WO2010072823A1

WO2010072823A1 - PYRAZOLE[1,5a]PYRIDINE DERIVATIVES

Info

Publication number: WO2010072823A1
Application number: PCT/EP2009/067883
Authority: WO
Inventors: Jorge Salas Solana; Carmen Almansa Rosales; Josep Comelles Espuga; Montserrat Fontes Ustrell; Robert Soliva Soliva; José Javier PASTOR PORRAS
Original assignee: Palau Pharma, S. A.
Priority date: 2008-12-24
Filing date: 2009-12-23
Publication date: 2010-07-01
Also published as: AR074870A1; TW201035095A

Abstract

Pyrazolo[1,5-a]pyridine derivatives of formula I, wherein the meaning for R₁, R₂ and R₃ is as disclosed in the description. These compounds are useful as JAK3 kinase inhibitors.

Description

Pyrazolo[1 ,5-a] pyridine derivatives

Field of the invention

The present invention relates to a new series of pyrazolo[1 ,5-a]pyhdine derivatives, as well as to processes for their preparation, to pharmaceutical compositions comprising them and to their use in therapy.

Background of the invention

The Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases that play pivotal roles in pathways that modulate cellular functions in the lympho- hematopoietic system that are critical for cell proliferation and cell survival. JAKs are involved in the initiation of cytokine-triggered signaling events by activating through tyrosine phosphorylation the signal transducers and activators of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as transplant rejection and autoimmune diseases, as well as in solid and hematologic malignancies such as leukemias and lymphomas and in myeloproliferative disorders, and has thus emerged as an interesting target for drug invention.

Four members of the JAK family have been identified so far: JAK1 , JAK2, JAK3 and Tyk2. Unlike JAK1 , JAK2 and Tyk2, whose expression is ubiquitous, JAK3 is mainly found in hematopoietic cells. JAK3 is associated in a non-covalent manner with the γc subunit of the receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL- 15. These cytokines play an important role in the proliferation and differentiation of T lymphocytes. JAK3-deficient mouse T cells do not respond to IL-2. This cytokine is fundamental in the regulation of T lymphocytes. In this regard, it is known that antibodies directed against the IL-2 receptor are able to prevent transplant rejection. In patients with X severe combined immunodeficiency (X-SCID), very low levels of JAK3 expression as well as genetic defects in the γc subunit of the receptor have been identified, which indicates that immunosuppression is a consequence of an alteration in the JAK3 signaling pathway. Animal studies have suggested that JAK3 not only plays a critical role in T and B lymphocyte maturation, but also that JAK3 is required to maintain lymphocyte function. Modulation of the immunological activity through this new mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.

JAK3 has also been shown to play an important role in mast cells, because antigen-induced degranulation and mediator release have been found to be substantially reduced in mast cells from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation nor IgE receptor expression levels. On the other hand, JAK3-/- and JAK3+/+ mast cells contain the same intracellular mediators. Therefore, JAK3 appears to be essential in the IgE-induced release of mediators in mast cells and its inhibition would be, thus, an effective treatment for allergic reactions.

In conclusion, JAK3 kinase inhibitors have been recognised as a new class of effective immunosuppresive agents useful for transplant rejection prevention and in the treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, systemic lupus erythematosus, type I diabetes and complications from diabetes, allergic reactions and leukemia (see e.g. O'Shea J.J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje

M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch.

Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).

Accordingly, it would be desirable to provide novel compounds that are capable of inhibiting JAK/STAT signaling pathways, and in particular which are capable of inhibiting JAK3 activity, and which are good drug candidates. Compounds should exhibit good activity in in vitro and in in vivo pharmacological assays, good oral absorption when administered by the oral route, as well as be metabolically stable and exhibit a favourable pharmacokinetic profile. Moreover, compounds should not be toxic and exhibit few side effects.

Description of the invention

One aspect of the invention relates to a compound of formula I

I or a salt thereof, wherein:

Ri represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, R₇-Ci_-4alkyl, halogen, -CN, -CONR₄R₄, -COR₅, -CO₂R₅, -OR₄, -SO₂R₅, -SO₂NR₄R₄, -NR₄R₄, -NR₆COR_4, -NR₆CONR₄R₄, -NR₆CO₂R₅, -NR₆SO₂R₅ or Cy-i, wherein Cyi is optionally substituted with one or more R₈;

R₂ represents hydrogen, C-i-₄alkyl haloC-i-₄alkyl, hydroxyCi_-4alkyl, R₇-C-i_-4alkyl or Cy₂, wherein Cy₂ is optionally substituted with one or more R₈; R₃ represents C-|.₄alkyl, haloC-|.₄alkyl, hydroxyC-|.₄alkyl, R-ιrCi-₄alkyl,

-CONR₉R₉, -COR10, -CO₂Ri₀, -SO₂Ri₀, -SO₂NR₉R₉ or Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂; or R₂ and R₃ can be bonded completing, together with the N atom, a Cy₄ group, wherein Cy₄ is optionally substituted with one or more Ri₂; each R₄ independently represents hydrogen or R₅; each R₅ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi- ₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, Cyi-Ci_-4alkyl or Cy-i, wherein Cyi is optionally substituted with one or more R₈; R₆ represents hydrogen or Ci_-4alkyl; R₇ represents -CN, -CONR₄R₄, -COR₅, -CO₂R₅, -OR₄, -SO₂R₅,

-SO₂NR₄R₄, -NR₄R₄, -NR₆COR_4, -NR₆CONR₄R₄, -NR₆CO₂R₅, -NR₆SO₂R₅ or Cy-i, wherein Cyi is optionally substituted with one or more R₈; each R₈ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi- ₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, halogen or hydroxyl; each R₉ independently represents hydrogen or Ri₀; each R₁₀ independently represents Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, Rn -C-i _-4alkyl or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃;

R₁₁ represents halogen, -CN, -CONR₁₄R₁₄, -COR₁₅, -CO₂R₁₅, -OR₁₄, -OCONR₁₄R₁₄, -SO₂R₁₅, -SO₂NR₁₄R₁₄, -NR₁₄R₁₄, -NR₆COR₁₄, -NR₆CONR₁₄R₁₄, -NR₆CO₂R₁₅, -NR₆SO₂R₁₅ or Cy₅, wherein Cy₅ is optionally substituted with one or more R₁₃; each R₁₂ independently represents C_1-4alkyl, haloC_1-4alkyl, hyd HDXyC_{1 -4}alkyl, R₁₁-C_1-4alkyl, or R₁₂ represents any of the meanings described for R₁₁ ; each R₁₃ independently represents C_1-4alkyl, haloC_1-4alkyl, C₁^aIkOXyC_1- ₄alkyl, hyd HDXyC_{1 -4}alkyl, cyanoC_1-4alkyl, halogen, -CN, -CONR₁₆R₁₆, -COR₁₇, - CO₂R₁₇, -OR₁₆, -OCONR₁₆R₁₆, -SO₂R₁₇, -SO₂NR₁₆R₁₆, -NR₁₆R₁₆, -NR₆COR_16, -NR₆CONR₁₆R₁₆, -NR₆CO₂R₁₇ or -NR₆SO₂R₁₇; each R₁₄ independently represents hydrogen or R₁₅; each R₁₅ independently represents C_1-4alkyl, haloC_1-4alkyl, C₁^aIkOXyC_1- ₄alkyl, hyd TOXyC_{1 -4}alkyl, cyanoC_1-4alkyl, Cy₅-C_{1 -4}alkyl or Cy₅, wherein Cy₅ is optionally substituted with one or more R₁₃; each R₁₆ independently represents hydrogen or R₁₇; each R₁₇ independently represents C_1-4alkyl, haloC_1-4alkyl, C₁^aIkOXyC_1- ₄alkyl, hyd TOXyC_{1 -4}alkyl or cyanoC_1-4alkyl;

Cy₁ represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups; Cy₂ represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups; Cy₃ represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups;

Cy₄ represents a 3- to 7-membered monocyclic heterocyclic ring that is saturated or partially unsaturated, which is optionally fused to a 5- or 6-membered carbocyclic or heterocyclic ring that is saturated, partially unsaturated or aromatic, wherein Cy₄ optionally contains from 1 to 4 heteroatoms in total independently selected from N, S and O; and wherein one or more C or S atoms of Cy₄ are optionally oxidized forming CO, SO or SO₂ groups; and

Cy₅ represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups. The present invention also relates to the salts and solvates of the compounds of formula I.

Some compounds of formula I can have chiral centers 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 JAK, particularly JAK3, kinase inhibitors and therefore can be useful for the treatment or prevention of any disease mediated by this kinase.

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

or a salt thereof, wherein: Ri represents hydrogen, d-₄alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, R₇-C_1-4alkyl, halogen, -CN, -CONR₄R₄, -COR₅, -CO₂R₅, -OR₄, -SO₂R₅, -SO₂NR₄R₄, -NR₄R₄, -NR₆COR_4, -NR₆CONR₄R₄, -NR₆CO₂R₅, -NR₆SO₂R₅ or Cy-i, wherein Cyi is optionally substituted with one or more R₈; R₂ represents hydrogen, C-i-₄alkyl haloC-i-₄alkyl, hydroxyCi_-4alkyl,

R₇-Ci_-4alkyl or Cy₂, wherein Cy₂ is optionally substituted with one or more R₈;

R₃ represents C-i-₄alkyl, haloC-i-₄alkyl, hydroxyCi_-4alkyl, Rn-Ci_-4alkyl, -CONR₉R₉, -COR10, -CO₂Ri₀, -SO₂Ri₀, -SO₂NR₉R₉ or Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂; or R₂ and R₃ can be bonded completing, together with the N atom, a Cy₄ group, wherein Cy₄ is optionally substituted with one or more Ri₂; each R₄ independently represents hydrogen or R₅; each R₅ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi- ₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, Cyi-Ci_-4alkyl or Cyi, wherein Cyi is optionally substituted with one or more R₈; R₆ represents hydrogen or Ci_-4alkyl;

R₇ represents -CN, -CONR₄R₄, -COR₅, -CO₂R₅, -OR₄, -SO₂R₅, -SO₂NR₄R₄, -NR₄R₄, -NR₆COR_4, -NR₆CONR₄R₄, -NR₆CO₂R₅, -NR₆SO₂R₅ or Cy-i, wherein Cyi is optionally substituted with one or more R₈; each R₈ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi-

₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, halogen or hydroxyl; each R₉ independently represents hydrogen or Ri₀; each Ri₀ independently represents Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, Rn-Ci-₄alkyl or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; Rn represents halogen, -CN, -CONRi₄Ri₄, -CORi₅, -CO₂Ri₅, -ORi₄,

-OCONRi₄Ri₄, -SO₂Ri₅, -SO₂NRi₄Ri₄, -NRi₄Ri₄, -NR₆CORi_4, -NR₆CONRi₄Ri₄, -NR₆CO₂Ri₅, -NR₆SO₂Ri₅ or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; each Ri₂ independently represents Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, Rn-Ci-₄alkyl, or Ri₂ represents any of the meanings described for Rn ; each Ri₃ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi- ₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, halogen, -CN, -CONRi₆Ri₆, -CORi₇, - CO₂Ri₇, -ORi₆, -OCONRi₆Ri₆, -SO₂Ri₇, -SO₂NRi₆Ri₆, -NRi₆Ri₆, -NR₆CORi_6, -NR₆CONR₁₆R₁₆, -NR₆CO₂R₁₇ or -NR₆SO₂R₁₇; each R₁₄ independently represents hydrogen or R₁₅; each R₁₅ independently represents C_1-4alkyl, haloC_1-4alkyl, C₁^aIkOXyC_1- ₄alkyl, hyd TOXyC_{1 -4}alkyl, cyanoC_1-4alkyl, Cy₅-C_{1 -4}alkyl or Cy₅, wherein Cy₅ is optionally substituted with one or more R₁₃; each R₁₆ independently represents hydrogen or R₁₇; each R₁₇ independently represents C_1-4alkyl, haloC_1-4alkyl, C₁^aIkOXyC_1- ₄alkyl, hyd TOXyC_{1 -4}alkyl or cyanoC_1-4alkyl;

Cy₅ represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups; for use in therapy.

Another aspect of the 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 a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.

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 at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. 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 transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

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 mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.

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 at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.

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 transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAKs, particularly JAK3, in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.

Another aspect of the present invention relates to a method of treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.

Another aspect of the present invention relates to a method of treating or preventing a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas in a subject in need thereof, especially a human being, which comprises administering to said subject 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) reacting a compound of formula VIII with a compound of formula IX

VIII IX wherein R₁, R₂ and R₃ have the meaning described in claim 1 and X represents halogen; or

(b) converting, in one or a plurality of steps, a compound of formula XII into a compound of formula I

XN wherein R₁ has the meaning described in claim 1 ; 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 C_1-4 alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

A C_1-4alkoxy group, as a group or part of a group, means a group of formula -OC_1-4alkyl, wherein the C_1-4alkyl moiety has the same meaning as previously described. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and fe/t-butoxy.

Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo. A C_1-4alkoxyC₁-₄alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C_1-4alkyl group with one or more C_1-4alkoxy groups as defined above, which can be the same or different. Examples include, among others, the groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert- butoxymethyl, dimethoxymethyl, 1 -methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1 ,2-diethoxyethyl, 1 -butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2- butoxypropyl, 1 -methoxy-2-ethoxypropyl, 3-tert-butoxypropyl and 4-methoxybutyl.

A haloCi_-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci_-4alkyl 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, the groups 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 hydroxyCi_-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci_-4alkyl group with one or more hydroxy groups. Examples include, among others, the groups hydroxymethyl, 1 - hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyl, 1 -hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3- hydroxybutyl, 2-hydroxybutyl and 1 -hydroxybutyl. A cyanoCi_-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci_-4alkyl group with one or more cyano groups. Examples include, among others, the groups cyanomethyl, dicyanomethyl,

1 -cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2,3-dicyanopropyl and 4-cyanobutyl.

A CyrCi-₄alkyl group means a group resulting from the replacement of one hydrogen atom from a Ci_-4alkyl group with one Cyi group. Examples include, among others, the groups (morpholin-4-yl)methyl, 2-(morpholin-4-yl)ethyl, 3- (morpholin-4-yl)propyl, 4-(morpholin-4-yl)butyl, (piperazin-i -yl)methyl, (4- methylpiperazin-1 -yl)methyl, 2-(4-methylpiperazin-1 -yl)ethyl, 3-(4-methylpiperazin- 1 -yl)propyl, 4-(4-methylpiperazin-1 -yl)butyl, (4-ethylpiperazin-1 -yl)methyl, (4- propylpiperazin-1 -yl)methyl, (4-butylpiperazin-1 -yl)methyl, (1 ,1 -dioxothiomorpholin- 4-yl)methyl, 2-(1 ,1 -dioxotiomorpholin-4-yl)ethyl, 3-(1 ,1 -dioxothiomorpholin-4- yl)propyl and 4-(1 ,1 -dioxothiomorpholin-4-yl)butyl. A Cy₅-Ci-₄alkyl group means a group resulting from the replacement of one hydrogen atom from a Ci_-4alkyl group with one Cy₅ group. Examples include, among others, the groups (morpholin-4-yl)methyl, 2-(morpholin-4-yl)ethyl, 3- (morpholin-4-yl)propyl, 4-(morpholin-4-yl)butyl, (indolinyl-1 -yl)methyl, 2-(indolinyl- 1 -yl)ethyl, 3-(indolinyl-1 -yl)propyl, 4-(indolinyl-1 -yl)butyl, (pyridin-1 -yl)methyl, (4- methylpyridin-1 -yl)methyl, 2-(4-methylpyhdin-1 -yl)ethyl, 3-(4-methylpyhdin-1 - yl)propyl, 4-(4-methylpyridin-1 -yl)butyl, (4-ethylpyridin-1 -yl)methyl, (4- propylpyhdin-1 -yl)methyl, (4-butylpyhdin-1 -yl)methyl, (1 ,1 -dioxothiomorpholin-4- yl)methyl, 2-(1 ,1 -dioxothiomorpholin-4-yl)ethyl, 3-(1 ,1 -dioxothiomorpholin-4- yl)propyl and 4-(1 ,1 -dioxothiomorpholin-4-yl)butyl.

A R₇-Ci_-4alkyl group means a group resulting from the replacement of one hydrogen atom from a Ci_-4alkyl group with one R₇ group.

A RirCi-₄alkyl group means a group resulting from the replacement of one hydrogen atom from a C-|.₄alkyl group with one Rn group. A Cyi group refers to a 3- to 7-membered monocyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 3 heteroatoms independently selected from N, S and O. Cyi is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C or N atom. When Cyi is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO₂ groups. Cyi is optionally substituted as disclosed above in the definition of a compound of formula I, said substituents can be the same or different and can be placed on any available position of the ring system. Examples of Cyi group include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 - dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopiperidinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, 2-oxo-pyrrolidinyl, 2-oxo- piperidinyl, 4-oxo-piperidinyl, 2-oxo-piperazinyl, 2-oxo-1 ,2-dihydropyridinyl, 2-oxo- 1 ,2-dihydropyrazinyl, 2-oxo-1 ,2-dihydropyrimidinyl, 3-oxo-2,3-dihydropyridazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

A Cy₂ group refers to a 3- to 7-membered monocyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 3 heteroatoms independently selected from N, S and O. Cy₂ is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C atom. When Cy₂ is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO₂ groups. Cy₂ is optionally substituted as disclosed above in the definition of a compound of formula I, said substituents can be the same or different and can be placed on any available position of the ring system. Examples of Cy₂ group include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 - dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopipehdinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, 2-oxo-pyrrolidinyl, 2-oxo- piperidinyl, 4-oxo-piperidinyl, 2-oxo-piperazinyl, 2-oxo-1 ,2-dihydropyridinyl, 2-oxo- 1 ,2-dihydropyrazinyl, 2-oxo-1 ,2-dihydropyrimidinyl, 3-oxo-2,3-dihydropyridazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, tetrazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.

A Cy₃ group refers to a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic rings may be formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they can be formed by two rings bonded through a single common C atom forming a spiro ring. Cy₃ is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C atom. In Cy₃ one or more C or S atoms of a saturated or partially unsaturated ring are optionally oxidized forming CO, SO or SO₂ groups. Cy₃ is optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, said substituents can be the same or different and can be placed on any available position of the ring system. Examples of Cy₃ include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopipehdinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, 2-oxo-pyrrolidinyl, 2-oxo-pipehdinyl, 4-oxo-pipehdinyl, 2-oxo- piperazinyl, 2-oxo-1 ,2-dihydropyridinyl, 2-oxo-1 ,2-dihydropyrazinyl, 2-oxo-1 ,2- dihydropyhmidinyl, 3-oxo-2,3-dihydropyhdazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1 ,2,3- triazolyl, 1 ,2,4-triazolyl, tetrazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzooxazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, cinolinyl, naphthyridinyl, indazolyl, imidazopyridinyl, pyrrolopyridinyl, thienopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzo[1 ,3]dioxolyl, phtalimidyl, 1 -oxo-1 ,3-dihydroisobenzofuranyl, 1 ,3-dioxo-1 ,3- dihydroisobenzofuranyl, 2-oxo-2,3-dihydro-1 /-/-indolyl, 1 -oxo-2,3-dihydro-1 H- isoindolyl, perhydroquinolinyl, 1 -oxo-perhydroisoquinolinyl, 1 -oxo-1 ,2- dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazolinyl, 2-aza-bicyclo[2.2.1 ]heptanyl, 5-aza-bicyclo[2.1.1 ]hexanyl, 2/-/-spiro[benzofuran-3,4'-piperidinyl], 3H- spiro[isobenzofuran-1 ,4'-piperidinyl], 1 -oxo-2,8-diazaspiro[4.5]decanyl and 1 -oxo- 2,7-diazaspiro[4.5]decanyl.

A Cy₄ group refers to a 3- to 7-membered monocyclic heterocyclic ring, which is saturated or partially unsaturated. Cy₄ is optionally fused to a 5- or 6- membered carbocyclic or heterocyclic ring that is saturated, partially unsaturated or aromatic. Cy₄ contains from 1 to 4 heteroatoms in total independently selected from N, S and O. In Cy₄ one or more C or S atoms of a saturated or partially unsaturated ring are optionally oxidized forming CO, SO or SO₂ groups. Cy₄ is optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, said substituents can be the same or different and can be placed on any available position of the ring system. Examples of Cy₄ include, among others, azepanyl, aziridinyl, azetidinyl, 1 ,4-diazepanyl, pyrrolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolinyl, pyrrolinyl, pyrazolinyl, piperidinyl, homopipehdinyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxothiomorpholinyl, piperazinyl, homopiperazinyl, 2-oxo-azepanyl, 2-oxo-azetidinyl, 2-oxo-1 ,4-diazepanyl, 2-oxo- pyrrolidinyl, 2-oxo-piperazinyl, 2-oxo-pipehdinyl, 3-oxo-pipehdinyl, 4-oxo- piperidinyl, 2-oxo-imidazolidinyl, 2-oxo-oxazolidinyl, 2-oxo-1 ,2-dihydropyridinyl, 2- oxo-1 , 2-dihydropyrazinyl, 2-oxo-1 ,2-dihydropyrimidinyl, 3-oxo-2,3- dihydropyhdazinyl, 1 ,2,3,6-tetrahydropyridinyl, perhydroisoquinolinyl, 1 -oxo-1 , 2- dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazolinyl, 5-aza-bicyclo[2.1.1 ]hexanyl, 2- aza-bicyclo[2.2.1]heptanyl, 6-aza-bicyclo[3.2.1]octanyl, octahydro-pyrrolo[1 ,2- a]pyrazinyl, 2/-/-spiro[benzofuran-3,4'-pipehdinyl], 3/-/-spiro[isobenzofuran-1 ,4'- piperidinyl], 2,8-diazaspiro[4.5]decan-1 -onyl, 2,7-diazaspiro[4.5]decan-1 -onyl, 2- aza-bicyclo[2.2.1]heptan-6-onyl and 6-aza-bicyclo[3.2.1 ]octan-7-onyl

A Cy₅ group refers to a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic rings may be formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they can be formed by two rings bonded through a single common C atom forming a spiro ring. Cy₅ is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C or N atoms. In Cy₅ one or more C or S atoms of a saturated or partially unsaturated ring are optionally oxidized forming CO, SO or SO₂ groups. Cy₅ is optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, said substituents can be the same or different and can be placed on any available position of the ring system. Examples of Cy₅ include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopipehdinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo- piperazinyl, 2-oxo-1 ,2-dihydropyridinyl, 2-oxo-1 ,2-dihydropyrazinyl, 2-oxo-1 ,2- dihydropyrimidinyl, 3-oxo-2,3-dihydropyridazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1 ,2,3- triazolyl, 1 ,2,4-triazolyl, tetrazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzooxazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, cinolinyl, naphthyridinyl, indazolyl, imidazopyridinyl, pyrrolopyridinyl, thienopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzo[1 ,3]dioxolyl, phtalimidyl, 1 -oxo-1 ,3-dihydroisobenzofuranyl, 1 ,3-dioxo-1 ,3- dihydroisobenzofuranyl, 2-oxo-2,3-dihydro-1 /-/-indolyl, 1 -oxo-2,3-dihydro-1 H- isoindolyl, perhydroquinolinyl, 1 -oxo-perhydroisoquinolinyl, 1 -oxo-1 ,2- dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazolinyl, 2-aza-bicyclo[2.2.1 ]heptanyl, 5-aza-bicyclo[2.1.1 ]hexanyl, 2/-/-spiro[benzofuran-3,4'-piperidinyl], 3H- spiro[isobenzofuran-1 ,4'-piperidinyl], 1 -oxo-2,8-diazaspiro[4.5]decanyl and 1 -oxo- 2,7-diazaspiro[4.5]decanyl. In the above definitions of Cy₃ and Cy₅ when the examples listed refer to a bicycle in general terms, all possible dispositions of the atoms are included. Thus, for example, the term pyrazolopyridinyl can include groups such as 1 H- pyrazolo[3,4-£>]pyridinyl, 1 H-pyrazolo[1 ,5-a]pyridinyl, 1 H-pyrazolo[3,4-c]pyridinyl, 1 H-pyrazolo[4,3-c]pyridinyl and 1 H-pyrazolo[4,3-£>]pyridinyl, the term imidazopyrazinyl can include groups such as 1 H-imidazo[4,5-£>]pyrazinyl, imidazo[1 ,2-a]pyrazinyl and imidazo[1 ,5-a]pyrazinyl and the term pyrazolopyrimidinyl can include groups such as 1 H-pyrazolo[3,4-c/]pyhmidinyl, 1 H- pyrazolo[4,3-<3]pyrimidinyl, pyrazolo[1 ,5-a]pyrimidinyl and pyrazolo[1 ,5- c]pyrimidinyl. When in the definitions used throughout the present specification for cyclic groups the examples given refer to a radical of a ring in general terms, for example pyridyl, thienyl or indolyl, all the available bonding positions are included, unless a limitation is indicated in the corresponding definition for said cyclic group, for example that the ring is bonded through a C atom in Cy₂ and Cy₃, in which case such limitation applies. Thus for example, in the definitions of Cyi and Cy₅, which do not include any limitation regarding the bonding position, the term piperidinyl includes 1 -piperidinyl, 2-pipehdinyl, 3-piperidinyl and 4-pipehdinyl; and pyrrolidinyl includes 1 -pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.

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 , 2 or 3 substituents, and still more preferably with 1 or 2 substituents, provided that said group has enough positions susceptible of being substituted. The substituents can be the same or different and can be placed on any available position.

When a non-aromatic ring is present as a substituent of a non-aromatic ring, it can replace one hydrogen atom, or it can replace two hydrogen atoms on the same C atom thus forming a spiro ring. Likewise, when a non-aromatic ring is present as a substituent of an alkyl group, it can either replace one hydrogen atom, or it can replace two hydrogen atoms and share one C atom of said alkylgroup, forming groups such as the ones shown below:

When in the definition of a substituent two or more groups with the same numbering are indicated (e.g. -CONR₄R₄, -NRi₄Ri₄, -NR₆CONRi₆Ri₆, etc.), this does not mean that they must be the same. Each of them is independently selected from the list of possible meanings given for said group, and therefore they can be the same or different.

For the sake of clarity, throughout the present specification, the presence or absence of the term "independently selected from" or "independently represents" in a definition of a group or particular embodiment should not be considered as imposing any restrictions into said definition. All terms should be given their broadest possible meaning within the definition provided, which means that unless the contrary is explicitly mentioned, no limitation that two groups should be identical should be read into any definition of any term.

Throughout the present specification, by the term "treatment" is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).

As used herein, "prevention" refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also preventing the recurrence of a disease in a subject that has previously suffered said disease.

The invention thus relates to the compounds of formula I as defined above. In another embodiment, the invention relates to the compounds of formula I wherein Ri represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, R₇-C_1-4alkyl, halogen, -CN, -CONR₄R₄, -CO₂R₅, -OR₄ or -NR₆COR₄. In another embodiment, the invention relates to the compounds of formula I wherein Ri represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, R₇-C-ι-₄alkyl, halogen or -CN.

In another embodiment, the invention relates to the compounds of formula I wherein Ri represents hydrogen or -CN. In another embodiment, the invention relates to the compounds of formula I wherein Ri represents hydrogen.

In another embodiment, the invention relates to the compounds of formula I wherein Ri represents-CN.

In another embodiment, the invention relates to the compounds of formula I wherein R₇ in Ri represents -CN, -CONR₄R₄, -CO₂Rs, -OR₄ or -NR₆COR₄.

In another embodiment, the invention relates to the compounds of formula I wherein:

R₂ represents hydrogen, C-i-₄alkyl, haloC-i-₄alkyl, hydroxyCi_-4alkyl, R₇-C-i_-4alkyl or Cy₂, wherein Cy₂ is optionally substituted with one or more R₈; and R₃ represents C-|.₄alkyl, haloC-|.₄alkyl, hydroxyC-|.₄alkyl, R-ιrCi-₄alkyl,

-CONR₉R₉, -COR10, -CO₂Ri₀, -SO₂Ri₀, -SO₂NR₉R₉ or Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents hydrogen, Ci_-4alkyl, haloC-|.₄alkyl, hydroxyC-ι-₄alkyl or R₇- C_1-4alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents hydrogen, Ci_-4alkyl, haloC-i-₄alkyl or hydroxyCi_-4alkyl. In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents hydroxyCi_-4alkyl, Rn-Ci_-4alkyl or Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents a 3- to 7-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups, and wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups, and wherein Cy₃ is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents cyclohexyl, 2-pipehdinyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents cyclohexyl or 3-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents cyclohexyl, which is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents 3-piperidinyl, which is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃ represents 4-piperidinyl, which is optionally substituted with one or more Ri₂.

R₃ represents Cy₃; and Cy₃ represents a group of formula Cy_3a or Cy_3b:

Cy₃₃ Cy_3b wherein Ri_2a represents -CORi₅; and wherein additionally Cy_3a and Cy_3b are independently optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents Cy₃; and

Cy₃ represents a group of formula Cy_3a or Cy₃I₃; wherein Ri_2a represents

wherein additionally Cy_3a and Cy_3b are independently optionally substituted with one or more Ri₂ groups independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and Rn-Ci_-4alkyl.

R₃ represents Cy₃;

wherein additionally Cy_3a and Cy₃b are independently optionally substituted with one or more Ri₂ groups independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and Rn-Ci_-4alkyl; Ri₄ represents hydrogen; and

Ri5 represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents Cy₃; y

Cy₃ represents a group of formula Cy_3a or Cy₃I₃; wherein Ri_2a represents -

R₃ represents Cy₃;

Cy₃ represents a group of formula Cy_3a or Cy_3b; wherein Ri_2a represents

Ri₄ represents hydrogen; and

Ri₅ represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl.

R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; and wherein additionally Cy_3a is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein: R₃ represents Cy₃;

Cy₃ represents a group of formula Cy₃I₃; and wherein additionally Cy₃I₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents Cy₃; and

Cy₃ represents a group of formula Cy_3a; wherein R_12a represents -CORi₅. In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents Cy₃; and

Cy₃ represents a group of formula Cy₃b.

R₃ represents Cy₃;

Cy₃ represents a group of formula Cy_3a; wherein R-ι_2a represents -CORi₅; and

Ri₅ represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents hydrogen or -CN; and

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇-Ci- ₄alkyl. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN; and

Ri represents hydrogen or -CN; and

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl or hydroxyCi_-4alkyl.

Ri represents -CN; and

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl or hydroxyCi_-4alkyl.

Ri represents hydrogen or -CN; and

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN; and

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN; and

R₃ represents Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂.

In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents -CN ; and

In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇-Ci- ₄alkyl; and

R₃ represents Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇- Ci_-4alkyl; and R₃ represents Cy₃, wherein Cy₃ is optionally substituted with one or more

Ri₂.

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; and

R₃ represents Cy₃, wherein Cy₃ is optionally substituted with one or more

Ri represents -CN;

R₃ represents Cy₃, wherein Cy₃ is optionally substituted with one or more

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇-Ci- ₄alkyl;

R₃ represents Cy₃, and

Cy₃ represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups, wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇-Ci- ₄alkyl; R₃ represents Cy₃; and

Cy₃ represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups, and wherein Cy₃ is optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; and

Cy₃ represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups, and wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₂ represents hydrogen or C_1-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; and Cy₃ represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups, and wherein Cy₃ is optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN;

R₃ represents Cy₃; and

Cy₃ represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₃ represents Cy₃; and

Cy₃ represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN;

Ri represents -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇- Ci_-4alkyl;

R₃ represents Cy₃; and

Cy₃ represents cyclohexyl, optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇- C_1-4alkyl ;

R₃ represents Cy₃; and

Ri represents hydrogen or -CN;

Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; and Cy₃ represents cyclohexyl, wherein Cy₃ is optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN; R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇-

Ci_-4alkyl;

R₃ represents Cy₃; and

Cy₃ represents 3-piperidinyl or 4-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

Cy₃ represents 3-piperidinyl or 4-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; and Cy₃ represents 3-piperidinyl or 4-pipehdinyl, wherein Cy₃ is optionally substituted with one or more Ri₂.

Ri represents -CN; R₂ represents hydrogen or C_1-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃; and

Ri represents hydrogen or -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, or R₇- Ci_-4alkyl;

R₃ represents Cy₃; and Cy₃ represents 3-piperidinyl, optionally substituted with one or more Ri₂.

Ri represents -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, or R₇-Ci- ₄alkyl;

R₃ represents Cy₃; and

Cy₃ represents 3-piperidinyl, optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃; and

Cy₃ represents 3-piperidinyl, optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

Ri represents hydrogen or -CN, preferably -CN; R₂ represents hydrogen or C_1-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃; and

Cy₃ represents a group of formula Cy_3a or Cy₃I₃; wherein Ri_2a represents -CONRi₄Ri₄, -CORi5, -CO₂Ri₅, -SO₂Ri₅, -SO₂NRi₄Ri₄ or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; and wherein additionally Cy_3a and Cy_3b are independently optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN, preferably -CN; R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃; and

Cy₃ represents a group of formula Cy_3a or Cy_3b; wherein Ri_2a represents

wherein additionally Cy_3a and Cy_3b are independently optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN, preferably -CN;

Cy₃ represents a group of formula Cy_3a or Cy_3b; wherein Ri_2a represents

In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN, preferably -CN;

R₂ represents hydrogen or C_1-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃;

Cy₃ represents a group of formula Cy_3a or Cy_3b; wherein Ri_2a represents

wherein additionally Cy_3a and Cy_3b are independently optionally substituted with one or more Ri₂ groups independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and Rn-Ci_-4alkyl; Ri₄ represents hydrogen; and

Ri represents hydrogen or -CN;

R₂ represents hydrogen or C_1-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a or Cy₃I₃; wherein Ri_2a represents

Ri represents -CN; R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃;

Ri represents hydrogen or -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a or Cy₃b; wherein R_12a represents -COR₁₅;

Ri₄ represents hydrogen; and

R-₁₅ represents C-i-₄alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a or Cy_3b; wherein R_12a represents

Ri₄ represents hydrogen; and

Ri represents hydrogen or -CN, preferably -CN;

R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents

-CONRi₄Ri₄, -CORi₅, -CO₂Ri₅, -SO₂Ri₅, -SO₂NRi₄Ri₄ or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; and wherein additionally Cy_3a is optionally substituted with one or more Ri₂.

Ri represents hydrogen or -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃;

Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CONRi₄Ri₄, -CORi₅, -CO₂Ri₅, -SO₂Ri₅, -SO₂NRi₄Ri₄ or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; and wherein additionally Cy_3a is optionally substituted with one or more Ri₂.

Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents

-CONR₁₄R₁₄, -COR₁₅, -CO₂R₁₅, -SO₂R₁₅, -SO₂NR₁₄R₁₄ or Cy₅, wherein Cy₅ is optionally substituted with one or more R₁₃; and wherein additionally Cy_3a is optionally substituted with one or more R₁₂.

R₁ represents hydrogen or -CN, preferably -CN;

R₂ represents hydrogen, C_1-4alkyl, haloC_1-4alkyl, hydroxyC_1-4alkyl, or R₇-C_1- ₄alkyl;

R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein R_12a represents

-CONR₁₄R₁₄, -COR₁₅, -CO₂R₁₅, -SO₂R₁₅, -SO₂NR₁₄R₁₄ or Cy₅, wherein Cy₅ is optionally substituted with one or more R₁₃; and wherein additionally Cy_3a is optionally substituted with one or more R₁₂ groups independently selected from C_1-4alkyl, haloC_1-4alkyl, hyd TOXyC_{1 -4}alkyl and R₁₁-C_1- ₄alkyl.

R₁ represents hydrogen or -CN;

Cy₃ represents a group of formula Cy_3a; wherein R_12a represents -CONR₁₄R₁₄, -COR₁₅, -CO₂R₁₅, -SO₂R₁₅, -SO₂NR₁₄R₁₄ or Cy₅, wherein Cy₅ is optionally substituted with one or more R₁₃; and wherein additionally Cy_3a is optionally substituted with one or more R₁₂ groups independently selected from C_1-4alkyl, haloC_1-4alkyl, hyd TOXyC_{1 -4}alkyl and R₁₁-C_1- ₄alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents -CN;

Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CONR₁₄R₁₄, -COR₁₅, -CO₂R₁₅, -SO₂R₁₅, -SO₂NR₁₄R₁₄ or Cy₅, wherein Cy₅ is optionally substituted with one or more R₁₃; and wherein additionally Cy_3a is optionally substituted with one or more R₁₂ groups independently selected from C_1-4alkyl, haloC_1-4alkyl, hyd TOXyC_{1 -4}alkyl and R₁₁-C_1- ₄alkyl. In another embodiment, the invention relates to the compounds of formula I wherein:

R₁ represents hydrogen or -CN, preferably -CN;

R₂ represents hydrogen, C_1-4alkyl, haloC_1-4alkyl, hydroxyC_1-4alkyl or R₇-C_1- ₄alkyl; R₃ represents Cy₃;

Cy₃ represents a group of formula Cy_3a; wherein R_12a represents -COR₁₅; and wherein additionally Cy_3a is optionally substituted with one or more R₁₂.

R₁ represents hydrogen or -CN, preferably -CN;

R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein R_12a represents -COR₁₅; and wherein additionally Cy_3a is optionally substituted with one or more R₁₂ groups independently selected from C_1-4alkyl, haloC_1-4alkyl, hyd TOXyC_{1 -4}alkyl and R₁₁-C_1- ₄alkyl. In another embodiment, the invention relates to the compounds of formula I wherein:

R₁ represents hydrogen or -CN;

Cy₃ represents a group of formula Cy_3a; wherein R_12a represents -CORi₅; and wherein additionally Cy_3a is optionally substituted with one or more Ri₂. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; and wherein additionally Cy_3a is optionally substituted with one or more Ri₂.

Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; and wherein additionally Cy_3a is optionally substituted with one or more Ri₂ groups independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and Rn-Ci- ₄alkyl.

Ri represents hydrogen or -CN, preferably -CN;

R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, or R₇-Ci- ₄alkyl; R₃ represents Cy₃;

Cy₃ represents a group of formula Cy_3a; wherein R_12a represents -CORi₅; wherein additionally Cy_3a is optionally substituted with one or more Ri₂; and Ri5 represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents hydrogen or -CN, preferably -CN;

R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; wherein additionally Cy_3a is optionally substituted with one or more Ri₂ groups independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and Rn-Ci- ₄alkyl; and

Ri represents hydrogen or -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; wherein additionally Cy_3a is optionally substituted with one or more Ri₂; and Ri₅ represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃;

Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; wherein additionally Cy_3a is optionally substituted with one or more Ri₂; and R-₁₅ represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;

Cy₃ represents a group of formula Cy_3a; wherein R-ι_2a represents -CORi₅; wherein additionally Cy_3a is optionally substituted with one or more Ri₂ groups independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and Rn-Ci- ₄alkyl; and

Ri5 represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents -CN;

Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; wherein additionally Cy_3a is optionally substituted with one or more Ri₂ groups independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and Rii-Ci- ₄alkyl; and

Ri₅ represents Ci_-4alkyl or cyanoCi_-4alkyl, preferably cyanomethyl. In another embodiment, the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;

R₂ represents hydrogen or C_1-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; and

Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃; and Cy₃ represents a group of formula Cy_3a; wherein R_12a represents -CORi₅. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents hydrogen or -CN; R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl;

R₃ represents Cy₃;

Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; Cy₃ represents a group of formula Cy_3a; wherein Ri_2a represents -CORi₅; and

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; and Cy₃ represents a group of formula Cy_3b.

Ri represents -CN;

R₂ represents hydrogen or Ci_-4alkyl, preferably hydrogen, methyl or ethyl; R₃ represents Cy₃; and Cy₃ represents a group of formula Cy₃b. In another embodiment, the invention relates to the compounds of formula I wherein:

Ri represents hydrogen or -CN;

Cy₃ represents a group of formula Cy_3b; and Ri₄ represents hydrogen.

Ri represents -CN;

Cy₃ represents a group of formula Cy_3b; and Ri₄ represents hydrogen.

Furthermore, the present invention covers all possible combinations of the particular and preferred embodiments described above.

In another embodiment, the invention relates to a compound of formula I or a salt thereof selected from the list of compounds described in the examples 1 to 16.

In another embodiment, the invention relates to a compound of formula I selected from:

^rans-5-cyano-3-[6-(4-hydroxycyclohexylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyhdine, ^rans-5-cyano-3-[6-(4-hydroxycyclohexyl-Λ/-methylamino)pyhdin-2-yl]pyrazolo[1 ,5- a]pyridine, frans-5-cyano-3-[6-(Λ/-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2- yl]pyrazolo[1 ,5-a]pyridine,

5-cyano-3-[6-(piperidin-4-ylamino)pyhdin-2-yl]pyrazolo[1 ,5-a]pyhdine, 5-cyano-3-[6-(methyl(pipehdin-4-yl)amino)pyridin-2-yl]pyrazolo[1 ,5-a]pyhdine, 5-cyano-3-[6-(1 -(2-cyanoacetyl)piperidin-3-ylamino)pyhdin-2-yl]pyrazolo[1 ,5- a]pyridine,

(f?)-5-cyano-3-[6-(1 -(2-cyanoacetyl)pipehdin-3-ylamino)pyhdin-2-yl]pyrazolo[1 ,5- a]pyhdine, and

(f?)-5-cyano-3-[6-(Λ/-methyl-1 -(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2- yl]pyrazolo[1 ,5-a]pyridine, or a salt thereof.

In another embodiment, the invention relates to a compound of formula I selected from: ^ans-5-cyano-3-[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine,

^rans-5-cyano-3-[6-(N-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2- yl]pyrazolo[1 ,5-a]pyridine, 5-cyano-3-[6-(1 -(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine,

(/^:?)-5-cyano-3-[6-(1 -(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine, and (f?)-5-cyano-3-[6-(Λ/-methyl-1 -(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2- yl]pyrazolo[1 ,5-a]pyridine, or a salt thereof.

In another embodiment, the invention relates to a compound of formula I, which provides more than 50% inhibition of JAK3 activity at 10 μM, more preferably at 1 μM and still more preferably at 0.1 μM, in a JAK3 assay such as the one described in example 17.

In an additional embodiment, the invention relates to a compound of formula I, which provides more than 50% inhibition of JAK2 activity at 10 μM, more preferably at 1 μM, and still more preferably at 0.5 μM, in a JAK2 assay such as the one described in example 18. The compounds of the present invention 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, thfluoromethanesulfonic 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 judgment, 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. The compounds of formula I may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I, including all polymorphic forms ("polymorphs") thereof, 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 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 with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see for example Greene T.W. and Wuts P. G. M, "Protecting Groups in Organic Synthesis", John Wiley & Sons, 3^rd edition, 1999). As an example, as protecting group of an amino function the fe/t-butoxycarbonyl (BOC) group can be used. Whenever a protecting 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 different substituents are the meanings described above with regard to a compound of formula I.

In general, compounds of formula I can be obtained by the method described in Scheme 1 :

I

Scheme 1 wherein R₁, R₂ and R₃ have the meaning previously described in relation with a compound of formula I; X represents halogen; and A represents iodine, 2,4- dinitrophenolate, p-toluensulphonate or 2,4,6-trimethylbencenosulphonate.

Step a may be carried out by the reaction of a compound of formula Il with aminosulfonic acid in the presence of a HI aqueous solution; and of a base such as K₂CO₃, NaOH or KOH; in a solvent such as dichloromethane, tetrahydrofurane, water, ethanol, methanol, isopropanol or acetonithle; and heating preferably at reflux to obtain a compound of formula III.

Alternatively, step a may be carried out by the reaction of a compound of formula Il with 2,4-dinitrophenylhydroxylamine, o-(p-toluensulfonyl)hydroxylamine, or o-(mesitylsulfonyl)hydroxylamine (obtained in situ from methyl N- mesitylsulfonyloxyacetimidate in the presence of a 70% HCIO₄ aqueous solution; in a solvent such as dioxane; and cooling preferably at -5 ⁵C); in the presence of a solvent such as dichloromethane; and heating preferably from O ⁵C to room temperature to obtain a compound of formula III. In step b the reaction of a compound of formula III with ethyl propiolate may be carried out under O₂ atmposphere; in the presence of a base such as K₂CO₃,

NaOH or KOH; in a solvent such as N,N-dimethylformamide, dimethylsulfoxide, dichloromethane or toluene; and at room temperature to obtain a compound of formula IV.

Step c may be carried out by the reaction of a compound of formula IV with an acid such as H₂SO₄, polyphosphohc acid, HCI, HBr, or HI and water in 1 :1 proportion, heating preferably between 120 ⁵C and 50 ⁵C to obtain a compound of formula V. Step d may be carried out by the reaction of a compound of formula V with

N-bromosuccinimide (NBS) in the presence of benzoyl peroxide or azobisisobutyronitrile (AIBN); and of a solvent such as dichloromethane or carbon tetrachloride; and at room temperature to obtain a compound of formula Vl.

In step e the reaction between a compound of formula Vl with a compound of formula VII may be carried out using the conditions described in the literature for Suzuki's coupling reactions. For example, the reaction may be carried out in the presence of a Pd catalyst such as Pd(PPh₃)₄; in the presence of a base such as K₂CO₃; in a mixture of solvents such as a dimethoxyethane and water; and heating preferably at 85 ⁵C to obtain a compound of formula VIII. When X represents fluorine, step f may be carried out by the reaction of a compound of formula VIII with an amine of formula IX in the presence of a base such as diisopropylethylamine, thethylamine or K₂CO₃, in a solvent such as N- methylpyrrolidone, N,N-dimethylformamide, dimethylsulfoxide, dimethylamide or pyridine, and heating preferably at 190 ⁵C to obtain a compound of formula I. When X represents chlorine, bromine or iodine, step f may be carried out by the reaction of a compound of formula VIII with an amine of formula IX using the conditions described in the literature for Buchwald's coupling reactions. For example, the reaction may be carried out in the presence of a Pd catalyst such as Pd₂(dba)₃, and of a phosphine such as 2-dicyclohexylphosphino-2',4',6'- thisopropyl-biphenyl (X-Phos^®), in the presence of a base such as K₂CO₃, in a solvent such as fe/t-butanol, and heating preferably at 100 ⁵C to obtain a compound of formula I. Alternatively, a compound of formula VIII can be obtained by the method described in Scheme 2:

Scheme 2 wherein Ri has the meaning previously described in relation with a compound of formula I; X represents halogen; and A represents iodine, 2,4-dinitrophenolate, p- toluensulphonate or 2,4,6-thmethylbencenosulphonate.

In step a of scheme 2 the reaction of a compound of formula X with thmethylsilylacetilene may be carried out using the conditions described in the literature for Sonogashira's coupling reactions. For example, the reaction may be carried out in the presence of a Pd catalyst such as Pd(PPh₃)₄, of CuI, and of a base such as isopropylamine, and at room temperature to obtain a compound of formula Xl after the thmethylsilyl group deprotection in the conditions described in the literature for deprotection reactions of silyl groups.

In step b the reaction of a compound of formula Xl with a compound of formula III may be carried out in the presence of a base such as 1 ,8- diazabicyclo[5.4.0]undec-7-ene, K₂CO₃, diisopropylethylamine, thethylamine, KOH, Cs₂CO₃, potassium tert-butoxide in a solvent such as acetonithle, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, ethanol or dimethylsulfoxide, at room temperature or heating preferably between 40 ⁵C and 80 ⁵C to obtain a compound of formula VIII.

Alternatively, a compound of formula I can be obtained by the method described in Scheme 3:

wherein R₁, R₂ and R₃ have the meaning previously described in relation with a compound of formula I; and X represents halogen.

In step a of scheme 3 the reaction of a compound of formula VIII with diphenylmethanimine may be carried out using the conditions described in the literature for Buchwald's coupling reactions. For example, the reaction may be carried out in the presence of a Pd catalyst such Pd₂(dba)₃; of a phosphine such as 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP); and of a base such as sodium fe/t-butoxide; in a solvent such as toluene; and heating preferably at reflux to obtain, after an acidic hydrolysis step in the presence of an acid such as HCI, an amine of formula XII.

Finally, in step b an amine of formula XII is converted into a compound of formula I in one or several steps using conversion reactions of amino groups well- known in organic chemistry under the standard experimental conditions. For a compound of formula I wherein R₂ is different than hydrogen, step b should be carried out two times. Said transformations include, for example: the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e. by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium cyanoborohydhde or sodium thacetoxyborohydride; the conversion of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of catalytic amounts of a base such as 4-dimethylaminopyhdine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as thethylamine or pyridine; the conversion of an amine into an amide, carbamate or urea under standard conditions.

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 standard experimental conditions. Said transformations can be carried out upon R-i, R₂ or R₃ groups and include, for example: the reduction of a nitro group to give an amino group, for example by treatment with hydrogen, hydrazine or formic acid in the presence of a suitable catalyst such as Pd/C; or by treatment with sodium borohydride in the presence of NiCI₂, Or SnCI₂; the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e. by treatment with an aldehyde or a ketone in the presence of a reducing agent such as sodium cyanoborohydhde or sodium thacetoxyborohydride; the conversion of an amine into a sulfonamide by reaction with a sulfonyl halide, such as sulfonyl chloride, optionally in the presence of catalytic amounts of a base such as 4-dimethylaminopyhdine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as thethylamine or pyridine; the conversion of an amine into an amide, carbamate or urea under standard conditions; the alkylation of an amide by treatment with an alkylating agent under basic conditions; the conversion of an alcohol into an ether, ester or carbamate under standard conditions; the partial or total oxidation of an alcohol to give ketones, aldehydes or carboxylic acids under standard oxidizing conditions; the reduction of an aldehyde or a ketone to an alcohol by treatment with a reducing agent such as sodium borohydride; the reduction of a carboxylic acid or a carboxylic acid derivative to an alcohol by treatment with a reducing agent such as diisobutylaluminium hydride or LiAIH₄; the conversion of an alcohol into a halogen by reaction with SOCI₂, PBr₃, tetrabutylammonium bromide in the presence of P₂O₅ or Pl₃; the conversion of a halogen atom into an amine by reaction with an amine, optionally in the presence of a suitable solvent, and preferably heating; the conversion of a primary amide into a -CN group or vice versa, under standard conditions.

Likewise, any of the aromatic rings of the compounds of the present invention can undergo electrophilic aromatic substitution reactions or nucleophilic aromatic substitution reactions, widely described in the literature. 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.

The compounds of formula Il and X are commercially available or can be prepared by well-known methods described in the literature starting from commercially available compounds using interconversion reactions such those described above for a compound of formula I, and can be protected with suitable protecting groups.

As mentioned above, the compounds of the present invention act by inhibiting JAK/STAT signaling pathways, particularly by inhibiting JAK3 activity.

Therefore, the compounds of the invention are expected to be useful to treat or prevent diseases in which JAKs, particularly JAK3, play a role in mammals, including human beings. These diseases include, but are not limited to, transplant rejection; immune, autoimmune and inflammatory diseases; neurodegenerative diseases; and proliferative disorders (see e.g. O'Shea J.J. et al, Nat. Rev. Drug.

Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004,

10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).

Acute or chronic transplant rejection reactions that can be treated or prevented with the compounds of the present invention include any kind of cell, tissue or organ xenotransplants or allografts, such as of heart, lung, liver, kidney, pancreas, uterus, joints, pancreatic islets, bone marrow, limbs, cornea, skin, hepatocytes, pancreatic beta cells, pluhpotential cells, neuronal cells and myocardial cells, as well as graft-versus-host reactions (see e.g. Rousvoal G. et al, Transpl. Int. 2006, 19(12):1014-21 ; Borie DC. et al, Transplantation 2005,

79(7):791 -801 ; Paniagua R. et al, Transplantation 2005, 80(9):1283-92; Higuchi T. et al, J. Heart Lung Transplant. 2005, 24(10):1557-64; Saemann MD. et al, Transpl Int. 2004, 17(9):481 -89; Silva Jr HT. et al, Drugs 2006, 66(13):1665-1684).

Immune, autoimmune and inflammatory diseases that can be treated or prevented with the compounds of the present invention include among others, rheumatic diseases (e.g. rheumatoid arthritis and psoriatic arthritis), autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis and inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), scleroderma, type I diabetes and complications from diabetes, type B hepatitis, type C hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, suppression of HIV replication, infertility of autoimmune origin, autoimmune thyroid disease (Grave's disease), interstitial cystitis, and mast cell- mediated allergic reactions such as asthma, angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis (see e.g. Sorbera LA. et al, Drugs of the Future 2007, 32(8):674-680; O'Shea J.J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Muller-Ladner U. et al, J. Immunol. 2000, 164(7): 3894-3901 ; Walker JG. et al, Ann. Rheum. Dis. 2006, 65(2):149-56; Milici AJ. et al, Arthritis Rheum .2006, 54 (9, Suppl): abstr 789; Kremer JM. et al, Arthritis Rheum. 2006, 54, 41 16, presentation no. L40; Cetkovic-Cvrlje M. et al, Arch Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82; Malaviya R. et al, J. Pharmacol. Exp. Ther. 2000, 295(3):912-26; Malaviya R. et al, J. Biol. Chem. 1999, 274(38):27028-38; Wilkinson B et al, Ann. Rheum. Dis. 2007, 66(Suppl 2): Abst. THU0099; Matsumoto M. et al, J. Immunol. 1999, 162(2):1056- 63).

Neurodegenerative diseases that can be treated or prevented with the compounds of the present invention include, among others, amyotrophic lateral sclerosis and Alzheimer's disease (see e.g. Trieu VN. et al, Biochem. Biophys. Res. Commun. 2000, 267(1 ):22-5). Proliferative disorders that can be treated or prevented with the compounds of the present invention include, among others, leukemias, lymphomas, glioblastoma multiforme, colon carcinoma, as well as thromboembolic and allergic complications associated with these diseases (see e.g. Sudbeck EA. et al, Clin. Cancer Res. 1999, 5(6):1569-82; Narla RK. et al, Clin. Cancer Res. 1998, 4(10):2463-71 ; Lin Q. et al, Am J. Pathol. 2005, 167(4):969-80; Tibbies HE. et al, J. Biol. Chem. 2001 , 276(21 ):17815-22).

It has been found that certain compounds of formula I, besides inhibiting JAK3 activity, also inhibit JAK2 kinase to varying degrees, and therefore can also be useful for the treatment or prevention of any disease mediated by JAK2 kinase. A group of such JAK2-mediated diseases are myeloproliferative disorders, including polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome (see e.g. Geron I. et al, Cancer cell 2008, 13:321 -330; Pardanani A. et al, Leukemia 2007, 21 (8):1658-68; Mathur A. et al, Biochem Pharmacol 2009, 78(4):382-9; Manshouh T. et al, Cancer Sci. 2008, 99(6):1265-73; Wernig G. et al, Cancer cell 2008, 13(4):31 1 -20. Elizabeth O. et al, Blood, 11 1 (12: 5663-5671 ).

Compounds of formula I that have been found to be particularly useful as JAK2 inhibitors include compounds of examples 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15. These compoundsthus can also be particularly useful, in addition to treating or preventing all the diseases mentioned in the preceding paragraphs, for the treatment or prevention of myeloproliferative disorders (MPD).

Thus, another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1v, 2p, 9b, 1 1 , 13, 14 and 15, for use in the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2 is a myeloproliferative disorder.

Another aspect of the present invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15, for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2 is a myeloproliferative disorder.

Another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15, for use in the treatment or prevention of a myeloproliferative disorder. In a preferred embodiment, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome.

Another aspect of the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1 v, 2p, 9b, 11 , 13, 14 and 15, for the manufacture of a medicament for the treatment or prevention of a myeloproliferative disorder. In a preferred embodiment, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome.

Biological assays that can be used to determine the ability of a compound to inhibit JAKs, particularly JAK3 and JAK2, are well known in the art. For example, a compound to be tested can be incubated in the presence of JAK3 or JAK2 to determine whether inhibition of JAK3 or JAK2 enzymatic activity occurs, as described in the assays of examples 17 and 18, respectively. Other in vitro useful assays that can be used to measure JAK3-inhibitory activity include cellular assays, for example IL-2-induced proliferation of human T lymphocytes. The immunosuppressive activity of the compounds of the invention can be tested using standard in vivo animal models for immune and autoimmune diseases, which are well known in the art. For example, the following assays can be used: delayed- type hypersensitivity (DTH) (see e.g. the method disclosed in Kudlacz E. et al, Am J. Transplant. 2004, 4(1 ):51 -7, the contents of which are incorporated herein by reference), rheumatoid arthritis models such as collagen-induced arthritis (see e.g. the method disclosed in the assay of Holmdahl R et al, APMIS, 1989, 97(7):575- 84, the contents of which are incorporated herein by reference), multiple sclerosis models such as experimental autoimmune encephalomyelitis (EAE) (see e.g. the method disclosed in Gonzalez-Rey et al, Am. J. Pathol. 2006, 168(4): 1 179-88, the contents of which are incorporated herein by reference) and transplant rejection models (see e.g. the various animal models disclosed in the references listed above in relation to the treatment of transplant rejection, incorporated herein by reference). Biological assays that can be used to determine the toxicity profile of the compounds of the invention are well known in the art. Several in vitro toxicity assays can be carried on such as a viability panel in different cell lines (e.g. HepG2).

For selecting active compounds against JAK3, testing at 10 μM must result in an activity of more than 50% inhibition of JAK3 activity in the test provided in example 17. More preferably, when tested in this assay 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.

For selecting active compounds for JAK2, testing at 10 μM must result in an activity of more than 50% inhibition of JAK2 activity in the test provided in example

18. More preferably, when tested in this assay compounds should exhibit more than 50% inhibition at 1 μM, and still more preferably, they should exhibit more than 50% inhibition at 0.5 μM.

The present invention also relates to a pharmaceutical composition that 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 addition 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, flavoring 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, flavoring 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 glycehdes, 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 or prevention 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 following examples illustrate the scope of the invention.

Examples

The following abbreviations have been used in the examples:

AcN: acetonitrile

BINAP: 2,2'-bis(diphenylfosfine)-1 ,1 '-binaphthyl

DBU: 1 ,8-diazabyciclo[5.4.0]undec-7-ene

DME: 1 ,2-dimethoxyethane

DMF: Λ/,Λ/-dimethylformamide EDC: Λ/-[3-(dimethylamino)propyl]-/V-ethylcarbodiimide

EDIPA: ethyl diisopropylamine

Et₂O: diethyl ether

EtOAc: ethyl acetate

EtOH: ethanol HOBT: 1 -hydroxybenzotriazole

HPLC: high performance liquid chromatography

KO¹Bu: potassium tert-butoxide

LC-MS: liquid chromatography-mass spectroscopy

MeOH: methanol NaO¹Bu: sodium fe/t-butoxide

NMP: N-methylpyrrolidone

Pd₂(dba)₃: ths(dibenzylideneacetone)dipalladium(0)

TBAF: tetrabutylammonium fluoride TEA: triethylamine THF: tetrahydrofuran TMSI: 1 -(trimethylsylyl)imidazole ._R: retention time X-Phos: 2-dicyclohexylphosphino-2',4',6'-thisopropyl-biphenyl

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

Method 1 : Waters Acquity UPLC BEH C18 Column (1.7μm, 2.1 x 50 mm), temperature 40 ⁵C, flow rate: 0.5 mL/min, eluent: AcN(A) / Ammonium bicarbonate 10 mM (B), gradient: 0 min 10% A - 3.75 min 90% A.

Method 2: YMC Column, 3 μm (50 mm x 4.6), temperature: 30 -C, flow rate: 2.6 mL/min, eluent A = H₂O (0.1 % HCOOH) B = AcN (0.1 % HCOOH), gradient: 0 min 5% B; 4.8 min 95% B; 6 min 95% B.

REFERENCE EXAMPLE 1 3-(6-Fluoropyridin-2-yl)pyrazolo[1 ,5-a]pyridine

To a 3-bromopyrazolo[1 ,5-a]pyhdine (2.40 g, 12.17 mmol) solution in DME (54 mL) under argon atmosphere, 6-fluoro-2-pyhdylboronic acid (1.80 g, 12.77 mmol), Pd(PPh₃)₄ (1.40 g, 1.21 mmol) and a solution of K₂CO₃ (3.70 g, 26.8 mmol) in H₂O (7 mL) were added. The resulting mixture was heated at 85 ⁰C for 5 h, cooled and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 1.21 g of the desired compound (47% yield). LC-MS (Method 2): t_R = 3.00 min; m/z = 214 (MH⁺).

REFERENCE EXAMPLE 2 2-Etynyl-6-fluoropyridine

a) 6-Fluoro-2-(trimethylsilyletinyl)pyridine

To a 2-bromo-6-fluoropyridine (5.0 g, 28.4 mmol), Pd(PPh₃)₄ (1.64 g, 1.42 mmol), CuI (0.27 g, 1.42 mmol) and EDIPA (5.3 ml_, 36.9 mmol) solution in toluene (115 ml_) under argon atmosphere, etinyltrimethylsilane (4.0 ml_, 28.4 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. The crude product obtained was filetered over Celite^®. The filtated solution was diluted with a saturated aqueous solution of NH₄CI and extracted three times with CH₂CI₂. The organic layers were dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/ CH₂CI₂ mixtures of increasing polarity as eluent, to afford 5.28 g of the desired compound (96% yield) LC-MS (Method 2): t_R = 3.62 min; m/z = 200 (MH⁺).

b) Title compound

To a solution of the compound obtained in the previous section (5.28 g, 27.3 mmol) in Et₂O (70 ml_ ) at -78 °-C, a 1 M solution of TBAF in THF (7.93 ml_, 7.93 mmol) was slowly added. The mixture was stirred at -78 ⁵C for 1 h. Then, was diluted with EtOAc and washed three times with H₂O. The organic layer was dried over MgSO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/ CH₂CI₂ mixtures of increasing polarity as eluent, to afford 2.34 g of the desired compound (70% yield). LC-MS (Method 2) : t_R = 2.10 min; m/z = 122 (MH⁺).

Following a similar procedure to that described in reference example 2, but using the corresponding starting material, the following compound was obtained:

REFERENCE EXAMPLE 3 5-Cyano-3-(6-fluoropyridin-2-yl)pyrazolo[1 ,5-a]pyridine a) 1-amino-4-cyanopyridinium 2,4,6-Trimethylbencenosulfonato

To a 4-cyanopyridine (0.72 g, 6.97 mmol) solution in CH₂CI₂ (10 ml_), at 0 ⁵C, a solution of o-2,4, 6-trimethylbencenosulfonylhydroxylamine (1.50 g, 6.97 mmol) in CH₂CI₂ (20 ml_) was slowly added. After the addition, the resulting solution was stirred at room temperature for 2 h Et₂O (320 ml_) was added. The precipitated was filtered and dried in a vacuum heater to afford 1.50 g of the desired compound (67% yield). LC-MS (Method 2): t_R = 1.52 min; m/z = 120 (MH⁺).

b) Title compound

To a solution of the compound obtained in the previous section (1.45 g, 4.54 mmol) and the reference example 2 (0.50 g, 4.13 mmol) in AcN (20 ml_ ) at 0 ⁵C, a DBU (1.24 ml_, 8.26 mmol) solution in AcN (7 ml_) was slowly added. The resulting mixture was heated at 50 ⁰C for 18 h. After that, was cooled and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0,48 g of the desired compound (45% yield). LC-MS (Method 2): t_R = 3.03 min; m/z = 239 (MH⁺).

REFERENCE EXAMPLE 4

3-(6-Bromopyridin-2-yl)pyrazolo[1 ,5-a]pyridine

Following a similar procedure to that described in reference example 3 but using 1 -aminopyridinium iodate instead of 1 -amino-4-cyanopyhdinium 2,4,6- thmethylbencenosulfonate, and the reference example 2a instead of the reference example 2, the desired compound was obtained (49 % yield). LC-MS (Method 2): t_R = 3.45 min; m/z = 274 (MH⁺).

REFERENCE EXAMPLE 5 3-Amino-1 -ethoxycarbonylpiperidine

a) 3-(tert-Butoxycarbonylamino)-1 -ethoxycarbonylpiperidine To a 3-te/t-butoxycarbonylaminopiperidine (500 mg, 2.49 mmol) solution in CH₂CI₂ (15 ml_) TEA (1 ,05 ml_, 7,49 mmol) and ethyl chloroformiate (0.48 ml_, 4. ,99 mmol) were added. The resulting mixture was stirred at room temperature for 12 h. After that, was concentrated to dryness, diluted with EtOAc and washed three times with H₂O. The organic layer was dried over Na₂SO₄ and concentrated to dryness, to afford the desired compound in quantitative yield.

b) Title compound

The compound obtained in the previous section and a 4 M solution of HCI in dioxane (8 ml_) were mixed in a flask. The resulting mixture was stirred at room temperature for 2 h and concentrated to dryness. The crude product thus obtained was purified over a SCX-2 column, using MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 379 mg of the desired compound (88% yield). LC-MS (Method 2): t_R = 1.35 min; m/z = 173 (MH⁺).

REFERENCE EXAMPLE 6 frans-4-Ethylaminocyclohexanol

To a solution of frans-4-aminocyclohexanol hydrochloride (250 mg, 1.65 mmol) in MeOH (5 ml_), a solution of KOH (200 mg, 3.56 mmol) and acetic acid (0,25 ml_) in MeOH (5 ml_) was added. After that, acetaldehyde (0.13 ml_, 2.31 mmol) and NaBH₃CN (176 mg, 2,8 mmol) were added. The resulting mixture was stirred at room temperature for 18 h. After that, was concentrated to dryness and diluted with a 4 M solution of HCI in dioxane (5 ml_), the volatil compounds were concentrated to dryness. The crude product obtained was chromatographed was purified over a SCX-2 column, using MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 72 mg of the desired compound (30% yield) LC-MS (Method 2): t_R = 0.535 min; m/z = 144 (MH⁺).

EXAMPLE 1

3-[6-(1-Hydroxymethylcyclopentylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine To a solution of the reference example 1 (40 mg, 0.18 mmol) in NMP (1.5 ml_), 1 - hydroxymethylcyclopentylamine (173 mg, 1.50 mmol) and EDIPA (0.13 ml_, 0.75 mmol) were added. The reaction mixture was heated at 190 ⁰C for 6 days. After cooling, was diluted with EtOAc and washed three times with a NaHCO₃ saturated aqueous solution. The organic layer was dried over MgSO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 30 mg of the title compound (52% yield). LC-MS (Method 2): t_R = 1.77 min; m/z = 309 (MH⁺).

Following a similar procedure to that described in example 1 , but using in each case the corresponding starting materials, the following compounds were obtained:

Following a similar procedure to that described in example 1 , but using reference example 3 instead of reference example 1 and in each case the corresponding starting materials, the following compounds were obtained:

EXAMPLE 2 5-Cyano-3-[6-(4-hydroxybutylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine To a solution of reference example 3 (40 mg, 0.17 mmol) in NMP (1.5 ml_), 4- amino-1 -butanol (45 mg, 0.50 mmol) and EDIPA (0.09 ml_, 0.50 mmol) were added. The reaction mixture was heated at 140 ⁰C for 1 h in a monomode microwave oven (250 W). After cooling, was diluted with EtOAc and washed three times with a NaHCO₃. The organic layer was dried over MgSO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/acetone mixtures of increasing polarity as eluent, to afford 21 mg of the title compound (41 % yield). LC-MS (Method 2): t_R = 2.47 min; m/z = 308 (MH⁺).

The following compounds were obtained following a similar procedure to that described in example 2, but using in each case the corresponding starting materials:

Reaction performed at 1 OO^aC instead of at 14O^aC.

EXAMPLE 3 frans-3-[6-(4-Acetylaminocyclohexylamino)pyridin-2-yl]pyrazolo[1 ,5- ajpyridine

To a solution of example 1 e (65 mg, 0.21 mmol) in DMF (2 ml_), acetic acid (0.013 ml_, 0.23 mmol), EDC (45 mg, 0.023 mmol), HOBT (31 mg, 0.23 mol), and EDIPA (0.074 ml_, 0.42 mmol) were added. The resulting mixture was stirred at room temperature for 18 h. The crude reaction thus obtained was concentrated to dryness, diluted with CH₂CI₂ and washed three times with a NaHCO₃ saturated aqueous solution. The organic layer was dried over MgSO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using CH₂CI₂/MeOH mixtures of increasing polarity as eluent, to afford 34 mg of the title compound (46% yield).

LC-MS (Method 2): t_R = 1.53 min; m/z = 350 (MH⁺).

EXAMPLE 4 frans-3-[6-(4-Metanosulfonylaminocyclohexylamino)pyridin-2- yl]pyrazolo[1 ,5-a] pyridine

To a solution of example 1 e (65 mg, 0.21 mmol) and TEA (0.030 ml_, 0.21 mmol) in DMF (2 ml_) methanesulfonyl chloride (0.017 ml_, 0.21 mmol) was added at 0 ⁵C. The resulting mixture was stirred at 0 ⁵C for 1 h, and after that at room temperature for 18 h. The crude product thus obtained was concentrated to dryness and chromatographed over silica gel using CH₂CVMeOH mixtures of increasing polarity as eluent, to afford 26 mg of the title compound (32% yield). LC-MS (Method 2): t_R = 1.63 min; m/z = 386 (MH⁺).

EXAMPLE 5 3-[6-(3-(2-Oxopyrrolidin-1-yl)phenylamino)pyridin-2-yl]pyrazolo[1,5- ajpyridine

To a solution of reference example 4 (50 mg, 0.18 mmol) in tert-butanol (2 ml_), K₂CO₃ (55 mg, 0.40 mmol), X-Phos (8.70 mg, 0.018 mmol), Pd₂(dba)₃ (8.35 mg, 0.0092 mmol) and 1 -(3-aminophenyl)pyrrolidin-2-one (35 mg, 0.20 mmol) were added at room temperature and under Ar atmosphere. The mixture was heated at 100 -C for 18 h. The reaction crude was diluted with MeOH and filtered over Celite^®. The filtrated solution was concentrated to dryness and chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 49 mg of the title compound (72% yield). LC-MS (Method 2): t_R = 2.73 min; m/z = 370 (MH⁺).

Following a similar procedure to that described in example 5, but using in each case the corresponding starting materials, the following compounds were obtained:

EXAMPLE 6 3-[6-(3-Hydroxyphenyl-Λ/-methylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine

a) 3-[6-(Λ/-Methyl-3-methoxyphenylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine

Following a similar procedure to that described in example 5 but using Λ/-methyl-3- methoxyaniline instead of 1 -(3-aminophenyl)pyrrolidin-2-one, the desired compound was obtained (73% yield). LC-MS (Method 2): t_R = 3.98 min; m/z = 331 (MH⁺).

b) Title compound

To a solution of the compound obtained in the previous section (60 mg, 0.17 mmol) in CHCI₃ (3 ml_), a BBr₃ 1 ,0 M solution in CH₂CI₂ (0.35 ml_, 0.35 mmol) was added. The reaction mixture was heated at a 65 ⁵C for 18 h. The crude of the reaction thus obtained was concentrated to dryness and chromatographed over silica gel using hexane/acetone mixtures of increasing polarity as eluent, affording 43 mg of the title compund (76% yield). LC-MS (Method 2): t_R = 3.07 min; m/z = 317 (MH⁺).

EXAMPLE 7

3-[6-(N-Cyclopropylcarbonylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine

a) 3-[6-(N-Diphenylmethylenamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine

To a solution of reference example 4 (1 18 mg, 0.43 mmol) in toluen (8.6 mL), NaO¹Bu (58 mg, 0.60 mmol), BINAP (21 mg, 0.034 mmol), Pd₂(dba)₃ (15 mg,

0.017 mmol) and benzophenonimine (0.1 1 mL, 0.65 mmol) were added at room teperature and under Ar atmosphere. The reaction mixture was stirred at 85 ⁵C for

7 h. The crude of the reaction thus obtained was concetrated to dryness and chromatographed over silica gel using hexane/EtOAc mixtures of increassing polarity as eluent, affording 130 mg of the desired compound (81 % yield). b) 3-(6-Aminopyridin-2-yl)pyrazolo[1 ,5-a] pyridine

To a solution of the compound obtained in the previous section (130 mg, 0.35 mmol) in MeOH (17 ml_), hydroxylamine hydrochloride (120 mg, 1.73 mmol) and DIPEA (0.302 ml_, 173 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The crude of the reaction was concetrated to dryness and chromatographed over silica gel using hexane/EtOAc mixtures of increassing polarity as eluent, affording 65 mg of the desired compound (89% yield). LC-MS (Method 2): t_R = 1.14 min; m/z = 21 1 (MH⁺).

c) Title compound

To a solution of the compound obtained in the previous section (19 mg, 0.09 mmol) in anhydrous THF (1 ml_), TEA (0.018 ml_, 0.135 mmol) was added, and then the chloride of the cyclopropanoic acid (0.010 ml_, 0.113 mmol) was slowly added at 0 ⁵C. The reaction mixture was stirred at room temperature for 4 days. The crude of the reaction thus obtained was concetrated to dryness and chormatographied over silica gel using CH₂CVMeOH mixtures of increasing polarity as eluent, affording 13 mg of the desired compound (50% yield). LC-MS (Method 2): t_R = 2.73 min; m/z = 279 (MH⁺).

EXAMPLE 8

(S)-3-[6-(1-Phenylethylamino)pyridin-2-yl]-5-hydroxymethylpyrazolo[1 ,5- a]pyridine

a) 1-Amino-4-ethoxycarbonylpyridinium 2,4-dinitrophenolate

To a solution of ethyl isocianate (1 g, 6.62 mmol) in AcN (4.41 mL), O-(2,4- dinitrophenyl)hydroxylamine (1.45 g, 7.28 mmol) was added. The reaction mixture was stirred at 40 ⁵C for 18 h. The crude of the reaction thus obtained was concetrated to dryness and extracted three times with Et₂O (3x15 mL). The solid thus obtained was filtered and dried, affording 1.58 g of the desired compound (58% yield).

b) 5-Ethoxycarbonyl-3-(6-fluoropyridin-2-yl)pyrazolo[1 ,5-a]pyridine Following a similar procedure to that described in section b of reference example 3, but using the compound obtained in previous section instead of 1 -amino-4- cyanopyridinium2,4,6-thmethylbencenosulfonate, the desired compound was obtained (64% yield). LC-MS (Method 2): t_R = 3.48 min; m/z = 286 (MH⁺).

c) δ-Carboxy-S-CΘ-fluoropyridin^-yOpyrazoloIl ,5-a]pyridine

To a solution of the compound obtained in the previous section (50 mg, 0.175 mmol) ina mixture DME/H₂O 2:1 (1.5 ml_), LiOH-H₂O (22 mg, 0.526 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The crude of the reaction thus obtained was diluted with EtOAc and extracted three times with a NaHCO₃. The aqueous layer was acidified to pH=1 with a HCI 1 N aqueous solution, and extracted three times with CH₂CI₂ (3x10 mL). The combined organic layers were dried over Na₂SO₄ and concentrated to dryness, affording 41 mg of the desired compound (91 % yield).

LC-MS (Method 2): t_R = 2.48 min; m/z = 258 (MH⁺).

d) (S)-5-Carboxy-3-[6-(1 -phenylethylamino)pyridin-2-yl]pyrazolo[1 ,5- ajpyridine Following a similar procedure to that described in example 1 , but using the compound obtained in the previous section instead reference example 1 , and (S)- 1 -phenylethylamine instead of 1 -hydroxymethylcyclopentylamine, the desired compound was obtained (100% yield).

e) (SJ-S-CΘ-CI-PhenylethylaminoJpyridin^-yO-S-methoxycarbonylpyrazoloIijS- ajpyridine

To a solution of the compound obtained in the previous section (57 mg, 0.16 mmol) in MeOH (5 mL), SOCI₂ (0.0023 mL, 0.032 mmol) was added. The reaction mixture was stirred The reaction mixture was stirred at room temperature for 18 h. The crude of the reaction thus obtained was concentrated to dryness, diluted with a NaHCO₃ saturated aqueous solution and extracted with CH₂CI₂ (3 x 5 mL). The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated to dryness, affording 28 mg of the desired compound (46% yield). LC-MS (Method 2): t_R = 3.17 min; m/z = 373 (MH⁺).

f) Title compound

To a solution of the compound obtained in the previous section (28 mg, 0.075 mmol) in anhydrous THF (2 ml_), at 0 ⁵C and under Ar atmosphere LiAIH₄ (5 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The crude of the reaction was diluted with EtOAc and washed with a sodium tartrate saturated aqueous solution (3 x 10 mL). The combined organic layers were dried over Na₂SO₄ and the solvent was evaporated to dryness. The crude of the reaction thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, affording 9.5 mg of the title compound (36% yield). LC-MS (Method 2): t_R = 1.90 min; m/z = 345 (MH⁺).

EXAMPLE 9

3-[6-(Piperidin-4-ylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine

a) 3-[6-(1 -Ethoxycarbonylpiperidin-4-ylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine Following a similar procedure to that described in example 1 , but using 1 - ethoxycarbonyl-4-aminopipehdine, the desired compound was obtained (49% yield). LC-MS (Method 2): t_R = 2.00 min; m/z = 366 (MH⁺).

b) Title compound

To a solution of the compound obtained in previous section (127 mg, 0.350 mmol) in EtOH (3 mL) a NaOH 1 N aqueous solution (2 mL) was added and the mixture thus obtained was heated at 100 ⁵C for 18 h. The reaction crude was cooled, concentrated to dryness and chromatographed over silica gel using CH₂CVMeOH mixtures of increasing polarity, obtaining 73 mg of the title compound (70% yield). LC-MS (Method 2): t_R = 1.02 min; m/z = 294 (MH⁺).

Following a similar procedure to that described in example 9, but using in each case the corresponding starting materials, the following compounds were obtained:

(1 ) Before purification, the crude product was acidified with a HCI 4M solution in dioxane (2 ml_). (2) obtained as example 11 section c.

EXAMPLE 10 3-[6-(1-Acetylpiperidin-4-ylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine

To a solution of example 9 (60 mg, 0.204 mmol) in DMF (2 ml_) acetic acid (0.014 ml_, 0.245 mmol), EDC (46 mg, 0.245 mmol), HOBt (33 mg, 0.245 mmol) and EDIPA (0,071 ml_, 0,408 mmol) were added. The mixture thus obtained was stirred at room temperature for 18 h. After that, the solvent was concentrated to dryness and the resulting crude reaction was partioned between CH₂CI₂ and a NaHCO₃ saturated aqueous solution The layers were separated and the aqueous layer was extracted twice with CH₂CI₂. The combined organic layers were dried over MgSO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/acetone mixtures of increasing polarity as eluent, to afford 25 mg of the title compound (37% yield). LC-MS (Method 2): t_R = 1.47 min; m/z = 336.

EXAMPLE 11

S-Cyano-S-IΘ-CmethyKpiperidin-^yOaminoJpyridin^-yllpyrazoloIijS- a]pyridine a) 5-cyano-3-[6-((1-ethoxycarbonyl)piperidin-4-ylamino)pyridin-2- yl]pyrazolo[1 ,5-a]pyridine

Following a similar procedure to that described in example 1 , but using reference example 3 and 4-amino-i -ethoxycarbonylpiperidine, the desired compound was obtained (48 % yield).

b) 5-cyano-3-[6-(N-methyl(1-ethoxycarbonyl)piperidin-4-ylamino)pyridin- 2-yl]pyrazolo[1 ,5-a]pyridine

To a solution of the compound obtained in the previous section (100 mg, 0.25 mmol) in THF (2 ml_), ¹BuOK (116 mg, 0,384 mmol) and MeI (2.27 ml_, 0.64 mmol) were added The reaction mixture was stirred at room temperature for 18 h and concentrated. The crude residue was chromatographed over silica gel using acetone/hexanes mixtures of increasing polarity as eluent to afford 0.022 g of the desired compound (16% yield).

c) Title compound

To a solution of the compound obtained in the previous section (22 mg, 0,054 mmol ) in AcN (2 ml_), TMSI (40 μl_,0,272 mmol) was added. The reaction mixture was stirred at 50 ⁵C for 18 h and concentrated. The crude residue was chromatographed over SCX silica gel to afford 5.8 mg of the title compound (32% yield). LC-MS (Method 2): t_R = 1.60 min; m/z = 332.

EXAMPLE 12 5-Cyano-3-[6-((1 -acetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5- ajpyridine

a) 5-cyano-3-[6-(piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine

Following a similar procedure to that described in example 1 1 section c, but using example 2d as starting material and 4 M HCI solution in dioxane, the desired compound was obtained (65 % yield).

b) Title compound To a solution of the compound obtained in the previous section (20 mg, 0.063 mmol) in DMF (1 ml_), acetic anhydride (12 μl_, 0.126 mmol) and TEA (28μl_, 0.189 mmol) were added The reaction mixture was stirred at room temperature for 18 h and the solvent was concentrated off. It was quenched with a NaHCO₃ saturated aqueous solution and extracted thrice with EtOAc. The combined organic phases were dried over anhydrous Mg₂SO₄, filtered and concentrated. The crude residue was chromatographed over silica gel using acetone/hexanes mixtures of increasing polarity as eluent to afford 20 mg of the title compound (85% yield). LC-MS (Method 2): t_R = 2.52 min; m/z = 361.

EXAMPLE 13

5-Cyano-3-[6-(1-(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine

Following a similar procedure to that described in example 12 section b, but using 2,5-dioxopyrrolidin-1 -yl-2-cyanoacetate, the title compound was obtained (55 % yield).

LC-MS (Method 2): t_R = 2.63 min; m/z = 386.

EXAMPLE 14

(fi)-5-Cyano-3-[6-(1-(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2- yl]pyrazolo[1 ,5-a]pyridine

Following a similar procedure to that described in example 13, but using 3-(F?)- amino-1 -ethoxycarbonylpipehdine as starting material, the title compound was obtained. (62% yield) LC-MS (Method 2): t_R = 2,63 min; m/z = 386.

Following a similar procedure to that described in example 14, but using the corresponding starting material, the following compound was obtained:

EXAMPLE 15

(H)-5-Cyano-3-[6-(/V-methyl-1-(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2- yl]pyrazolo[1 ,5-a] pyridine

a) (fi)-5-Cyano-3-[6-(Λ^methyl-1-(ethoxycarbonyl)piperidin-3-ylamino)pyridin- 2-yl]pyrazolo[1 ,5-a]pyridine

Following a similar procedure to that described in example 2 and in example 1 1 section b, but using 3-(F?)-amino-1 -ethoxycarbonylpipehdine and (f?)-5-cyano-3-[6- (1 -(ethoxycarbonyl)pipehdin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine respectevely as starting material, the desired compound was obtained (99 % yield).

a]pyridine

Following a similar procedure to that described in example 1 1 section c, but using the compound obtained in previous section, the desired compound was obtained.

c) Title compound Following a similar procedure to that described in example 13, but using the compound obtained in previous section, the title compound was obtained (27 % yield). LC-MS (Method 2): t_R = 2.92 min; m/z = 400.

EXAMPLE 16

(S)-5-Cyano-3-[6-(piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine

Following a similar procedure to that described in example 1 1 section c, but using example 2r as starting material, the title compound was obtained (74 % yield). LC-MS (Method 2): t_R = 2.20 min; m/z = 319.

EXAMPLE 17 Inhibition of JAK3 activity

The inhibition of JAK3 kinase activity was determined in 384-well assay microplates using the Z'-Lyte^® Kinase Assay kit-Tyr 6 Peptide, supplied by Invitrogen (Ref: PV4122), following manufacturer instructions.

In a final volume of 10 μL per well, 2.5 μl_ of the product to be tested were incubated dissolved in 4% DMSO (final concentration of the product to be tested, 0.1 -10000 nM), with 0.3 μg/mL of the catalytic domain of human JAK3 (amino acid sequence 281 -1 124), 2 μM of the substrate peptide Z'-Lyte^® Tyr 6 and 4 μM of ATP, all components were dissolved in 50 mm Hepes pH 7.5 buffer, 10 mm of Magnesium chloride (II), 1 mm of EGTA and 0.01 % of Brij^® 35. The reaction was started by adding 4 μM of ATP; after a 1 hour incubation period at 25^QC, 5 μL of development reagent were added to Z'-Lyte^® Tyr 6 and it was incubated for 1 hour at 25^QC. Phosphorylation was then quantified in each well using a Safire2^® fluorescence meter by Tecan.

The compounds of all examples showed more than 50% inhibition of JAK3 activity at 10 μM in this trial. The compounds 1 c, 1 f, 1 m, 1 o, 1 u, 1 v, 2p, 9b, 13, 14 and 15 showed more than 50% inhibition of JAK3 activity at 0.1 μM in this assay.

EXAMPLE 18 Inhibition of JAK2 activity

The inhibition of JAK2 kinase activity was determined in 384-well assay microplates using the Z'-Lyte^® Kinase Assay kit-Tyr 6 Peptide kit, supplied by Invitrogen (Ref: PV4122), following the manufacturer's instructions.

In a final volume of 10 μL per well, 2.5 μL of the product to be tested dissolved in 4% DMSO (final concentration of the product to be tested, 0.1 -10000 nM) was incubated with 0.5 μg/well of the catalytic domain of human JAK2, 2 μM of the substrate peptide Z'-Lyte^® Tyr 6 and 16 μM of ATP; all components were dissolved in 50 mM pH 7.5 Hepes buffer, 10 mM Magnesium chloride (II), 1 mM EGTA and 0.01 % Brij^® 35. The reaction was started by the addition of said 16 μM ATP; after incubation for 1 hour at 25^QC, 5 μl_ of A Z'-Lyte^® Tyr 6 development reagent was added and the mixture was incubated for 1 hour at 25^QC. Phosphorylation was then quantified in each well using a Safire2^® fluorescence microplate reader from Tecan.

The compounds 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15 showed more than 50% inhibition of JAK2 activity at 0.5 μM in this assay.

Claims

1.- A compound of formula I:

I or a salt thereof, wherein:

Ri represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, R₇-Ci_-4alkyl, halogen, -CN, -CONR₄R₄, -COR₅, -CO₂R₅, -OR₄, -SO₂R₅, -SO₂NR₄R₄, -NR₄R₄, -NR₆COR_4, -NR₆CONR₄R₄, -NR₆CO₂R₅, -NR₆SO₂R₅ or Cy-i_, wherein Cyi is optionally substituted with one or more R₈;

R₂ represents hydrogen, C-i-₄alkyl haloC-i-₄alkyl, hydroxyCi_-4alkyl, R₇-C-ι-₄alkyl or Cy₂, wherein Cy₂ is optionally substituted with one or more R₈;

R₃ represents C-i-₄alkyl, haloC-i-₄alkyl, hydroxyCi_-4alkyl, Rn-Ci_-4alkyl, -CONR₉R₉, -COR₁₀, -CO₂R₁₀, -SO₂R₁₀, -SO₂NR₉R₉ or Cy₃, wherein Cy₃ is optionally substituted with one or more R₁₂; or R₂ and R₃ can be bonded completing, together with the N atom, a Cy₄ group, wherein Cy₄ is optionally substituted with one or more R₁₂; each R₄ independently represents hydrogen or R₅; each R₅ independently represents C_1-4alkyl, haloC_1-4alkyl, C₁^aIkOXyC_1- ₄alkyl, hyd TOXyC_{1 -4}alkyl, cyanoC_1-4alkyl, Cy-ι-C_1-4alkyl or Cy₁, wherein Cy₁ is optionally substituted with one or more R₈;

R₆ represents hydrogen or C_1-4alkyl;

R₇ represents -CN, -CONR₄R₄, -COR₅, -CO₂R₅, -OR₄, -SO₂R₅, -SO₂NR₄R₄, -NR₄R₄, -NR₆COR_4, -NR₆CONR₄R₄, -NR₆CO₂R₅, -NR₆SO₂R₅ or Cy₁, wherein Cy₁ is optionally substituted with one or more R₈; each R₈ independently represents C_1-4alkyl, haloC_1-4alkyl, C₁^aIkOXyC_1- ₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, halogen or hydroxyl; each R₉ independently represents hydrogen or R₁₀; each R₁₀ independently represents Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, RirCi-₄alkyl or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; R₁₁ represents halogen, -CN, -CONRi₄Ri₄, -CORi₅, -CO₂Ri₅, -ORi₄,

-OCONRi₄Ri₄, -SO₂Ri₅, -SO₂NRi₄Ri₄, -NRi₄Ri₄, -NR₆CORi_4, -NR₆CONRi₄Ri₄, -NR₆CO₂Ri₅, -NR₆SO₂Ri₅ or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; each Ri₂ independently represents Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl, Rn-Ci-₄alkyl, or Ri₂ represents any of the meanings described for Rn ; each Ri₃ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi- ₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, halogen, -CN, -CONRi₆Ri₆, -CORi₇, - CO₂Ri₇, -OR₁₆, -OCONRi₆Ri₆, -SO₂Ri₇, -SO₂NRi₆Ri₆, -NRi₆Ri₆, -NR₆CORi₆, -NR₆CONRi₆Ri₆, -NR₆CO₂Ri₇ or -NR₆SO₂Ri₇; each Ri₄ independently represents hydrogen or Ri₅; each Ri₅ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi- ₄alkyl, hydroxyCi_-4alkyl, cyanoCi_-4alkyl, Cy₅-Ci_-4alkyl or Cy₅, wherein Cy₅ is optionally substituted with one or more Ri₃; each Ri₆ independently represents hydrogen or Ri₇; each Ri₇ independently represents Ci_-4alkyl, haloCi_-4alkyl, Ci_-4alkoxyCi-

₄alkyl, hydroxyCi_-4alkyl or cyanoCi_-4alkyl;

Cyi represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups;

Cy₂ represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups;

Cy₃ represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms independently selected from N,

S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups;

Cy₅ represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups.

2.- A compound according to claim 1 wherein R₁ represents hydrogen or -CN.

3.- A compound according to claim 2 wherein Ri represents -CN.

4.- A compound according to any of claims 1 to 3 wherein R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl or R₇-Ci _-4alkyl.

5.- A compound according to claim 4 wherein R₂ represents hydrogen, Ci_-4alkyl, haloCi_-4alkyl or hydroxyCi_-4alkyl.

6.- A compound according to claim 5 wherein R₂ represents hydrogen or Ci_-4alkyl.

7.- A compound according to claim 6 wherein R₂ represents hydrogen, methyl or ethyl.

8.- A compound according to claim 7 wherein R₂ represents hydrogen.

9.- A compound according to claim 7 wherein R₂ represents methyl

10.- A compound according to claim 7 wherein R₂ represents ethyl.

11.- A compound according to any of claims 1 to 10 wherein R₃ represents Cy₃, wherein Cy₃ is optionally substituted with one or more Ri₂.

12.- A compound according to claim 1 1 wherein Cy₃ represents a 5- or 6- membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more

C or S ring atoms are optionally oxidized forming CO, SO or SO₂ groups, wherein

Cy₃ is optionally substituted with one or more Ri₂.

13.- A compound according to claim 12 wherein Cy₃ represents cyclohexyl, 3- piperidinyl or 4-piperidinyl, wherein Cy₃ is optionally substituted with one or more

Ri₂.

14.- A compound according to claim 12 wherein Cy₃ represents cyclohexyl optionally substituted with one or more Ri₂.

15.- A compound according to claim 12 wherein Cy₃ represents 4-piperidinyl optionally substituted with one or more Ri₂.

16.- A compound according to claim 12 wherein Cy₃ represents 3-piperidinyl optionally substituted with one or more Ri₂.

17.- A compound according to claim 12 wherein Cy₃ represents a group of formula Cy_3a or Cy_3b:

Cy₃₃ Cy_3b wherein Ri_2a represents -CORi₅; and wherein additionally Cy_3a and Cy_3b are independently optionally substituted with one or more Ri₂.

18.- A compound according to claim 12 wherein Cy₃ represents a group of formula Cy₃₃:

Cy₃₃; wherein Ri_2a represents -CORi₅; and wherein additionally Cy_3a is optionally substituted with one or more Ri₂.

19.- A compound according to claim 12 wherein Cy₃ represents a group of formula Cy_3b:

wherein additionally Cy₃b is optionally substituted with one or more Ri₂.

20.- A compound according to any of claims 17 to 19, wherein each Ri₂ is independently selected from Ci_-4alkyl, haloCi_-4alkyl, hydroxyCi_-4alkyl and R₁₁- Ci_-4alkyl.

21.- A compound according to claim 12 wherein Cy₃ represents a group of formula Cy₃₃:

Cy₃₃; wherein Ri_2a represents -CORi₅.

22.- A compound according to claim 12 wherein Cy₃ represents a group of formula Cy_3b:

Cy_3b.

23.- A compound according to any of claims 17, 19 or 22 wherein Ri₄ represents hydrogen.

24.- A compound according to any of claims 17, 18 or 21 wherein Ri₅ represents Ci_-4alkyl or cyanoCi_-4alkyl.

25.- A compound according to claim 24 wherein Ri₅ represents cyanomethyl.

26.- A compound according to claim 1 selected from: ^ans-5-cyano-3-[6-(4-hydroxycyclohexylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine,

^ans-5-cyano-3-[6-(4-hydroxycyclohexyl-Λ/-methylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine, frans-5-cyano-3-[6-(Λ/-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2- yl]pyrazolo[1 ,5-a]pyridine,

5-cyano-3-[6-(piperidin-4-ylamino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine,

5-cyano-3-[6-(methyl(piperidin-4-yl)amino)pyridin-2-yl]pyrazolo[1 ,5-a]pyridine,

5-cyano-3-[6-(1 -(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine, (F?)-5-cyano-3-[6-(1 -(2-cyanoacetyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine, and

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

^rans-5-cyano-3-[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine,

^rans-5-cyano-3-[6-(N-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2- yl]pyrazolo[1 ,5-a]pyhdine, 5-cyano-3-[6-(1 -(2-cyanoacetyl)piperidin-3-ylamino)pyhdin-2-yl]pyrazolo[1 ,5- a]pyridine,

28.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

29.- A compound according to any of claims 1 to 27 for use in the treatment or prevention of a disease mediated by JAK3.

30.- A compound according to any of claims 1 to 27 for use in the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.

31.- A compound according to claim 30 for use in the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

32.- A compound according to any of claims 1 to 27 for use in the treatment or prevention of a disease mediated by JAK2.

33.- A compound according to any of claims 1 to 27 for use in the treatment or prevention of a myeloproliferative disorder.

34.- A compound according to claim 33 for use in the treatment or prevention of a disease selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome.

35.- A process for the preparation of a compound of formula I according to claim 1 , which comprises:

(a) reacting a compound of formula VIII with a compound of formula IX

VIM IX wherein R₁, R₂ and R₃ have the meaning described in claim 1 and X represents halogen; or (b) converting, in one or a plurality of steps, a compound of formula XII into a compound of formula I

XII wherein Ri has the meaning described in claim 1 ; or