PYRROLOPYRIMIDINE DERIVATIVES AS JAK3 INHIBITORS

FIELD OF THE INVENTION

The present invention relates to a new series of pyrrolopyrimidine 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 intervention.

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 immunosuppressive 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 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

wherein:

Cy₁represents phenyl or a 5- or 6-membered aromatic heterocycle bonded to the NH group through a C atom, each of which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein Cy₁can contain from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms of the optional 5- or 6-membered fused ring can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₁can be optionally substituted with one or more R₁;

Cy₂represents a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle, wherein the ring which contains the N atom which is bonded to the pyrrolopyrimidine moiety is saturated or partially unsaturated, wherein Cy₂contains from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂;

each R₁and R₂independently represent C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, halogen, —ON, —NO₂, —COR₃, —CO₂R₃, —CONR₃R₃, —COCONR₃R₃, —OR₃, —OCOR₄, —OCONR₄R₄, —OCO₂R₄, —SR₃, —SOR₄, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅CO₂R₄, —NR₅SO₂R₄, —C(═N—OH)R₄or Cy₃, wherein C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇;

R₃represents hydrogen or R₄;

R₄represents C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, or Cy₄, wherein C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl can be optionally substituted with one or more R₆and Cy₄can be optionally substituted with one or more R₈;

R₅represents hydrogen or C_1-4alkyl;

R₆represents halogen, —CN, —NO₂, —COR₉, —CO₂R₉, —CONR₉R₉, —OR₉, —OCOR₁₀, —OCONR₁₀R₁₀, —OCO₂R₁₀, —SR₉, —SOR₁₀, —SO₂R₁₀, —SO₂NR₉R₉, —SO₂NR₅COR₁₀, —NR₉R₉, —NR₅COR₉, —NR₅CONR₉R₉, —NR₅CO₂R₁₀, —NR₅SO₂R₁₀, —C(═N—OH)R₁₀or Cy₄, wherein Cy₄can be optionally substituted with one or more R₈;

R₇represents C_1-4alkyl that can be optionally substituted with one or more R₁₁, or R₇represents any of the meanings described for R₁₂;

R₈represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_i-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl or any of the meanings described for R₁₂;

R₉represents hydrogen or R₁₀;

R₁₀represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl, Cy₅-C_1-4alkyl or Cy₄, wherein Cy₄can be optionally substituted with one or more R₈;

R₁₁represents halogen, —CN, —NO₂, —COR₉, —CO₂R₉, —CONR₉R₉, —OR₉, —OCOR₁₀, —OCONR₁₀R₁₀, —OCO₂R₁₀, —SR₉, —SOR₁₀, —SO₂R₁₀, —SO₂NR₉R₉, —SO₂NR₅COR₁₀, —NR₉R₉, —NR₅COR₉, —NR₅CONR₉R₉, —NR₅CO₂R₁₀, —NR₅SO₂R₁₀, or —C(═N—OH)R₁₀;

R₁₂represents halogen, —CN, —NO₂, —COR₁₃, —CO₂R₁₃, —CONR₁₃R₁₃, —OR₁₃, —OCOR₁₄, —OCONR₁₄R₁₄, —OCO₂R₁₄, —SR₁₃, —SOR₁₄, —SO₂R₁₄, —SO₂NR₁₃R₁₃, —SO₂NR₅COR₁₄, —NR₁₃R₁₃, —NR₅COR₁₃, —NR₅CONR₁₃R₁₃, —NR₅CO₂R₁₄, —NR₅SO₂R₁₄or —C(═N—OH)R₁₄;

R₁₃represents hydrogen or R₁₄;

R₁₄represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl or hydroxyC_1-4alkyl;

or two R₁₃groups or two R₁₄groups on the same N atom can be bonded completing, together with the N atom, a 5- or 6-membered saturated ring, which can additionally contain one or two heteroatoms selected from N, S and O and which can be optionally substituted with one or more C_1-4alkyl groups;

each Cy_aand Cy₄independently represent a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring which can be carbocyclic or heterocyclic, in which case it can contain from 1 to 4 heteroatoms selected from N, S and O, wherein each Cy_aand Cy₄can be saturated, partially unsaturated or aromatic, and can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO₂groups;

Cy₅represents a ring selected from (a)-(c):

R₁₅represents hydrogen or C_1-4alkyl.

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 of any disease mediated by this kinase.

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

wherein:

each R₁and R₂independently represent C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, halogen, —CN, —NO₂, —COR₃, —CO₂R₃, —CONR₃R₃, —COCONR₃R₃, —OR₃, —OCOR₄, —OCONR₄R₄, —OCO₂R₄, —SR₃, —SOR₄, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅CO₂R₄, —NR₅SO₂R₄, —C(═N—OH)R₄or Cy₃, wherein C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇;

R₃represents hydrogen or R₄;

R₅represents hydrogen or C_1-4alkyl;

R₇represents C_1-4alkyl that can be optionally substituted with one or more R₁₁, or R₇represents any of the meanings described for R₁₂;

R₈represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl or any of the meanings described for R₁₂;

R₉represents hydrogen or R₁₀;

R₁₀represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl, Cy₅-C_1-4alkyl or Cy₄, wherein Cy₄can be optionally substituted with one or more R₈;

R₁₃represents hydrogen or R₁₄;

R₁₄represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl or hydroxyC_1-4alkyl;

each Cy₃and Cy₄independently represent a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring which can be carbocyclic or heterocyclic, in which case it can contain from 1 to 4 heteroatoms selected from N, S and O, wherein each Cy₃and Cy₄can be saturated, partially unsaturated or aromatic, and can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO₂groups;

Cy₅represents a ring selected from (a)-(c):

R₁₅represents hydrogen or C_1-4alkyl, 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 of at least one disease selected from transplant rejection, immune, autoimmune and inflammatory diseases, neurodegenerative diseases, and proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection and immune, autoimmune and 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 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 the treatment of a disease mediated by JAKs, particularly JAK3.

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

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment 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 of a disease mediated by JAKs, particularly JAK3.

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

Another aspect of the present invention relates to a method of treating at least one disease selected from transplant rejection, immune, autoimmune and inflammatory diseases, neurodegenerative diseases, and 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 and immune, autoimmune and inflammatory diseases.

Another aspect of the present invention relates to a method of treating 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 IV with a compound of formula V

wherein Cy₁and Cy₂have the previously described meaning; or

(b) 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_1-4alkyl, 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_2-4alkenyl group means a straight or branched alkyl chain which contains from 2 to 4 C atoms, and also contains one or two double bonds. Examples include the groups ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and 1,3-butadienyl.

A C_2-4alkynyl group means straight or branched alkyl chain which contains from 2 to 4 C atoms, and also contains one or two triple bonds. Examples include the groups ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1,3-butadiynyl.

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 tert-butoxy.

Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.

A C_1-4alkoxyC_1-4alkyl 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 haloC_1-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C_1-4alkyl group with one or more 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 hydroxyC_1-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C_1-4alkyl group with one or more 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 cyanoC_1-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C_1-4alkyl group with one or more cyano groups. Examples include, among others, the groups cyanomethyl, dicyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 2,3-dicyanopropyl and 4-cyanobutyl.

A Cy₅-C_1-4alkyl group means a group resulting from the replacement of one hydrogen atom from a C_1-4alkyl group with one Cy₅group. 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-1-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-ethyl piperazin-1-yl)methyl, (4-propylpiperazin-1-yl)methyl, (4-butylpiperazin-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 Cy₄-C₁₄alkyl group means a group resulting from the replacement of one hydrogen atom from a C_1-4alkyl group with one Cy₄group as defined above.

A group NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, R₉CO—C_1-4alkyl, NR₉R₉—C_1-4alkyl, R₁₀SO₂NR₅—C_1-4alkyl or NR₉R₉CONR₅—C_1-4alkyl means a group resulting from the replacement of one hydrogen atom from a C_1-4alkyl group with one —SO₂NR₉R₉, —CONR₉R₉, —SO₂NR₅COR₁₀, —NR₅COR₉, —COR₉, —NR₉R₉, —NR₅SO₂R₁₀or —NR₅CONR₉R₉group, respectively. For example, examples of a group NR₉R₉SO₂—C_1-4alkyl include, among others, the groups sulfamoylmethyl, 1-sulfamoylethyl, 2-sulfamoylethyl, 1-sulfamoylpropyl, 2-sulfamoylpropyl, 3-sulfamoylpropyl, 1-sulfamoylbutyl, 2-sulfamoylbutyl, 3-sulfamoylbutyl, 4-sulfamoylbutyl, N-methylsulfamoylmethyl, N,N-dimethylsulfamoylmethyl and N-ethyl-N-methylsulfamoylmethyl.

The term Cy₁refers to a phenyl group or a 5- or 6-membered aromatic heterocycle that must be bonded to the NH group through a C atom, wherein both the phenyl group and the 5- or 6-membered aromatic heterocycle can be optionally fused to a 5- or 6-membered carbocycle or heterocycle which can be saturated, partially unsaturated or aromatic. The Cy₁group, as a whole, can contain from 1 to 4 heteroatoms in total selected from N, O and S. When the second ring, i.e. the optional 5- or 6-membered carbocyclic or heterocyclic fused ring, is saturated or partially unsaturated, one or more C or S atoms of said ring can be optionally oxidized forming CO, SO or SO₂groups. The Cy₁group can be 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 any of the rings. Examples of Cy₁groups include, among others, 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, imidazopyrazinylz, 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-1H-indolyl, 1-oxo-2,3-dihydro-1H-isoindolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl and 4-oxo-3,4-dihydroquinazolinyl.

The term Cy₂refers to a 3- to 7-membered monocyclic or a 6- to 11-membered bicyclic heterocycle, with the proviso that the ring directly bonded to the pyrrolopyrimidine is saturated or partially unsaturated. When Cy₂is bicyclic, the second ring can be saturated, partially unsaturated or aromatic. Cy₂contains from 1 to 4 heteroatoms in total selected from N, O and S including the N atom bonding Cy₂to the pyrrolopyrimidine ring, so that Cy₂always contains at least one N atom. When Cy₂is a bicyclic ring, this can be formed 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 it can be formed by two rings sharing a C atom as a single common atom thus forming a spiro ring. In Cy₂one or more C or S atoms in any saturated or partially unsaturated ring can be optionally oxidized forming CO, SO or SO₂groups. The Cy₂group can be 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 Cy₂groups include, among others, azepanyl, aziridinyl, azetidinyl, 1,4-diazepanyl, pyrrolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolinyl, pyrrolinyl, pyrazolinyl, piperidinyl, homopiperidinyl, 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-piperidinyl, 3-oxo-piperidinyl, 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-dihydropyridazinyl, 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, 2H-spiro[benzofuran-3,4′-piperidinyl], 3H-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.

The term Cy₃or Cy₄refers to a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic carbocyclic or heterocyclic ring. When heterocyclic, it can contain from 1 to 4 heteroatoms 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. A Cy₃or Cy₄group can be saturated, partially unsaturated or aromatic. Cy₃and Cy₄can be bonded to the rest of the molecule through any available C or N atom. In Cy₃or Cy₄one or more C or S atoms of a saturated or partially unsaturated ring can be optionally oxidized forming CO, SO or SO₂groups. Cy₃and Cy₄can be 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 Cy₃or Cy₄groups 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, 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-1H-indolyl, 1-oxo-2,3-dihydro-1H-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, 2H-spiro[benzofuran-3,4′-piperidinyl], 3H-spiro[isobenzofuran-1,4′-piperidinyl], 2,8-diazaspiro[4.5]decan-1-onyl and 2,7-diazaspiro[4.5]decan-1-onyl.

In the above definitions of Cy₁, Cy₂, Cy₃and Cy₄, 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 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-b]pyridinyl, the term imidazopyrazinyl can include groups such as 1H-imidazo[4,5-b]pyrazinyl, imidazo[1,2-a]pyrazinyl and imidazo[1,5-a]pyrazinyl and the term pyrazolopyrimidinyl can include groups such as 1H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[4,3-d]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 Cy₁or through a N atom in Cy₂, in which case such limitation applies. Thus for example, in the definitions of Cy₃and Cy₄, which do not include any limitation regarding the bonding position, the term pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; thienyl includes 2-thienyl and 3-thienyl; and indolyl includes 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl.

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, alkenyl or alkynyl group, it can either replace one hydrogen atom, or it can replace two hydrogen atoms on the same C atom.

When in the definition of a substituent two or more groups with the same numbering are indicated (e.g. —NR₅CONR₃R₃, —NR₉R₉, —CONR₁₃R₁₃, 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.

In certain embodiments of the invention, Cy₂represents a phenyl group substituted at one or two of positions 3, 4 and 5 with a R₁group. This means that the phenyl group is either substituted with one R₁group at position 3, 4 or 5 of the phenyl ring, or with two R₁groups (which can be the same or different) at positions 3 and 4, positions 4 and 5 or positions 3 and 5 of the phenyl ring.

Throughout the present specification, the expressions “treatment” of a disease, “treating” a disease and the like refer both to curative treatment as well as palliative treatment or prophylactic treatment of said disease. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total). Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.

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 Cy₁represents phenyl or pyridyl, which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein Cy₁can contain from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms of the 5- or 6-membered fused ring can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₁can be optionally substituted with one or more R₁.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁represents phenyl, pyridyl or a ring of formula Cy_1a,

wherein in ring A X₁, X₂and X₃are selected from C, N, O and S and the dashed lines represent single or double bonds, wherein one or two C or S atoms of ring A can be optionally oxidized forming CO, SO or SO₂groups, and wherein the phenyl, pyridyl and Cy_1agroups can be optionally substituted with one or more R₁.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁represents phenyl, 3-pyridyl, 4-pyridyl or a ring of formula Cy_1a, each of which can be optionally substituted with one or more R₁.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁represents phenyl, pyridyl, benzo[1,3]dioxolyl or benzooxazolyl, each of which can be optionally substituted with one or more R₁.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁represents phenyl, 3-pyridyl, 4-pyridyl, 5-benzo[1,3]dioxolyl or 6-benzooxazolyl, which can be optionally substituted with one or more R₁.

In another embodiment, the invention relates to the compounds of formula wherein Cy₁represents phenyl optionally substituted with one or more R₁.

In another embodiment, the invention relates to the compounds of formula wherein Cy₁represents phenyl substituted with one or more R₁.

In another embodiment, the invention relates to the compounds of formula wherein Cy₁represents phenyl substituted with one, two or three R₁.

In another embodiment, the invention relates to the compounds of formula wherein Cy₁represents phenyl substituted with one or two R₁.

In another embodiment, the invention relates to the compounds of formula wherein Cy₁represents phenyl substituted at one or two of positions 3, 4 and 5 with an R₁.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁represents phenyl substituted with one R₁, which is placed at position 3 or 4 of the phenyl ring.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, halogen, —CN, —NO₂, —COR₃, —CO₂R₃, —CONR₃R₃, —COCONR₃R₃, —OR₃, —OCOR₄, —OCONR₄R₄, —OCO₂R₄, —SR₃, —SOR₄, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅CO₂R₄, —C(═N—OH)R₄or Cy₃, wherein C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —COCONR₃R₃, —OR₃, —SR₃, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅SO₂R₄or Cy₃, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —COCONR₃R₃, —OR₃, —SR₃, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃or Cy₃, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, —CN, —OR₃, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅SO₂R₄or Cy₃, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, haloC_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —CN, —OR₃, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅SO₂R₄or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃in R₁represents Cy_3a, and Cy_3arepresents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O, wherein said ring can be bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO₂groups, wherein said Cy_3acan be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃in R₁represents Cy_3b, and Cy_3brepresents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O with the proviso that it contains at least 1 N atom, wherein said ring is bonded to the rest of the molecule through a N atom, wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein said Cy_3bcan be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₄in R₁represents Cy_4a, and Cy_4arepresents a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O and which can be bonded to the rest of the molecule through any available C or N atom, wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein said Cy₄, can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3a, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy_3acan be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3b, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy_3bcan be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3a, wherein Cy_3acan be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄, —C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3a, wherein Cy₃, can be optionally substituted with one or more R₇and wherein Cy₄, can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄, —C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3b, wherein Cy_3bcan be optionally substituted with one or more R₇and wherein Cy_4acan be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3a, wherein Cy₃, can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy_4a-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3a, wherein Cy_3acan be optionally substituted with one or more R₇and wherein Cy₄, can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy_4a-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3b, wherein Cy_3bcan be optionally substituted with one or more R₇and wherein Cy₄, can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₁represents C_1-4alkyl, halogen, haloC_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —CN, —OR₃, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅SO₂R₄or Cy_3a, wherein Cy₃, can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein R₃in R₁represents hydrogen or R₄and R₄in R₁represents C_1-4alkyl or Cy₄, wherein C_1-4alkyl can be optionally substituted with one or more R₆and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein R₃in R₁represents hydrogen or R₄and R₄in R₁represents C_1-4alkyl, Cy₄-C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl or Cy₄, wherein any Cy₄can be optionally substituted with one or more R₈.

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

Cy₁represents phenyl substituted with one or more R₁, preferably one or two R₁; and

each R₁represents C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, halogen, —CN, —NO₂, —COR₃, —CO₂R₃, —CONR₃R₃, —COCONR₃R₃, —OR₃, —OCOR₄, —OCONR₄R₄, —OCO₂R₄, —SR₃, —SOR₄, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅CO₂R₄, —C(═N—OH)R₄or Cy₃, wherein C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

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

Cy₁represents phenyl substituted with one or more R₁, preferably one or two R₁; and

each R₁represents C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —COCONR₃R₃, —OR₃, —SR₃, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅SO₂R₄or Cy₃, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

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

Cy₁represents phenyl substituted with one or more R₁, preferably one or two R₁; and

each R₁represents C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy₃can be optionally substituted with one or more R₇.

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

Cy₁represents phenyl substituted with one or more R₁, preferably one or two R₁; and

each R₁represents C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3a, wherein the C_1-4alkyl group can be optionally substituted with one or more R₆and Cy_3acan be optionally substituted with one or more R₇.

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

Cy₁represents phenyl substituted with one or more R₁, preferably one or two R₁; and

each R₁represents C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

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

Cy₁represents phenyl substituted with one or more R₁, preferably one or two R₁; and

each R₁represents C_1-4alkyl, halogen, haloC_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —CN, —OR₃, —SO₂R₄, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₃R₃, —NR₅COR₃, —NR₅SO₂R₄or Cy_3a, wherein Cy_3acan be optionally substituted with one or more R₇.

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

Cy₁represents a ring of formula Cy_1b:

one of R₁₇, R₁₈or R₁₉represents hydroxyC_1-4alkyl, —CN, —OR₃, —SO₂R₄, —SO₂NR₃R₃, —NR₅COR₃, —NR₅SO₂R₄or Cy_3a, wherein Cy_3acan be optionally substituted with one or more R₇; and

the remainder of R₁₇, R₁₈and R₁₉as well as R₁₆and R₂₀are selected from hydrogen, C_1-4alkyl, halogen and C_1-4alkoxy.

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

Cy₁represents phenyl substituted at one or two of positions 3, 4 and 5 with an R₁; and

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

Cy₁represents phenyl substituted at one or two of positions 3, 4 and 5 with an R₁; and

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

Cy₁represents phenyl substituted at one or two of positions 3, 4 and 5 with an R₁; and

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

Cy₁represents phenyl substituted with one R₁, which is placed at position 3 or 4 of the phenyl ring; and

R₁represents C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, halogen, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

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

Cy₁represents phenyl substituted with one R₁, which is placed at position 3 or 4 of the phenyl ring; and

R₁represents hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

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

Cy₁represents phenyl substituted with one R₁, which is placed at position 3 or 4 of the phenyl ring; and

R₁represents hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄, —C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy_3b, wherein Cy_3bcan be optionally substituted with one or more R₇and wherein Cy₄, can be optionally substituted with one or more R₈.

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

Cy₁represents phenyl substituted with one R₁, which is placed at position 3 or 4 of the phenyl ring;

R₁represents hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, Cy₄-C_1-4alkyl, NR₉R₉SO₂—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, R₁₀CONR₅SO₂—C_1-4alkyl, R₉CONR₉—C_1-4alkyl, —CONR₃R₃, —OR₃, —SO₂NR₃R₃, —SO₂NR₅COR₄, —NR₅COR₃or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈;

R₃in R₁represents hydrogen or R₄; and

R₄in R₁represents C_1-4alkyl or Cy₄, wherein C_1-4alkyl can be optionally substituted with one or more R₆and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents a 5- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle, wherein the ring which contains the N atom which is bonded to the pyrrolopyrimidine is saturated or partially unsaturated, wherein Cy₂contains from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents a 5- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle, wherein the ring which contains the N atom which is bonded to the pyrrolopyrimidine moiety is saturated, wherein Cy₂contains from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents a saturated 5- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle, wherein Cy₂contains from 1 to 3 heteroatoms selected from N, O and S, wherein one or more C or S atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents a saturated 5- to 7-membered monocyclic heterocycle which contains from 1 to 2 heteroatoms selected from N, O and S, wherein one or more C or S atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂is selected from (a)-(i):

wherein one or more C or S atoms of Cy₂can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂is selected from (a)-(g):

wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂is selected from (a)-(f):

wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂is selected from (b), (c), (d), (e), (h) and (i):

wherein one or more C or S atoms of Cy₂can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (b):

wherein one or more C atoms of Cy₂can be optionally oxidized forming CO groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (b):

which can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (c):

wherein one or more C atoms of Cy₂can be optionally oxidized forming CO groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (c):

which can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (d)

wherein one or more C or S atoms of Cy₂can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (d)

which can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (e):

wherein one or more C atoms of Cy₂can be optionally oxidized forming CO groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (e):

which can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (h):

wherein one or more C atoms of Cy₂can be optionally oxidized forming CO groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (h):

which can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (i):

wherein one or more C atoms of Cy₂can be optionally oxidized forming CO groups, and wherein Cy₂can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (i):

which can be optionally substituted with one or more R₂.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂is optionally substituted with one, two, three or four R₂.

In another embodiment, the invention relates to the compounds of formula I wherein each R₂represents C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅SO₂R₄or Cy₃, wherein C_1-4alkyl can be optionally substituted with one or more R₆and wherein Cy₃can be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₃in R₂represents Cy_3c, and Cy_3crepresents a saturated 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring which can be carbocyclic or heterocyclic, in which case it can contain from 1 to 4 heteroatoms selected from N, S and O, wherein Cy_3ccan be bonded to the rest of the molecule through any available C or N atom, wherein one or more C or S atoms of the ring can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy_3ccan be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₂represents C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅SO₂R₄or Cy₃, wherein C_1-4alkyl can be optionally substituted with one or more R₆and wherein Cy_3ccan be optionally substituted with one or more R₇.

In another embodiment, the invention relates to the compounds of formula I wherein each R₂represents C_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, haloC_1-4alkyl, Cy₄-C_1-4alkyl, R₉CO—C_1-4alkyl, NR₉R₉—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, R₁₀SO₂NR₅—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, NR₉R₉CONR₅—C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅SO₂R₄or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₂represents C_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, haloC_1-4alkyl, Cy₄-C_1-4alkyl, R₉CO—C_1-4alkyl, NR₉R₉—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, R₁₀SO₂NR₅—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, NR₉R₉CONR₅—C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅SO₂R₄or Cy₃, wherein Cy_3ccan be optionally substituted with one or more R₇and wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₂represents C_1-4alkyl, —COR₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃or —NR₅SO₂R₄, wherein C_1-4alkyl can be optionally substituted with one or more R₆.

In another embodiment, the invention relates to the compounds of formula I wherein each R₂represents C_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, haloC_1-4alkyl, Cy₄-C_1-4alkyl, R₉CO—C_1-4alkyl, NR₉R₉—C_1-4alkyl, R₉CONR₅—C_1-4alkyl, R₁₀SO₂NR₅—C_1-4alkyl, NR₉R₉CO—C_1-4alkyl, NR₉R₉CONR₅—C_1-4alkyl, —COR₉, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃or —NR₅SO₂R₄, wherein Cy₄can be optionally substituted with one or more R₈.

In another embodiment, the invention relates to the compounds of formula I wherein each R₂represents C_1-4alkyl, hydroxyC_1-4alkyl, haloC_1-4alkyl, halogen, —COR₃, —CONR₃R₃, —OR₃or —NR₃R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₃in R₂represents hydrogen or R₄and R₄in R₂represents C_1-4alkyl optionally substituted with one or more R₆.

In another embodiment, the invention relates to the compounds of formula I wherein R₃in R₂represents hydrogen or R₄and R₄in R₂represents C_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl or haloC_1-4alkyl.

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

Cy₂represents a 5- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle, wherein the ring which contains the N atom which is bonded to the pyrrolopyrimidine moiety is saturated, wherein Cy₂contains from 1 to 4 heteroatoms selected from N, O and S, wherein one or more C or S atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂; and

each R₂represents C_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃, —NR₅SO₂R₄or Cy₃, wherein C_1-4alkyl can be optionally substituted with one or more R₆and wherein Cy₃can be optionally substituted with one or more R₇.

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

each R₂represents C_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, haloC_1-4alkyl, halogen, —CN, —COR₃, —CO₂R₃, —CONR₃R₃, —OR₃, —NR₃R₃, —NR₅COR₃or Cy₃, wherein Cy₃can be optionally substituted with one or more R₇.

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

each R₂represents C_1-4alkyl, —COR₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃or —NR₅SO₂R₄, wherein C_1-4alkyl can be optionally substituted with one or more R₆.

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

Cy₂represents a saturated 5- to 7-membered monocyclic or 6- to 11-membered bicyclic heterocycle, wherein Cy₂contains from 1 to 3 heteroatoms selected from N, O and S, wherein one or more C or S atoms can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂; and

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

each R₂represents C_1-4alkyl, —COR₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃or —NR₅SO₂R₄, wherein C_1-4alkyl can be optionally substituted with one or more R₆.

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

Cy₂is selected from (a)-(i):

wherein one or more C or S atoms of Cy₂can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂; and

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

Cy₂is selected from (a)-(i):

wherein one or more C or S atoms of Cy₂can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂; and

each R₂represents C_1-4alkyl, —COR₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃or —NR₅SO₂R₄, wherein C_1-4alkyl can be optionally substituted with one or more R₆.

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

Cy₂is selected from (a)-(g):

wherein Cy₂can be optionally substituted with one or more R₂; and

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂is selected from (b), (c), (d), (e), (h) and (i):

wherein one or more C or S atoms of Cy₂can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂; and

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂is selected from (b), (c), (d), (e), (h) and (i):

wherein one or more C or S atoms of Cy₂can be optionally oxidized forming CO, SO or SO₂groups, and wherein Cy₂can be optionally substituted with one or more R₂; and

each R₂represents C_1-4alkyl, —COR₃, —OR₃, —NR₃R₃, —NR₅COR₃, —NR₅CONR₃R₃or —NR₅SO₂R₄, wherein C_1-4alkyl can be optionally substituted with one or more R₆.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₂represents (b):

wherein one or more C atoms of Cy₂can be optionally oxidized forming CO groups, and wherein Cy₂can be optionally substituted with one or more R₂; and