H), 1.55-1.78 (complex signal, 4 H), 2.05 (t, J = 6.3 Hz, 2 H), 3.01 (t, J = 6.3 Hz, 2 H), 7.13 (d, J = 2.4 Hz, 1 H), 7.18 (dd, J = 8.7 Hz, J' = 2.4 Hz, 1 H), 8.13 (d, J = 8.7 Hz, 1 H).

REFERENCE EXAMPLE 7B

1 -Oxo-1 ,2,3,4-tetrahydronaphthalen-6-yl trifluoromethanesulfonate

Following a similar procedure to that described in reference example 7, but starting from 6-hydroxy-1 ,2,3,4-tetrahydronaphthalen-1-one, the desired compound was obtained.

¹H NMR (300 MHz, CDCI₃) δ (TMS): 2.18 (quint, J = 6.3 Hz, 2 H), 2.69 (t, J = 6.3 Hz, 2 H), 3.02 (t, J = 6.3 Hz, 2 H), 7.19-7.23 (complex signal, 2 H), 8.13 (d, J = 8.1 Hz, 1 H).

REFERENCE EXAMPLE 8 Ethyl Λ/-[2-(3-methoxyphenyl)ethyl]carbamate To a solution of 3-methoxyphenetylamine (25.00 g, 0.17 mol) and TEA (25 ml_, 0.18 mol) in CH₂CI₂ (500 ml_), cooled at 0 ⁰C, ethyl chloroformate (19.53 g, 0.18 mol) was added dropwise and the reaction mixture was stirred at 0 ⁰C for 1.5 h. Water was then added and the phases were separated. The aqueous phase was reextracted with CH₂CI₂. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated to afford the desired compound (quantitative yield).

¹H NMR (300 MHz, CDCI₃) δ (TMS): 1.23 (t, J = 7.2 Hz, 3 H), 2.78 (t, J = 6.9 Hz, 2 H), 3.43 (q, J = 6.6 Hz, 2 H), 3.80 (s, 3 H), 4.10 (q, J = 6.9 Hz, 2 H), 4.69 (broad s, 1 H), 6.74-6.79 (complex signal, 3 H), 7.22 (t, J = 7.8 Hz, 1 H).

REFERENCE EXAMPLE 9 6-Methoxy-1 ,2,3,4-tetrahydroisoquinolin-1 -one

A mixture of ethyl Λ/-[2-(3-methoxyphenyl)ethyl]carbamate (18.98 g, 85.0 mmol, obtained in reference example 8) and polyphosphoric acid (60 g) was heated at 120 ⁰C for 3h and then allowed to cool to 60 ⁰C. Water and EtOAc were added and the mixture was allowed to cool to room temperature. The phases were separated and the aqueous phase was reextracted several times with CHCI₃. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 10.24 g of the desired compound (yield: 68%). ¹H NMR (300 MHz, CDCI₃) δ (TMS): 2.97 (m, 2 H), 3.55 (m, 2 H), 3.85 (s, 3 H), 6.31 (broad s, 1 H), 6.70 (d, J = 2.1 Hz, 1 H), 6.85 (dd, J = 8.7 Hz, J¹ = 2.4 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H).

REFERENCE EXAMPLE 10 2-(2-Chlorophenyl)-6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-1 -one

To a solution of 6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (1.50 g, 8.5 mmol, obtained in reference example 9) in /V-methylpyrrolidone (4 ml_) under argon, 1- bromo-2-chlorobenzene (2.34 g, 12.3 mmol), copper (I) iodide (0.33 g, 1.7 mmol) and potassium carbonate (2.33 g, 16.9 mmol) were added and the mixture was heated at 200 ⁰C overnight. It was allowed to cool and CHCI₃ and 1 N NaOH were added. The phases were separated and the aqueous phase was reextracted 2 times with CHCI₃. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product thus obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 2.01 g of the desired compound (yield: 77%). LC-MS (method 1): t_R = 8.05 min; m/z = 288.1/290.1 [M+Hf.

REFERENCE EXAMPLE 11 2-(2-Chlorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-1-one

To a solution of 2-(2-chlorophenyl)-6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (2.01 g, 7.0 mmol, obtained in reference example 10) in dry CH₂CI₂ (40 mL) under argon, cooled at -78 ⁰C, boron tribromide (1M in CH₂CI₂, 13.9 mL, 13.9 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. After cooling with ice, 1N HCI was added and the mixture was stirred at 30 ⁰C for 30 min. The phases were then separated and the aqueous phase was reextracted with CHCI₃. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated to afford 1.86 g of the desired compound (yield: 98%). LC-MS (method 1): t_R = 6.41 min; m/z = 274.1/276.1 [M+H]⁺.

REFERENCE EXAMPLE 12

2-(2-Chlorophenyl)-1 -oxo-1 ,2,3,4-tetrahydroisoquinolin-6-y I trifluoromethanesulfonate

To a solution of 2-(2-chlorophenyl)-6-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (1.82 g, 6.7 mmol, obtained in reference example 11) in CH₂CI₂ (50 mL), pyridine (1.1 mL, 13.3 mmol) was added. The solution was cooled at 0 ⁰C and trifluoromethanesulfonic anhydride (2.06 g, 7.3 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. After dilution with water, the phases were separated and the aqueous phase was reextracted with CH₂CI₂. The combined organic phases were washed with 1 N HCI, dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 2.14 g of the desired compound (yield: 80%). LC-MS (method 1): t_R = 9.65 min; m/z = 406.0/408.0 [M+H]⁺.

REFERENCE EXAMPLE 13 2-Ethy l-6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-1 -one

To a solution of 6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (3.00 g, 16.9 mmol, obtained in reference example 9) in toluene (40 ml_) and THF (40 ml_), sodium hydride (55% in mineral oil, 3.80 g, 87.2 mmol) was added portionwise. Ethyl iodide (6.73 g, 43.2 mmol) was then added and the mixture was heated at 50 ⁰C overnight. Additional ethyl iodide portions (6.73 g, 43.2 mmol) were added for 3 consecutive days while the mixture was heated at 50 ⁰C. The reaction mixture was allowed to cool to room temperature and some drops of MeOH were added to destroy the excess of hydride. It was diluted with EtOAc and water and the phases were separated. The aqueous phase was thoroughly reextracted with EtOAc and the combined organic phases were washed with 2N NaOH and 1N HCI. The organic phase was dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 1.60 g of the title compound (yield: 46%).

¹H NMR (300 MHz, CDCI₃) δ (TMS): 1.20 (t, J = 7.2 Hz, 3 H), 2.95 (t, J = 6.6 Hz, 2 H), 3.51-3.64 (complex signal, 4 H), 3.64 (s, 3 H), 6.65 (d, J = 2.7 Hz, 1 H), 6.83 (dd, J = 8.7 Hz, J' = 2.7 Hz, 1 H), 8.02 (d, J = 8.7 Hz, 1 H).

REFERENCE EXAMPLE 14

2-Ethy l-6-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-i -one Following a similar procedure to that described in reference example 11 , but starting from 2-ethyl-6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (obtained in reference example 13), the desired compound was obtained. LC-MS (method 1): t_R = 4.66 min; m/z = 192.1 [M+H]⁺.

REFERENCE EXAMPLE 15

2-Ethy 1-1 -oxo-1 ,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate

Following a similar procedure to that described in reference example 12, but starting from 2-ethyl-6-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (obtained in reference example 14), the desired compound was obtained. LC-MS (method 1): t_R = 8.44 min; m/z = 324.0 [M+H]⁺.

REFERENCE EXAMPLE 16

2-Benzyl-6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-i -one

Following a similar procedure to that described in reference example 13, but using benzyl bromide instead of ethyl iodide, the desired compound was obtained. LC-MS (method 1): t_R = 8.50 min; m/z = 268.0 [M+H]⁺.

REFERENCE EXAMPLE 17 2-Benzyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoHn-1-one

Following a similar procedure to that described in reference example 11 , but starting from 2-benzyl-6-methoxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (obtained in reference example 16), the desired compound was obtained. LC-MS (method 1): t_R = 6.53 min; m/z = 254.2 [M+H]⁺.

REFERENCE EXAMPLE 18

2-Benzy 1-1 -oxo-1 ,2,3,4-tetrahydroisoquinolin-6-y I trifluoromethanesulfonate Following a similar procedure to that described in reference example 12, but starting from 2-benzyl-6-hydroxy-1 ,2,3,4-tetrahydroisoquinolin-1-one (obtained in reference example 17), the desired compound was obtained. LC-MS (method 1): t_R = 9.82 min; m/z = 386.1 [M+H]⁺.

REFERENCE EXAMPLE 19 Methyl 4-methoxy-2-methylbenzoate

Following a similar procedure to that described in reference example 1, but starting from 4-methoxy-2-methylbenzoic acid, the desired compound was obtained. LC-MS (method 1): t_R = 8.23 min; m/z = 181.0 [M+H]⁺.

REFERENCE EXAMPLE 20 Methyl 2-(bromomethyl)-4-methoxybenzoate

Following a similar procedure to that described in reference example 2, but starting from methyl 4-methoxy-2-methylbenzoate (obtained in reference example 19), the desired compound was obtained. ¹H NMR (300 MHz, CDCI₃) δ (TMS): 3.85 (s, 3 H), 3.91 (s, 3 H), 4.96 (s, 2 H), 6.86 (dd, J = 8.7 Hz, J' = 2.4 Hz, 1 H), 6.97 (d, J = 2.4 Hz₁ 1 H), 7.98 (d, J = 8.7 Hz, 1 H).

REFERENCE EXAMPLE 21 2-Benzyl-5-methoxy-2,3-dihydroisoindol-1 -one

Following a similar procedure to that described in reference example 3, but starting from methyl 2-(bromomethyl)-4-methoxybenzoate (obtained in reference example 20) and benzylamine, the desired compound was obtained. LC-MS (method 1 ): t_R = 7.37 min; m/z = 254.2 [M+H]⁺.

REFERENCE EXAMPLE 22 2-Benzyl-5-hydroxy-2,3-dihydroisoindol-1-one Following a similar procedure to that described in reference example 11 , but starting from 2-benzyl-5-methoxy-2,3-dihydroisoindol-1-one (obtained in reference example 21), the desired compound was obtained. LC-MS (method 1): t_R = 6.01 min; m/z = 240.2 [M+H]⁺.

REFERENCE EXAMPLE 23

2-Benzyl-1-oxo-2,3-dihydroisoindol-5-yl trifluoromethanesulfonate

Following a similar procedure to that described in reference example 12, but starting from 2-benzyl-5-hydroxy-2,3-dihydroisoindol-1-one (obtained in reference example 22), the desired compound was obtained. LC-MS (method 1): t_R = 9.19 min; m/z = 372.1 [M+H]⁺.

REFERENCE EXAMPLE 24 6-(2-Nitrophenylamino)-1 ,2,3,4-tetrahydronaphthalen-1 -one

To a solution of 6-amino-1 ,2,3,4-tetrahydronaphthalen-1-one (0.48 g, 2.9 mmol) in DMSO ( 20 mL), potassium terf-butoxide (0.36 g, 3.1 mmol) was added and the mixture was stirred at room temperature for 5 min. Then, 1-fluoro-2-nitrobenzene (0.46 g, 3.1 mmol) was added and the mixture was stirred at room temperature overnight. After diluting with EtOAc and water, the phases were separated and the aqueous phase was reextracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.15 g of the title compound (yield: 18%).

LC-MS (method 1): t_R = 9.18 min; m/z = 283.1 [M+H]⁺.

REFERENCE EXAMPLE 25 2-Benzyl-5-(2-nitrophenyl)-2,3-dihydroisoindol-1-one A solution of 2-benzyl-1-oxo-2,3-dihydroisoindol-5-yl trifluoromethanesulfonate (200 mg, 0.54 mmol, obtained in reference example 23) in toluene (20 ml_) was refluxed for 30 min under argon and then allowed to cool to room temperature. Palladium acetate (II) (12 mg, 0.05 mmol), (±) 2,2'-bis(diphenylphosphino)-1 ,1'- binaphthyl (26 mg, 0.04 mmol) and cesium carbonate (245 mg, 0.75 mmol) were added and the mixture was inertized with argon. Then, 2-nitroaniline (89 mg, 0.65 mmol) was added and the mixture was heated under argon at 110 ⁰C overnight. The reaction mixture was allowed to cool to room temperature, diluted with CHCI₃ and filtered through a pad of celite. The filtrate was diluted with additional CHCI₃ and water. The phases were separated and the aqueous phase was reextracted 2 times with CHCI₃. The combined organic phases were washed with 2N HCI and then dried over Na₂SO₄. The solvent was evaporated and the crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 35 mg of the title compound (yield: 18%). LC-MS (method 1): t_R = 9.16 min; m/z = 360.2 [M+H]⁺.

REFERENCE EXAMPLES 26-35

Following a similar procedure to that described in reference example 25, but starting from the appropriate compounds in each case, the compounds in the following table were obtained:

EXAMPLE 1 5-(2,4-Difluorophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one

A solution of 5-bromo-2-phenyl-2,3-dihydroisoindol-1-one (200 mg, 0.69 mmol, obtained in reference example 3) in toluene (25 mL) was refluxed for 30 min under argon and then allowed to cool to room temperature. Palladium acetate (II) (9 mg, 0.04 mmol), (±) 2,2'-bis(diphenylphosphino)-1 ,1^I-binaphthyl (26 mg, 0.04 mmol) and cesium carbonate (310 mg, 0.97 mmol) were added and the mixture was inertized with argon. Then, 2,4-difluoroaniline (89 mg, 0.69 mmol) was added and the mixture was heated at 110 ⁰C overnight. The reaction mixture was allowed to cool to room temperature and filtered through a pad of celite. The filtrate was diluted with CHCb and water. The phases were separated and the aqueous phase was reextracted 2 times with CHCI₃. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using CHCI₃-MeOH mixtures of increasing polarity as eluent, to afford 28 mg of the title compound (yield: 12%). LC-MS (method 1): t_R = 9.25 min; m/z = 337.2 [M+H]⁺.

EXAMPLES 1A-1C

Following a similar procedure to that described in example 1 , but starting from the appropriate compound in each case, the compounds in the following table were obtained:

EXAMPLE 2

2-(2-Chlorophenyl)-6-(2,4-difluorophenylamino)-1, 2,3,4- tetrahydroisoquinolin-1-one

Following a similar procedure to that described in example 1 , but starting from 2- (2-chlorophenyl)-1 -oxo-1 ,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (obtained in reference example 12) and 2,4-difluoroaniline, the desired compound was obtained. LC-MS (method 1): t_R = 9.20 min; m/z = 385.1/387.1 [M+H]⁺. EXAMPLES 2A-2C

Following a similar procedure to that described in example 2, but starting from the appropriate compounds in each case, the compounds in the following table were obtained:

EXAMPLE 3 5-(2,4-Difluorophenylamino)-2,2-dimethylindan-1-one

Following a similar procedure to that described in example 1 , but starting from 5- bromo-2,2-dimethylindan-1-one (obtained in reference example 4) and 2,4- difluoroaniline, the desired compound was obtained. LC-MS (method 1): t_R = 9.17 min; m/z = 288.0 [M+H]⁺.

EXAMPLE 3A

Following a similar procedure to that described in example 3, but starting from the appropriate compounds, the compound in the following table was obtained:

m/z

Method t_R (min) [M+H]⁺

2,2-Dimethyl-5-(2-(2- Reference example 4

3A hydroxyethyl)phenylamino)ind and 2-aminophenetyl 1 7.66 296.2 an-1-one alcohol

EXAMPLE 4 6-(2,4-Difluorophenylamino)-2,2-dimethyl-1 ,2,3,4-tetrahydronaphthalen-1-one

Following a similar procedure to that described in example 1 , but starting from 2,2- dimethyl-1 -oxo-1 ,2,3,4-tetrahydronaphthalen-6-yl trifluoromethanesulfonate

(obtained in reference example 7) and 2,4-difluoroaniline, the desired compound was obtained. LC-MS (method 1): t_R = 10.07 min; m/z = 302.0 [M+H]⁺.

EXAMPLES 4A-4E

Following a similar procedure to that described in example 4, but starting from the appropriate compounds, the compounds in the following table were obtained:

EXAMPLE 5 5-(2-Amino-4-fluorophenylamino)-2,2-dimethylindan-1-one

To a solution of 5-(4-fluoro-2-nitrophenylamino)-2,2-dimethylindan-1-one (0.26 g, 0.83 mmol, obtained in reference example 28) in EtOH (10 ml_), tin (II) chloride (0.94 g, 5.94 mmol) was added and the mixture was heated to reflux for 3 h. It was allowed to cool and diluted with CHCI₃. The organic phase was washed with saturated NaHCO₃ and the aqueous phase was reextracted with CHCI₃. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 88 mg of the title compound (yield: 38%). LC-MS (method 1): t_R = 8.12 min; m/z = 285.0 [M+H]⁺.

EXAMPLES 5A-5F

Following a similar procedure to that described in example 5, but starting from the appropriate compound in each case, the compounds in the following table were obtained:

EXAMPLE 6 5-(2-Aminophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one

Following a similar procedure to that described in example 5, but starting from 5- (2-nitrophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one (obtained in reference example 26), the desired compound was obtained. LC-MS (method 1): t_R = 8.34 min; m/z = 316.1 [M+H]⁺.

EXAMPLES 6A-6B

Following a similar procedure to that described in example 6, but starting from the appropriate compound in each case, the compounds in the following table were obtained:

EXAMPLE 7 6-(2-Aminophenylamino)-2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 6-(2-nitrophenylamino)-2,2-dimethyl-1 ,2,3,4-tetrahydronaphthalen- 1-one (120 mg, 0.39 mnnol, obtained in reference example 35) in EtOH (5 ml_), 10% Pd on active carbon (21 mg) was added and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 6 h. It was then filtered over a pad of celite to remove the Pd catalyst and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 79 mg of the title compound (yield: 73%). LC-MS (method 1): t_R = 8.64 min; m/z = 281.0 [M+H]⁺.

EXAMPLE 8

6-(2-Aminophenylamino)-1,2,3,4-tetrahydronaphthalen-1-one

Following a similar procedure to that described in example 7, but starting from 6- (2-nitrophenylamino)-1 ,2,3,4-tetrahydronaphthalen-1-one (obtained in reference example 24), the desired compound was obtained.

LC-MS (method 1): t_R = 6.94 min; m/z = 253.1 [M+H]⁺.

EXAMPLE 9

6-(2,4-Difluorophenylamino)-2-(3-pyridylmethyl)-1 ,2,3,4- tetrahydroisoquinolin-1-one

a) 6-(2,4-Difluoropheny lamino)-1 ,2,3,4-tetrahydroisoquinolin-1 -one

To a solution of 2-benzyl-6-(2,4-difluorophenylamino)-1 , 2,3,4- tetrahydroisoquinolin-1-one (0.73 g, 2.0 mmol, obtained in example 2B) in acetic acid (25 mL), 10% Pd on active carbon (0.24 g) was added and the mixture was vigorously stirred under a hydrogen atmosphere at 120 ⁰C overnight. It was then allowed to cool to room temperature and filtered over a pad of celite to remove the Pd catalyst. The solvent was evaporated and the crude product thus obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 287 mg of the title compound (yield: 53%). LC-MS (method 1): t_R = 6.63 min; m/z = 275.1 [M+H]⁺.

b) Title compound

To a solution of 6-(2,4-difluorophenylamino)-1 ,2,3,4-tetrahydroisoquinolin-1-one (80 mg, 0.29 mmol, obtained in section a) in toluene (2.5 ml_) and THF (2.5 ml_), sodium hydride (55% in mineral oil, 34 mg, 0.79 mmol) was added portionwise. After cooling at 0 ⁰C, 3-chloromethylpyridine hydrochloride (72 mg, 0.44 mmol) was added and the mixture was heated at 90 ⁰C overnight. The reaction mixture was allowed to cool to room temperature and some drops of MeOH were added to destroy the excess of hydride. It was diluted with EtOAc and 2N NaOH, the phases were separated and the aqueous phase was reextracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using EtOAc-MeOH mixtures of increasing polarity as eluent, to afford 6 mg of the title compound (yield: 5%). LC-MS (method 1): t_R = 5.55 min; m/z = 366.1 [M+H]⁺.

EXAMPLE 10 6-[Λ/-(2,4-Difluorophenyl)-Λ/-(3-hydroxypropyl)amino]-2,2-dimethyl-1, 2,3,4- tetrahydronaphthalen-1 -one

a) 6-[Λ/-(2,4-Difluorophenyl)-W-(3-(tetrahydropyran-2-yloxy)propyl)amino]- 2,2-dimethy 1-1 ,2,3,4-tetrahydronaphthalen-1 -one

To a suspension of 6-(2,4-difluorophenylamino)-2,2-dimethyl-1 , 2,3,4- tetrahydronaphthalen-1-one (1.94 g, 6.44 mmol, obtained in example 4) in dry toluene (70 mL), sodium hydride (0.56 g, 55% dispersion in oil, 12.83 mmol) and 15-crown-5 (47 mg, 0.21 mmol) were added under argon and the mixture was stirred at room temperature for 20 min. Then, 3-bromopropanol tetrahydropyranyl ether (1.44 g, 6.44 mmol) was added and the mixture was heated at 90 ⁰C for 4 h. It was allowed to cool and diluted with EtOAc and saturated NaHCO₃. The phases were separated and the aqueous phase was reextracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated to afford the desired compound (quantitative yield). LC-MS (method 1): t_R = 11.98 min; m/z = 444.2 [M+H]⁺.

b) Title compound

A solution of 6-[Λ/-(2,4-difluorophenyl)-Λ/-(3-(tetrahydropyran-2- yloxy)propyl)amino]-2,2-dimethyl-1 ,2,3,4-tetrahydronaphthalen-1-one (6.44 mmol, obtained in section a) in a mixture of acetic acid (74 ml_), THF (37 ml_) and water (18 ml_) was heated at 50 ⁰C overnight. The solvent was evaporated and the residue was diluted with EtOAc and washed with saturated NaHCO₃. The organic phase was dried over Na₂SO₄, the solvent was evaporated and the crude product thus obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 2.02 g of the title compound (yield: 87 %).

LC-MS (method 1): t_R = 9.09 min; m/z = 360.1 [M+H]⁺.

EXAMPLE 11

6-[W-(2,4-Difluorophenyl)-W-(2-hydroxyethyl)amino]-2,2-dimethyl-1 , 2,3,4- tetrahydronaphthalen-1 -one

a) 6-[W-(2,4-Difluorophenyl)-W-(2-(tetrahydropyran-2-yloxy)ethyl)amino]-2,2- dimethyl-1 ,2,3,4-tetrahydronaphthalen-1 -one

Following a similar procedure to that described in example 10 section a, but starting from 6-(2,4-difluorophenylamino)-2,2-dimethyl-1 ,2,3,4- tetrahydronaphthalen-1-one (obtained in example 4) and 2-bromoethanol tetrahydropyranyl ether, the desired compound was obtained. LC-MS (method 1): t_R = 11.28 min; m/z = 430.1 [M+H]⁺. b) Title compound

Following a similar procedure to that described in example 10 section b, but starting from 6-[Λ/-(2,4-difluorophenyl)-Λ/-(2-(tetrahydropyran-2-yloxy)ethyl)amino]- 2,2-dimethyl-1 ,2,3,4-tetrahydronaphthalen-1-one (obtained in section a), the desired compound was obtained. LC-MS (method 1): t_R = 8.95 min; m/z = 346.0 [M+H]⁺.

EXAMPLE 12 6-[W-(2,4-Difluorophenyl)-W-(2-(morpholin-4-yl)ethyl)amino]-2,2-dimethyl-

1 ,2,3,4-tetrahydronaphthalen-1 -one

a) 2-[/V-(2,4-Difluorophenyl)-N-(2,2-dimethyl-1-oxo-1 ,2,3,4- tetrahydronaphthalen-6-yl)amino]ethyl methanesulfonate

To a solution of 6-[Λ/-(2,4-difluorophenyl)-Λ/-(2-hydroxyethyl)amino]-2,2-dimethyl- 1 ,2,3,4-tetrahydronaphthalen-1-one (149 mg, 0.43 mmol, obtained in example 11) in dry CH₂CI₂ (4 mL), TEA (56 mg, 0.56 mmol) was added and the mixture was cooled to 0 ⁰C. Methanesulfonyl chloride (52 mg, 0.45 mmol) was added and the mixture was stirred at room temperature overnight. After dilution with water, the phases were separated. The aqueous phase was reextracted with CHCI₃, the combined organic phases were dried over Na₂SO₄ and the solvent was evaporated to afford the desired compound (quantitative yield). ¹H NMR (300 MHz, CDCI₃) δ (TMS): 1.19 (s, 6 H), 1.92 (t, J = 6.3 Hz₁ 2 H), 2.85 (t, J = 6.3 Hz, 2 H), 2.98 (s, 3 H), 4.04 (t, J = 6.0 Hz, 2 H), 4.42 (t, J = 6.0 Hz, 2 H), 6.35 (d, J = 2.4 Hz, 1 H)₁ 6.51 (dd, J = 8.7 Hz, J¹ = 2.4 Hz, 1 H), 7.00 (m, 2 H), 7.32 (m, 1 H), 7.91 (d, J = 8.7 Hz, 1 H).

b) Title compound

A mixture of 2-[Λ/-(2,4-difluorophenyl)-Λ/-(2,2-dimethyl-1-oxo-1 , 2,3,4- tetrahydronaphthalen-6-yl)amino]ethyl methanesulfonate (183 mg, 0.43 mmol, obtained in section a) and morpholine (75 mg, 0.86 mmol) in acetonitrile (4 mL) was stirred at 70 ⁰C overnight. Additional morpholine (38 mg, 0.43 mmol) was added and the mixture was stirred at 70 ⁰C for another 24 h. The solvent was evaporated and the residue was diluted with CHCb and saturated NaHCO₃. The phases were separated and the aqueous phase was reextracted with CHCI_3. The combined organic phases were dried over Na₂SO₄ and the solvent was evaporated. The crude product thus obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 75 mg of the title compound (yield: 42 %). LC-MS (method 1): t_R = 6.27 min; m/z = 415.1 [M+H]⁺.

EXAMPLE 13 Biological assays

Inhibition of p38α enzyme activity (test 1):

In a final volume of 25 μl_, a total of 5 μl_ of the test product (final concentration, 0.001-10 μM), 5-10 mil of p38α with 0.33 mg/mL of myelin basic protein, Mg²⁺ acetate (10 mM) and [γ³³P-ATP] (100 μM, specific activity 500 cpm/pmol) in buffer Tris 25 mM pH7.5, EGTA 0.02 mM is incubated. The reaction is started by adding Mg²⁺[γ ³³P-ATP]. After incubation for 40 min at room temperature, the reaction is quenched by adding 5 μL of 3% phosphoric acid solution. The reaction mixture (10 μl_) is passed through a filter (P30) and washed three times for 5 min with a 75 mM phosphoric acid solution and once with methanol before drying it and counting it, by liquid scintillation.

Inhibition of p38α enzyme activity (test 2):

Compound stocks in 100% DMSO are first diluted in DMSO to a concentration of 1x10^"3 up to 3.2x10^"8 M and then further diluted in kinase assay buffer (10 mM Tris-HCI, pH 7.2, 10 mM MgCI₂, 0.01% tween 20, 0.05% NaN₃, 1 mM DTT) to a concentration range of 4x10^"5 up to 1.3x10^"9 M. Of each compound solution 5 μL is transferred into a 384-wells black Optiplate (Packard, 6007279), followed by the addition of 5 μl_ of ATP (Boehringer, 519987), 5 μl of Fluorescein-labeled EGFR peptide substrate and 5 μl_ of active p38α kinase (GST-tagged fusion protein corresponding to full-length human p38α; expressed in E.coli by Upstate, 14-251), all diluted in kinase assay buffer (see final concentrations in Table 1). The mixture is incubated for 2 hours at room temperature (RT). The reaction is stopped by the addition of 60 μl_ of IMAP binding reagent, which has been diluted 400-fold in IMAP binding buffer (stock concentration 5 times diluted in MiIIi Q). After incubation for 30 min at RT, FP is measured on an Analyst™ multimode fluorescence plate reader (Molecular Devices) at excitation wavelength of 485 nm and emission wavelength of 530 nm (1 sec/well).

Table 1 : assay conditions

Kinase Final Substrate Final ATP final (from Upstate) concentration concentration concentration

p38α/SAPK2a, 0.30 U/mL LVEPLTPSGEAPNQK-(FI) 24O nM 20 μM active

Data handling is performed as follows: percentage effects are calculated based on no-p38-enzyme-addition as the maximum inhibitory effect and with p38 enzyme addition as the minimum inhibitory effect. In each experiment, individual compound concentrations are tested in duplicate and percentage effect is calculated for each concentration.

Inhibition of TNF-α release induced by LPS in human peripheral blood mononuclear cells (PBMCs):

PBMCs: Heparinized venous blood, obtained from healthy volunteers, is diluted with an equal volume of saline phosphate buffer without calcium or magnesium. Aliquots of 30 ml_ of the mixture are transferred to 50 ml_ centrifuge tubes containing 15 ml_ of Ficoll-Hypaque (1.077 g/mL). The tubes are centrifuged at 1200 x g for 20 min at room temperature without braking. Approximately two-thirds of the band of platelets lying above the mononuclear cells is removed with a pipette. The mononuclear cells are carefully transferred to a 50 mL tube, washed twice with saline phosphate buffer, centrifuged at 300 x g for 10 min at room temperature and resuspended in RPMI supplemented with 1% inactivated fetal bovine serum at a cell density of 2x10⁶ cells/mL Assay: 100 μl_ of mononuclear cells (2x10⁶ cells/mL) are incubated in 96-well plates with 50 μL of the test product (final concentration, 0.001-10 μM) and 50 μl_ LPS (E. coli 055B5, Sigma) at a final concentration of 400 ng/mL for 19 h at 37 ⁰C in an atmosphere with CO₂ at 5%. The amount of TNFα released in the supernatant is quantified using a commercial ELISA kit (Biosource International).

Compounds of all examples exhibited more than 50% inhibition at 10 μM in at least one of the above assays.

Claims

1.- A compound of general formula I

I wherein:

A represents CR1R2 or NR3; R₁ and R₂ independently represent hydrogen or Ci_-4 alkyl;

R₃ represents -(CH₂)_P-Cy¹, C_1-4 alkyl or C_1-4 hydroxyalkyl; m represents 1 or 2;

R₄ represents one or more groups selected from hydrogen, halogen, C_1-4 alkyl,

Ci_-4 haloalkyl, NH₂ and C_1-4 hydroxyalkyl; p represents 0, 1 or 2;

Cy¹ represents phenyl, heteroaryl or 0₃.₇ cycloalkyl, which can all be optionally substituted with one or more R₅;

R₅ represents C_1-4 alkyl, halogen, C_1-4 alkoxy, C_1-4 haloalkyl or C_1-4 haloalkoxy;

R₆ represents hydrogen or R₇; R₇ represents C_1-6 alkyl optionally substituted with one or more groups selected from halogen, -OR₈-, -NO₂, -CN, -COR₈-, -CO₂R₈', -CONR₉ R₉ , -NR₉ R₉ ,

-NR₉COR₈', -NR₉CONR₉ R₉', -NR₉CO₂R₈, -NR₉SO₂R₈, -SR₈', -SOR₈, -SO₂R₈,

-SO₂NR₉ R₉' and Cy²;

R₈ represents Ci_-4 alkyl, Ci_-4 haloalkyl or C_1-4 hydroxyalkyl; R₈' represents hydrogen or R₈;

R₉ represents Ci_-4 alkyl or Ci_-4 hydroxyalkyl;

R₉' represents hydrogen or R_g; and

Cy² represents phenyl, heteroaryl, C_3-7 cycloalkyl or heterocyclyl, which can all be optionally substituted with one or more groups selected from Ci_-4 alkyl, halogen, C_1-4 alkoxy, Ci_-4 haloalkyl and Ci_-4 haloalkoxy; or a salt thereof.

2.- A compound according to claim 1 wherein A represents CR₁Ra_.

3.- A compound according to claim 1 wherein A represents NR₃.

4.- A compound according to any of claims 1 to 3 wherein m is 1.

5.- A compound according to any of claims 1 to 3 wherein m is 2.

6.- A compound according to any of claims 1 , 2, 4 or 5 wherein Ri is identical to

R₂.

7.- A compound according to any of claims 1 , 3, 4 or 5 wherein R₃ represents -(CH₂)_P-Cy¹.

8.- A compound according to any of claims 1 to 7 wherein R₄ represents one or two groups selected from hydrogen, halogen, Ci_-4 alkyl, C_1-4 haloalkyl, NH₂ and

Ci_-4 hydroxyalkyl.

9.- A compound according to claim 8 wherein R₄ represents one or two groups selected from halogen, C_1-4 alkyl, Ci_-4 haloalkyl, NH₂ and Ci_-4 hydroxyalkyl.

10.- A compound according to any of claims 1 to 9 wherein R₆ represents hydrogen or Ci_₆ alkyl optionally substituted with one group selected from -OR₈',

-NR₉R₉' and Cy².

11.- A compound according to claim 10 wherein Re represents hydrogen.

12.- A compound according to claim 1 selected from:

5-(2,4-Difluorophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one;

2-Benzyl-5-(2,4-difluorophenylamino)-2,3-dihydroisoindol-1-one;

5-(2,4-Difluorophenylamino)-2-methyl-2,3-dihydroisoindol-1-one;

5-(2,4-Difluorophenylamino)-2-(3-hydroxypropyl)-2,3-dihydroisoindol-1-one; 2-(2-Chlorophenyl)-6-(2,4-difluorophenylamino)-1 ,2,3,4-tetrahydroisoquinolin-1 - one;

6-(2,4-Difluorophenylamino)-2-ethyl-1 ,2,3,4-tetrahydroisoquinolin-1-one;

2-Benzyl-6-(2,4-difluorophenylamino)-1 ,2,3,4-tetrahydroisoquinolin-1-one;

2-Benzyl-6-(2-(2-hydroxyethyl)phenylamino)-1 ,2,3,4-tetrahydroisoquinolin-1-one; 5-(2,4-Difluorophenylamino)-2,2-dimethylindan-1 -one;

2,2-Dimethyl-5-(2-(2-hydroxyethyl)phenylamino)indan-1-one;

6-(2,4-Difluorophenylamino)-2,2-dimethyl-1 ,2,3,4-tetrahydronaphthalen-1-one; 2,2-Dimethyl-6-phenylamino-1 ,2,3,4-tetrahydronaphthalen-1-one;

2,2-Dimethyl-6-(2-(2-hydroxyethyl)phenylamino)-1 ,2,3,4-tetrahydronaphthalen-1- one;

2,2-Dimethyl-6-(2-hydroxymethylphenylamino)-1 ,2,3,4-tetrahydronaphthalen-1- one;

2,2-Diethyl-6-(2,4-difluorophenylamino)-1 _l2,3,4-tetrahydronaphthalen-1-one;

6-(2,4-Difluorophenylamino)-1 ,2,3,4-tetrahydronaphthalen-1-one;

5-(2-Amino-4-fluorophenylamino)-2,2-dimethylindan-1-one;

5-(2-Amino-6-methylphenylamino)-2,2-dimethylindan-1-one; 5-(2-Amino-5-methylphenylamino)-2,2-dimethylindan-1 -one;

5-(5-Amino-2-methylphenylamino)-2,2-dimethylindan-1-one;

5-(3-Amino-2-methylphenylamino)-2,2-dimethylindan-1-one;

5-(3-Aminophenylamino)-2,2-dimethylindan-1-one;

5-(3-Amino-4-methylphenylamino)-2,2-dimethylindan-1-one; 5-(2-Aminophenylamino)-2-phenyl-2,3-dihydroisoindol-1 -one;

5-(2-Amino-4-fluorophenylamino)-2-phenyl-2,3-dihydroisoindol-1-one;

5-(2-Aminophenylamino)-2-benzyl-2,3-dihydroisoindol-1-one;

6-(2-Aminophenylamino)-2_l2-dimethyl-1 ,2,3,4-tetrahydronaphthalen-1-one;

6-(2-Aminophenylamino)-1 ,2,3,4-tetrahydronaphthalen-1 -one; 6-(2,4-Difluorophenylamino)-2-(3-pyridylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-1- one;

6-[Λ/-(2,4-Difluorophenyl)-Λ/-(3-hydroxypropyl)amino]-2,2-dimethyl-1 , 2,3,4- tetrahydronaphthalen-1 -one;

6-[Λ/-(2,4-Difluorophenyl)-Λ/-(2-hydroxyethyl)amino]-2,2-dimethyl-1 , 2,3,4- tetrahydronaphthalen-1-one; and

6-[Λ/-(2,4-Difluorophenyl)-Λ/-(2-(morpholin-4-yl)ethyl)amino]-2,2-dimethyl-1 ,2,3,4- tetrahydronaphthalen-1 -one.

13.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

14.- Use of a compound of formula I according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by p38.

15.- Use according to claim 14, wherein the disease mediated by p38 is selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption diseases, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.