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

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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):

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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

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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):

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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

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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,

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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:

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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)

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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)

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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):

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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

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

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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

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 (c):

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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

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

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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

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 (d)

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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 Cy₂represents (d)

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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 (e):

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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

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

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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

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 (h)

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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

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

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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

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 (i)

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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

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

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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

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:

Cy₁represents phenyl substituted with one or more R₁; and

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:

Cy₁represents phenyl substituted with one or more R₁; and

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

Cy₁represents phenyl substituted with one or more R₁; and

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

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂represents a 5- to 7-membered saturated 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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂is selected from (a)-(g):

embedded image

wherein Cy₂can be optionally substituted with one or more R₂.

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

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂is selected from (a)-(i):

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂is selected from (b), (c), (d), (e), (h) and (i):

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂represents (b):

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂represents (c):

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂represents (d)

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂represents (e):

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂represents (h)

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁; and

Cy₂represents (i):

embedded image

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:

Cy₁represents phenyl substituted with one or more R₁;

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

Cy₁represents phenyl substituted with one or more R₁;

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.

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, 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 14.

In another embodiment, the invention relates to a compound of formula I selected from the list of compounds described in examples 1 to 13.

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, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others. Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases. Examples of these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, N-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^rdedition, 1999). As an example, as protecting group of an amino function the tert-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 in two steps by the method described in Scheme 1:

embedded image

wherein Cy₁and Cy₂have the meaning previously described in relation with a compound of formula I.

In a first step (step a), the reaction between a compound of formula II and a compound of formula III may be carried out in the presence of a base such as triethylamine, K₂CO₃, Cs₂CO₃or diisopropylethylamine, a solvent such as ethanol, tetrahydrofuran/H₂O or any polar solvent, and heating preferably at reflux to obtain a compound of formula IV.

Step b may be carried out by the reaction between a compound of formula IV and an amine of formula V in the presence of 4M dioxane/HCl_(g)solution, a solvent such as n-butanol or methoxyethanol, and irradiating with a microwave oven preferably at around 170° C. to obtain a compound of formula I.

Alternatively, step b may be carried out by the reaction between a compound of formula IV and an amine of formula V in the presence of a Pd catalyst such as Pd₂(dba)₃, a phosphine such as 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, and a base such as potassium carbonate, in a solvent such as tert-butanol, and heating preferably at reflux to obtain a compound of formula I.

The compounds of formula II, III and V are commercially available or can be prepared by well-known methods described in the literature, and can be protected with suitable protecting groups.

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 Cy₁or Cy₂groups 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 NiCl₂, or SnCl₂;

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 cyanoborohydride or sodium triacetoxyborohydride;

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-dimethylaminopyridine, in a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, optionally in the presence of a base such as triethylamine 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 alkylation of a thiol to give a thioeter 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 diisobutylaluminum hydride or LiAlH₄;

the oxidation of a thioeter to a sulfoxide or sulfone under standard conditions;

the conversion of an alcohol into a halogen by reaction with SOCl₂, PBr₃, tetrabutylammonium bromide in the presence of P₂O₅, or PI₃;

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.

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 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 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, pluripotential 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 D C. 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 M D. et al, Transpl Int. 2004, 17(9):481-89; Silva Jr H T. et al, Drugs 2006, 66(13):1665-1684).

Immune, autoimmune and inflammatory diseases that can be treated 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, angioedema, anaphylaxis, bronchitis, rhinitis and sinusitis (see e.g. Sorbera L A. 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 J G. et al, Ann. Rheum. Dis. 2006, 65(2):149-56; Milici A J. et al, Arthritis Rheum. 2006, 54 (9, Suppl): abstr 789; Kremer J M. et al, Arthritis Rheum. 2006, 54, 4116, 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 with the compounds of the present invention include, among others, amyotrophic lateral sclerosis and Alzheimer's disease (see e.g. Trieu V N. et al, Biochem. Biophys. Res. Commun. 2000, 267(1):22-5).

Proliferative disorders that can be treated 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 E A. et al, Clin. Cancer Res. 1999, 5(6):1569-82; Narla R K. et al, Clin. Cancer Res. 1998, 4(10):2463-71; Lin Q. et al, Am J. Pathol. 2005, 167(4):969-80; Tibbles H E. et al, J. Biol. Chem. 2001, 276(21):17815-22).

Biological assays that can be used to determine the ability of a compound to inhibit JAKs, particularly JAK3, are well known in the art. For example, a compound to be tested can be incubated in the presence of JAK3 to determine whether inhibition of JAK3 enzymatic activity occurs, as described in the assay of example 14. 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 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 González-Rey et al, Am. J. Pathol. 2006, 168(4): 1179-88, 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).

For selecting active compounds, testing at 10 μM must result in an activity of more than 50% inhibition of JAK3 activity in the test provided in example 14. 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.

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 glycerides, or on a hydrophilic base such as polyethylene glycols (macrogol).

The compounds of the invention can also be formulated for their topical application for the treatment of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract. Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.

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

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

The following examples illustrate the scope of the invention.

EXAMPLES

The following abbreviations have been used in the examples:

AcN: acetonitrile

n-BuOH: 1-butanol

DIEA: N,N-diisopropylethylamine

DMAP: 4-(dimethylamino)pyridine

DMF: N,N-dimethylformamide

EDC: N-[3-(dimethylamino)propyl]-M-ethylcarbodiimide

EtOAc: ethyl acetate

EtOH: ethanol

HBTU: O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

HOBT: 1-hydroxybenzotriazole

HPLC: high performance liquid chromatography

LC-MS: liquid chromatography-mass spectroscopy

MeOH: methanol

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

TEA: triethylamine

THF: tetrahydrofuran

t_R: retention time

X-Phos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl

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

Method 1: Column X-Terra, MS C18 5 μm (100 mm×2.1 mm), temperature: 30° C., flow: 0.35 mL/min, eluent: A=AcN, B=NH₄HCO₃10 mM, gradient: 0 min 10% A; 10 min 90% A; 15 min 90% A; 15.01 min 10% A.

Method 2: Column Waters Acquity UPLC BEH C18 (1.7 μm, 2.1 mm×50 mm), temperature: 40° C., flow: 0.5 mL/min, eluent: ACN (A)/ammonium bicarbonate 10 mM (B), gradient: 0 min 10% A-3.75 min 90% A.

Method 3: Column Tracer Excel 120, ODSB 5 μm (10 mm×0.21 mm), temperature: 30° C., flow: 0.35 mL/min, eluent: A=AcN, B=0.1% HCOOH, gradient: 0 min 10% A-10 min 90% A.

Method 4: Column YMC, 3 μm (50 mm×4.6), temperature: 30° C., flow: 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.

Method 5: Column Symmetry C₁₈3.5 μm (4.6×75 mm), temperature: 30° C., flow: 1.0 mL/min, eluent: A=H₂O (0.1% HCOOH) B=AcN (0.07% HCOOH), gradient: 0 min 5% B; 7 min 100% B.

REFERENCE EXAMPLE 1
[4-(3-Hydroxypiperidin-1-yl)phenyl]amine
a) 4-(3-Hydroxypiperidin-1-yl)nitrobenzene

To a 4-fluoronitrobenzene solution (1 g, 7.09 mmol) in AcN (16 mL), 3-hydroxypiperidine hydrochloride (1.04 g, 7.57 mmol) and DIEA (1.32 mL, 7.57 mmol) were added. The mixture was stirred and refluxed for 18 h. The resulting mixture was cooled until room temperature and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 1.15 g of the desired compound (51% yield).

b) Title Compound

To a NiCl₂.6H₂O (222 mg, 0.93 mmol) suspension in MeOH (50 mL) NaBH₄(74 mg, 1.95 mmol) was added at room temperature and a solution of the compound obtained in the previous section (0.51 g, 2.33 mmol) in THF (30 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated to dryness. The residue obtained was divided between a 1N NaOH solution and EtOAc. Phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 450 mg of the desired compound (99% yield).

LC-MS (method 1): t_R=3.06 min; m/z=193 (MH⁺).

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

Reference

HPLC
t_R

Example
Compound name
Starting Material
method
(min)
m/z

1a
[4-(3-tert-
3-tert-
1
5.41
308

butoxycarbonylaminopyrrolidin-
butoxycarbonylaminopyrrolidine

1-yl)phenyl]amine

1b
[4-(3-hydroxypyirrolidin-1-yl)phenyl]amine
3-hydroxypyirrolidine
1
2.53
179

REFERENCE EXAMPLE 2
4-(4-aminophenyl)-1-[2-(trimethylsylanyl)ethoxymethyl]-pyrazol
a) 4-(4-nitrophenyl)-1-[2-(trimethylsylanyl)ethoxymethyl]-pyrazol

To a 4-(4-nitrophenyl)-1H-pyrazol (0.2 g, 1.05 mmol) and DIEA (0.55 mL, 3.15 mmol) solution in CHCl₃(3 mL) (2-trimethylsylanyl)ethoxymethyl chloride is added. The resulting mixture was stirred for 18 h at room temperature. H₂O was added and extracted thrice with CHCl₃. The organic phase was dried over Na₂SO₄and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 320 mg of the desired compound (95% yield).

b) Title Compound

Following a similar procedure to that described in reference example 1 section b, but starting with the compound obtained in previous section, the desired compound was obtained (83% yield).

LC-MS (method 1): t_R=8.31 min; m/z=290 (MH⁺).

Following a similar procedure to that described in reference example 2, but using in each case the corresponding starting materials, these compounds are obtained:

Reference

HPLC
t_R

Example
Compound name
Starting material
method
(min)
m/z

2a
3-(4-aminophenyl)-1-[2-
3-(4-nitrophenyl)-1H-
1
8.54
290.17

(trimethylsylanyl)ethoxymethyl]-
pyrazol

pyrazol

REFERENCE EXAMPLE 3
N-(3-Aminophenyl)-N-methylacetamide
a) N-(3-Nitrophenyl)-N-methylacetamide

To a solution of 3-nitro-N-methylaniline (650 mg, 4.27 mmol) in CH₂Cl₂(10 mL) under Ar-atmosphere, acetyl chloride (0.33 mL, 4.7 mmol), a catalytic amount of DMAP and DIEA (1.49 mL, 8.5 mmol) were added. The resulting mixture was stirred at room temperature overnight. The resulting residue was diluted with H₂O, the phases were separated and the aqueous phase extracted with CH₂Cl₂. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product thus obtained was directly used in the next step.

LC-MS (method 5): t_R=1.43 min; m/z=195 (MH⁺).

b) Title Compound

To a solution of the compound obtained in the previous section (0.96 g, 4.97 mmol) in MeOH (13 mL) under Ar-atmosphere, 10% Pd/C (128 mg) was added at room temperature. The resulting mixture was stirred under H₂overnight, filtered and the filtrate was concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0.45 g of the desired compound (56% yield).

LC-MS (method 2): t_R=1.02 min; m/z=165 (MH⁺).

Following a similar procedure to that described in reference example 3, but using the corresponding starting material, the following compound was obtained:

Reference

Starting
HPLC
t_R

example
Compound name
material
method
(min)
m/z

3a
N-(3-aminophenyl)-N-
cyclopropane
5
1.38
191

methylcyclopropane-
carbonyl

carboxamide
chloride

REFERENCE EXAMPLE 4
4-(Imidazol-1-ylmethyl)piperidine
a) 4-Piperidylmethanol

To a mixture of LiAlH₄(8.82 g, 0.23 mol) and THF (125 mL), cooled at 0° C., a solution of ethyl isonipecotate (18 mL, 0.117 mol) in THF (325 mL) was added dropwise under Ar-atmosphere, the mixture was stirred at room temperature overnight. A mixture of H₂O (12.03 mL) and THF (25 mL), followed by a mixture of 15% NaOH (10.03 mL) and H₂O (32.4 mL) were slowly added at 0° C. The resulting mixture was washed with THF, filtered and concentrated to dryness. The residue was partitioned between H₂O and CHCl₃, the phases were separated, the aqueous phase was extracted with CHCl₃and the combined organic phases were dried over Na₂SO₄and concentrated to afford 8.2 g of the desired product (61% yield).

b) (1-tert-Butoxycarbonylpiperidin-4-yl)methanol

To a solution of the compound obtained in the previous section (15.3 g, 133 mmol) in DMF (160 mL), at 0° C. and under Ar-atmosphere, di-tert-butyl dicarbonate (29 g, 133 mmol) in DMF (80 mL) was added. The solution was stirred at room temperature overnight, and concentrated to dryness. The residue was dissolved in a mixture of THF (100 mL), MeOH (100 mL) and 1N NaOH (100 mL) and stirred at room temperature for 18 h. The organic phase was evaporated and the aqueous phase was extracted thrice with CHCl₃. The combined organic phases were dried over Na₂SO₄and concentrated to dryness to afford 23.0 g of the desired product (80% yield).

c) (1-tert-Butoxycarbonylpiperidin-4-yl)methyl mesylate

To a solution of the product obtained in the previous section (6.8 g, 31 mmol) and DIEA (5.75 mL, 33 mmol) in CH₂Cl₂(50 mL), at 0° C. and under Ar-atmosphere, methanesulfonyl chloride (2.4 mL, 31 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and treated with H₂O, the phases were separated and the aqueous phase was extracted with CH₂Cl₂. The combined organic phases were dried over Na₂SO₄and concentrated to afford the title compound in quantitative yield.

¹H NMR (300 MHz, CDCl₃) δ (TMS): 4.12 (broad d, J=11.8 Hz, 2H), 4.04 (d, J=6.5 Hz, 2H), 2.98 (s, 3H), 2.69 (broad t, J=12.4 Hz, 2H), 1.89 (m, 1H), 1.72 (broad d, J=12.9 Hz, 2H), 1.43 (s, 9H), 1.25 (m, 2H).

d) 1-tert-Butoxycarbonyl-4-(imidazol-1-ylmethyl)piperidine

To a solution of the compound obtained in the previous section (400 mg, 1.36 mmol) in THF (5 mL), K₂CO₃(188 mg, 1.36 mmol) and imidazole (93 mg, 1.36 mmol) were added. The mixture was stirred and refluxed overnight. The crude product obtained was partitioned between EtOAc and 0.05 N aqueous NaOH solution. The phases were separated and the organic phase was dried over Na₂SO₄and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using CHCl₃/MeOH/NH₃mixtures of increasing polarity as eluent, to afford 170 mg of the desired product (47%).

e) Title Compound

The compound obtained in the previous section (170 mg, 0.64 mmol) and a 4 M dioxane/HCl_(g)mixture (5 mL) were mixed in a flask under Ar-atmosphere. The mixture was stirred at room temperature overnight and concentrated to dryness, to afford the title compound in quantitative yield.

¹H NMR (300 MHz, MeOD) δ (TMS): 8.96 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 4.18 (d, J=7.2 Hz, 2H), 3.36-3.32 (m, 2H), 2.95-2.87 (m, 2H), 2.25-2.10 (m, 1H), 1.78-1.74 (m, 2H), 1.49-1.44 (m, 2H).

REFERENCE EXAMPLE 5
N-tert-Butyl-N′-(4-piperidylmethyl)urea hydrochloride
a) 4-Aminomethyl-1-tert-butoxycarbonylpiperidine

To a solution of 4-(aminomethyl)piperidine (100 g, 0.88 mol) in CHCl₃(550 mL), cooled at 0° C. and under Ar-atmosphere, a solution of di-tert-butyl dicarbonate (98 g, 0.45 mol) in CHCl₃(350 mL) was added. The resulting mixture was stirred at room temperature for 48 h, washed with H₂O and the aqueous phase extracted with CHCl₃. The combined organic phases were dried over Na₂SO₄and the solvents were removed to afford 84.5 g of the title compound (88% yield).

¹H NMR (80 MHz, CDCl₃) δ (TMS): 4.11 (broad d, J=13.4 Hz, 2H), 2.69 (m, 4H), 1.45 (s, 9H), 1.8-0.8 (complex signal, 7H).

b) N-tert-Butyl-N'-[(1-tert-butoxycarbonylpiperidin-4-yl)methyl]urea

To a solution of 4-aminomethyl-1-tert-butoxycarbonylpiperidine (5 g, 23 mmol) obtained in the previous section in DMF (20 mL), tert-butyl isocyanate (2.63 mL, 23 mmol) was added dropwise under Ar-atmosphere. The reaction mixture was stirred at room temperature overnight and concentrated to dryness to afford the desired compound in quantitative yield.

c) Title Compound

Following a similar procedure to that described in section e of reference example 4, but using the compound obtained in the previous section, the title compound of the example was obtained in quantitative yield.

¹H NMR (300 MHz, CD₃OD) δ (TMS): 4.92 (s, 4H), 3.37 (m, 2H), 2.97 (m, 4H), 1.95 (m, 2H), 1.80 (m, 1H), 1.43 (m, 2H), 1.31 (s, 9H).

REFERENCE EXAMPLE 6
4-Hydroxy-2-methylpiperidine

To a solution of 2-methyl-4-piperidone (250 mg, 2.21 mmol) in MeOH (8 mL), NaBH₄(175 mg, 4.62 mmol) was added at 0° C. The resulting mixture was stirred at room temperature overnight. The crude product was partitioned between H₂O and EtOAc and the phases were separated. The organic phase was dried over Na₂SO₄and concentrated to dryness to afford the desired compound in quantitative yield.

LC-MS (method 2): t_R=0.31 min; m/z=116 (MH⁺). 1807/78

REFERENCE EXAMPLE 7
(6S,8R)-8-Hydroxy-1,4-diazabicyclo[4.3.0]nonane dihydrochloride
a) (2S,4R)-N-tert-Butoxycarbonylaminoacetyl-4-hydroxyproline methyl ester

To a mixture of N-(tert-butoxycarbonyl)glycine (950 mg, 5.368 mmol), DIEA (2.82 mL, 16.10 mmol) and HBTU (2.07 g, 5.368 mmol) in 30 mL DMF at 0° C., L-4-hydroxyproline methyl ester hydrochloride (995 mg, 5.368 mmol) was added and the suspension thus obtained was stirred at room temperature overnight. The mixture was concentrated to dryness and partitioned between CHCl₃and 0.2 M NaHCO₃solution. The combined organic phases were dried over Na₂SO₄and concentrated to dryness to afford the desired compound (80%).

LC-MS (method 2): t_R=1.25 min; m/z=303.3 (MH⁺).

b) (6S,8R)-2,5-Dioxo-8-hydroxy-1,4-diazabicyclo[4.3.0]nonane

To a solution of the compound obtained in the previous section (1.3 g, 4.30 mmol) in CH₂Cl₂(2 mL), trifluoroacetic acid (1 mL) was added. The solution was stirred at room temperature for 2 h. A 2N aqueous NaHCO₃solution (2 mL) was added and the mixture evaporated to dryness. The crude product was diluted with a mixture of CHCl₃/MeOH/NH₃(10:5:1, 10 mL) and the solution thus obtained was filtered over silica gel. The filtrate was concentrated to dryness to afford the desired compound in quantitative yield.

LC-MS (method 2): t_R=0.28 min; m/z=171.2 (MH⁺).

c) Title Compound

A solution of the compound obtained in the previous section (914 mg, 5.37 mmol) in THF (10 mL) was added to a solution of LiAlH₄(815 mg, 21.48 mmol) in THF (21 mL) and under Ar-atmosphere. The resulting mixture was refluxed for 1 h and stirred at room temperature overnight. H₂O (0.82 mL), 15% aqueous NaOH solution (0.82 mL) and H₂O (2.45 mL) were added in this order to the resulting solution. The resulting suspension was stirred for 1 h at room temperature and after the addition of THF (9 mL) the resulting solid was filtered and washed with EtOH. The filtrate was neutralized with a mixture of 2N HCl and Dowex 50w×8 (10 g), and stirred at room temperature overnight. The suspension thus obtained was filtered and washed with a mixture of H₂O/MeOH. NH₄OH/25% MeOH (75 mL) was added stirred for 2 h at room temperature. The resulting suspension was filtered and washed with MeOH. The resulting crude product was redissolved in 4M HCl in 1,4-dioxane (5 mL) and concentrated to dryness to afford the desired product (26%).

LC-MS (method 2): t_R=0.28 min; m/z=143 (MH⁺).

Following a similar procedure to that described in reference example 7 sections a, b, and c, but using the corresponding starting materials, the next compounds were obtained:

Reference

HPLC
t_R

Example
Compound name
Reagents for step a)
method
(min)
m/z

7a
(S)-1,4-
L-proline methyl ester
2
0.34
127

diazabicyclo[4.3.0]nonane
hydrochloride

dihydrochloride
N-(tert-butoxycarbonyl)glycine

7b
(6S,3S)-3-methyl-
L-proline methyl ester
2
0.35
141

1,4-
hydrochloride

diazabicyclo[4.3.0]nonane
N-(tert-butoxycarbonyl)-L-alanine

dihydrochloride

Example 1
2-[4-(4-morpholino)phenyl]amino-4-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine
a) 2-Chloro-4-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine solution (0.16 g, 0.86 mmol) in EtOH (2 mL), piperidine (0.085 mL, 0.86 mmol) and TEA (0.24 mL, 1.7 mmol) were added. The reaction was stirred and refluxed for 18 h. The resulting mixture was cooled until room temperature and evaporated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0.18 g of the desired compound (88° A) yield).

b) Title Compound

A mixture of the compound obtained in previous section (90 mg, 0.38 mmol), [4-(4-morpholino)phenyl]amine (123 mg, 0.57 mmol) and a 4M dioxane/HCl_(g)solution (0.1 mL) in n-BuOH (2 mL) was irradiated in a microwave oven at 170° C. for 40 min. n-BuOH was evaporated and the residue was purified by preparative HPLC. 26.5 mg (18% yield) of the title compound was obtained

LC-MS (method 1): t_R=8.03 min; m/z=379 (MH⁺).

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

Reagent for
Reagent for step
HPLC
t_R

Example
Compound name
step a)
b)
method
(min)
m/z

1a
4-(4-methylpiperidin-
4-
[4-(4-
1
8.69
393.2

1-yl)-2-[4-(4-
methylpiperidine
morpholino)phenyl]amine

morpholino)phenyl]amino-

7H-pyrrolo[2,3-

d]pyirimidine

1b
2-(3-
4-
3-amino-N-tert-
1
7.62
387.1

aminosulfonylphenyl)amino-
methylpiperidine
butylbenzenesulfonamide

4-(4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1c
2-(3-tert-
4-
3-amino-N-tert-
1
9.44
443.2

butylaminosulfonylphenyl)amino-
methylpiperidine
butylbenzenesulfonamide

4-(4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1d
2-[4-(3-
4-
Reference
1
8.10
393.2

hydroxypyrrolidin-1-
methylpiperidine
example 1b

yl)phenyl]amino-4-

(4-methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyirimidine

1e
4-(4-methylpiperidin-
4-
N-tert-
1
8.14
391.2

1-yl)-2-[4-(piperidin-
methylpiperidine
butoxycarbonyl-3-

3-yl)phenyl]amino-

(4-

7H-pyrrolo[2,3-

aminophenyl)piperidine

d]pyrimidine

1f
2-(3-
piperidine
3-
1
9.56
340.1

methyltiophenyl)amino-

methyltiophenylamine

4-(piperidin-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1g
2-(3-
piperidine
3-
1
9.41
338.1

ethoxyphenyl)amino-

ethoxyphenylamine

4-(piperidin-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1h
2-[4-(3-
4-
Reference
1
7.50
392.2

aminopyrrolidin-1-
methylpiperidine
example 1a

yl)phenyl]amino-4-

(4-methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1i
2-(3-
piperidine
3-amino-N-tert-
1
6.99
373.1

aminosufonilphenyl)amino-

butylbenzenesulfonamide

4-(piperidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

1j
2-(3-tert-
piperidine
3-amino-N-tert-
1
8.87
429.1

butylaminosufonilphenyl)amino-

butylbenzenesulfonamide

4-

(piperidin-1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1k
2-[4-(3-
piperidine
Reference
1
6.99
378.2

aminopyrrolidin-1-

example 1a

yl)phenyl]amino-4-

(piperidin-1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1l
2-[4-(3-tert-
piperidine
Reference
1
9.69
478.2

butoxycarbonyl

example 1a

aminopyrrolidin-1-

yl)phenyl]amino-4-

(piperidin-1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1m
4-(piperidin-1-yl)-2-
piperidine
N-tert-
1
7.45
377.2

[4-(3-

butoxycarbonyl-3-

piperidinil)phenyl]amino-

(4-

7H-pyrrolo[2,3-

aminophenyl)piperidine

d]pyrimidine

1n
2-[3-
4-
3-
3
6.99
350.2

acetylphenyl]amino-
methylpiperidine
acetylphenylamine

4-(4-methylpiperidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

1o
4-(4-methylpiperidin-
4-
3-(piperidin-1-
1
10.75
391.2

1-yl)-2-[(3-piperidin-
methylpiperidine
yl)phenylamine

1-yl)phenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

1p
4-(4-methylpiperidin-
4-
[3-(4-
1
8.94
393.2

1-yl)-2-[3-(4-
methylpiperidine
morpholino)phenyl]amine

morpholino)phenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

1q
2-(3-
4-
3-
1
9.37
333.1

cyanophenyl)amino-
methylpiperidine
aminobenzonitrile

4-(4-methylpiperidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

1r
4-(4-methylpiperidin-
4-
3,4-
1
8.60
368.1

1-yl)-2-(3,4-
methylpiperidine
dimethoxyphenylamine

dimethoxyphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

1s
2-[(3,4-
4-
3,4-
1
9.22
352.1

methylendioxy)phenyl]amino-
methylpiperidine
(methylendioxy)phenylamine

4-(4-

methylpiperidin-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1t
2-[(3-
4-
(3-
1
7.70
365.1

acetylamino)phenyl]amino-
methylpiperidine
acetylamino)phenylamine

4-(4-

methylpiperidin-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1u
2-(4-
4-
4-amino-N-tert-
1
7.56
387.0

aminosufonilphenyl)amino-
methylpiperidine
butylbenzenesulfonamide

4-(4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1v
2-[(4-
4-
(4-
1
7.05
351.1

carbamoil)phenyl]amino-
methylpiperidine
carbamoil)phenyl

4-(4-

amine

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1w
4-(4-
1-
3-amino-N-tert-
4
1.43
416.2

acetylpiperazine-1-
acetylpiperazine
butylbenzenesulfonamide

yl)-2-(3-

aminosulfonylphenyl)amino-

7H-

pyrrolo[2,3-

d]pyrimidine

1x
2-(3-
2-
3-amino-N-tert-
1
1.8
373.2

aminosulfonylphenyl)amino-
methylpyrrolidine
butylbenzenesulfonamide

4-(2-methyl-

1-pyrrolidinil)-7H-

pyrrolo[2,3-

d]pyrimidine

1y
2-(3-
1-
3-amino-N-tert-
1
7.72
449.9

aminosulfonylphenyl)amino-
phenylpiperazine
butylbenzenesulfonamide

4-(4-

phenylpiperazin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1z
2-(3-
4-phenyl-
3-amino-N-tert-
1
8.31
446.9

aminosulfonylphenyl)amino-
1,2,3,6-
butylbenzenesulfonamide

4-(4-phenyl-
tetrahidropyridine

1,2,3,6-

tetrahidropyridin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1aa
2-[4-(2-
homopiperidine
2-(4-
1
7.73
352.0

hydroxyethyl)phenyl]amino-

aminophenyl)ethanol

4-

(homopiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ab
2-[4-(3-
homopiperidine
N-tert-
1
7.07
391.1

piperidinyl)phenyl]amino-

butoxycarbonyl-3-

4-

(4-

(homopiperidin-1-

aminophenyl)piperidine

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ac
2-(3-
homopiperidine
3-amino-N-tert-
1
7.43
387.0

aminosulfonylphenyl)amino-

butylbenzenesulfonamide

4-

(homopiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ad
2-(3-
3-
3-amino-N-tert-
4
1.42
430.2

aminosulfonylphenyl)amino-
acetamidopiperidine
butylbenzenesulfonamide

4-(3-

acetamidopiperidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ae
2-(3-
homopiperazine
3-amino-N-tert-
1
4.19
388.0

aminosulfonylphenyl)amino-

butylbenzenesulfonamide

4-

([1,4]diazepan-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1af
2-(3-
4-
3-amino-
4
1.32
389.2

aminosulfonylphenyl)amino-
hydroxypiperidine
benzenesulfonamide

4-(4-

hydroxypiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ag
2-(3-
3-
3-amino-
4
1.43
389.2

aminosulfonylphenyl)amino-
hydroxypiperidine
benzenesulfonamide

4-(3-

hydroxypiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ah
2-(3-
4-
3-amino-N-tert-
2
1.41
403

aminosulfonylphenyl)amino-
hydroxymethylpiperidine
butylbenzenesulfonamide

4-(4-

hydroxymethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1ai
2-(3-
4-
3-amino-N-tert-
4
2.58
463.2

aminosulfonylphenyl)amino-
benzylpiperidine
butylbenzenesulfonamide

4-(4-

benzilpiperidin-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1aj
2-(3-
4-
3-amino-N-tert-
4
2.43
449.2

aminosulfonylphenyl)amino-
phenylpiperidine
butylbenzenesulfonamide

4-(4-

phenylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ak
2-(3-
3-
3-amino-
4
1.50
403.2

aminosulfonylphenyl)amino-
hydroxymethylpiperidine
benzenesulfonamide

4-(3-

hydroxymethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1al
2-(3-
2-
3-amino-
4
1.80
385.2

aminosulfonylphenyl)amino-
azabiciclo[2,2,
benzenesulfonamide

4-(2-
1]heptane

azabiciclo[2,2,1]heptan-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1am
2-(3-
perhydroisoquinoline
3-amino-
4
2.52
427.2

aminosulfonylphenyl)amino-

benzenesulfonamide

4-

(perhydroisoquinolin-

2-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1an
2-[(4-N,N-
4-
N,N-diethyl-1,4-
1
10.39
379.2

diethylamine)phenyl]amino-
methylpiperidine
phenylendiamine

4-(4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ao
4-(3-methylpiperidin-
3-
[4-(4-
1
8.64
393

1-yl)-2-[4-(4-
methylpiperidine
morpholino)phenyl]amine

morpholino)phenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

1ap
2-(3-
3-(N-tert-
3-amino-
2
1.23
374.3

aminosulfonylphenyl)amino-
butoxycarbonyl-
benzenesulfonamide

4-(3-
N-

methylaminoazetidin-
methylamino)azetidine

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1aq
2-[4-(3-
piperidine
Reference
1
7.49
393.1

hydroxypiperidin-1-

example 1

yl)phenyl]amino-4-

(piperidin-1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1ar
2-[4-(3-
4-
Reference
1
8.13
407.1

hydroxypiperidin-1-
methylpiperidine
example 1

yl)phenyl]amino-4-

(4-methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1as
2-(3-
4-
3-
1
10.34
399.1

phenylaminophenyl)amino-
methylpiperidine
(phenylaminophenyl)amine

4-(4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1at
2-(4-
4-
4-aminophenol
1
7.62
324.1

hydroxyphenyl)amino-
methylpiperidine

4-(4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1au
2-[4-(2-
4-
2-(4-
1
7.84
352.1

hydroxyethyl)phenyl]amino-
methylpiperidine
aminophenyl)ethanol

4-(4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1av
4-(4-methylpiperidin-
4-
4-(piperidin-1-
1
10.51
391.1

1-yl)-2-[4-(piperidin-
methylpiperidine
yl)aniline

1-yl)phenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

1aw
4-(4-methylpiperidin-
4-
3-(pyiridyn-4-
1
9.00
385.1

1-yl)-2-[3-(pyridin-4-
methylpiperidine
yl)aniline

yl)phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

1ax
2-(3-
4-
3-aminophenol
1
8.05
324.1

hydroxyphenyl)amino-
methylpiperidine

4-(4-

methylpiperidine-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1ay
2-(benzofuran-5-
4-
(benzofuran-5-
1
9.49
348.1

yl)amino-4-(4-
methylpiperidine
yl)amine

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1az
2-(3-
(R)-3-
3-amino-
4
1.27
375.1

aminosulfonylphenyl)amino-
hydroxypyrrolidine
benzenosulfonamide

4-[(R)-3-

hydroxypyrrolidin-1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

1ba
4-(4-methylpiperidin-
4-
4-(1,1-
1
8.10
441.1

1-yl)-2-[4-(1,1-
methylpiperidine
dioxotiomorpholin-

dioxotiomorpholin-4-

4-yl)aniline

yl)phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

1bb
2-(3-
pyrrolidine
3-amino-N-tert-
4
1.63
359.2

aminosulfonylphenyl)amino-

butylbenzenesulfonamide

4-(pyrrolidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

1bc
4-(4-methylpiperidin-
4-
4-
1
8.24
386.1

1-yl)-2-[4-
methylpiperidine
(methylsulfonyl)aniline

(methylsulfonyl)phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

1bd
4-(4-methylpiperidin-
4-
3-
1
8.12
386.0

1-yl)-2-[3-
methylpiperidine
(methylsulfonyl)aniline

(methylsulfonyl)phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

1be
4-(4-methylpiperidin-
4-
N-(3-
1
8.06
401.0

1-yl)-2-[3-
methylpiperidine
aminophenyl)methanosulfonamide

(methylsulfonylamino)phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

1bf
2-(4-
4-
4-
1
9.33
333.1

cyanophenyl)amino-
methylpiperidine
aminobenzonitrile

4-(4-methylpiperidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

1bg
4-(4-methylpiperidin-
4-
Reference
1
7.99
374.1

1-yl)-2-[4-(pirazol-4-
methylpiperidine
example 2

yl)phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

1bh
4-(4-methylpiperidin-
4-
Reference
1
8.22
374.1

1-yl)-2-[4-(pirazol-3-
methylpiperidine
example 2a

yl)phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

1bi
2-(3-
4-
3-amino-
4
2.23
441.2

aminosulfonylphenyl)amino-
trifluoromethylpiperidine
benzenesulfonamide

4-(4-

trifluoromethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1bj
2-(3-
3-(n-
3-amino-
4
2.22
459.2

aminosulfonylphenyl)amino-
butoxycarbonyl)pyrrolidine
benzenesulfonamide

4-[3-(n-

butoxycarbonyl)pyrrolidin-

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

1bk
2-(3-
4-
3-amino-N-tert-
4
1.98
431.2

aminosulfonylphenyl)amino-
(ethoxymethyl)piperidine
butylbenzenesulfonamide

4-[4-

(ethoxymethyl)piperidin-

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

1bl
2-(3-
homopiperidine
(3-
1
7.84
324.1

hydroxyphenyl)amino-

hydroxyphenyl)amine

4-(homopiperidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

1bm
2-(3-
homopiperidine
(3-
2
2.14
365

acetylaminophenyl)amino-

acetylaminophenyl)amine

4-

(homopiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1bn
2-(3-
4-(2-
3-amino-
4
1.52
417.2

aminosulfonylphenyl)amino-
hydroxyethyl)piperidine
benzenesulfonamide

4-[4-(2-

hydroxyethyl)piperidin-

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

1bo
2-(3-
(S)-2-
3-amino-
4
1.45
389.2

aminosulfonylphenyl)amino-
(hydroxymethyl)pyrrolidine
benzenesulfonamide

4-[(S)-2-

(hydroxymethyl)pyrrolidin-

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

1bp
2-(3-
4,4-
3-amino-
4
2.13
409.2

aminosulfonylphenyl)amino-
difluoropiperidine
benzenesulfonamide

4-(4,4-

difluoropiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1bq
2-(3-
3-
3-
2
1.75
393.3

acetylaminophenyl)amino-
acetylpiperidine
acetylaminophenylamine

4-(3-

acetylpiperidin-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1br
2-(3-
(S)-3-
3-amino-
4
1.42
389.2

aminosulfonylphenyl)amino-
hydroxypiperidine
benzenesulfonamide

4-[(S)-3-

hydroxypiperidin-1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

1bs
2-(3-
4-
3-amino-
4
1.67
403.1

aminosulfonylphenyl)amino-
methoxypiperidine
benzenesulfonamide

4-(4-

methoxypiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

1bt
2-(3-
(R)-3-
3-amino-
4
1.43
389.2

aminosulfonylphenyl)amino-
hydroxypiperidine
benzenesulfonamide

4-[(R)-3-

hydroxypiperidin-1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

1bu
2-(3-
(R)-2-
3-amino-
4
1.45
389.2

aminosulfonylphenyl)amino-
(hydroxymethyl)pyrrolidine
benzenesulfonamide

4-[(R)-2-

(hydroxymethyl)pyrrolidin-

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

1bv
2-(3-
thiazolidine
3-amino-N-tert-
2
1.72
377.2

aminosulfonylphenyl)amino-

butylbenzenesulfonamide

4-

(thiazolidin-3-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1bw
4-(3-acetylpiperidin-
3-
3-amino-N-tert-
1
6.26
415

1-yl)-2-(3-
acetylpiperidine
butylbenzenesulfonamide

aminosulfonylphenyl)amino-

7H-

pyrrolo[2,3-

d]pyrimidine

1bx
2-(3-
4-
3-amino-
4
1.83
391.1

aminosulfonylphenyl)amino-
fluoropiperidine
benzenesulfonamide

4-(4-

fluoropiperidin-1-yl)-

7H-pyrrolo[2,3-

d]pyrimidine

1by
2-(3-
4-
3-amino-
4
1.70
431

aminosulfonylphenyl)amino-
hydroxyethylpiperidine
benzenesulfonamide

4(4-

hydroxyethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1bz
2-(3-
3-
3-amino-
2
1.46
402

aminosulfonylphenyl)amino-
dimethylaminopyrrolidine
benzenesulfonamide

4-(3-

dimethylaminopyrrolidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

1aa
2-(3-
thiazolidine
3-
2
1.78
355

acetylaminophenyl)amino-

aminoacetanilide

4-(thiazolidin-

3-yl)-7H-pyrrolo[2,3-

d]pyrimidine

Example 2
4-(2-Azabicyclo[2.2.1]heptan-2-yl)-2-(3-fluoro-4-methoxyphenyl)amino-7H-pyrrolo[2,3-d]pyrimidine
a) 4-(2-Azabicyclo[2.2.1]heptan-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 1 section a, but using 2-aza-bicyclo[2.2.1]heptane hydrochloride instead of piperidine, the desired compound was obtained (78% yield).

LC-MS (method 2): t_R=2.04 min; m/z=249 (MH⁺).

b) Title Compound

To a solution of the compound obtained in the previous section (100 mg, 0.402 mmol) in tert-butanol (2 mL), K₂CO₃(167 mg, 1.20 mmol), X-Phos (19 mg, 0.04 mmol), Pd₂(dba)₃(18 mg, 0.02 mmol) and 3-fluoro-4-methoxyphenylamine (69 mg, 0.48 mmol) were added at room temperature and under Ar-atmosphere. The reaction mixture was heated at 100° C. overnight and the crude product thus obtained was diluted with MeOH and filtered over Celite®. The filtrate was concentrated to dryness and chromatographed over silica gel using CHCl₃/MeOH mixtures of increasing polarity as eluent, to afford 24 mg of the desired compound (17% yield).

LC-MS (method 2): t_R=2.53 min; m/z=354 (MH⁺).

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

Regeant for
Regeant for step
HPLC
t_R

Example
Compound name
step a)
b)
method
(min)
m/z

2a (1)
2-(3-
2-benzyl-2,8-
3-amino-
4
2.22
532

aminosulfonylphenyl)amino-
diaza-
benzenesulfonamide

4-(2-benzyl-
spiro[4.5]decan-

2,8-diaza-
1-one

spiro[4.5]decan-1-
hydrochloride

one-8-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2b (1)
2-(3-
2-methyl-2,8-
3-amino-
4
1.60
456

aminosulfonylphenyl)amino-
diaza-
benzenesulfonamide

4-(2-methyl-
spiro[4.5]decan-

2,8-diaza-
1-one

spiro[4.5]decan-1-
hydrochloride

one-8-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2c (1)
2-[4-(2-
4-
4-amino-1-(2-
4
1.47
447

hydroxyethylamino-
hydroxymethylpiperidine
hydroxyethyl)benzene-

sulfonyl)phenyl]amino-

sulfonamide

4-(4-

hydroxymethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2d (1)
4-(4-
4-
4-amino-N-(2-
4
1.28
516

hydroxymethylpiperidin-
hydroxymethylpiperidine
(morpholin-4-

1-yl)-2-[4-(2-

yl)ethyl)benzene-

(morpholin-4-

sulfonamide

yl)ethylaminosulfonyl)-

phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2e (1)
(S)-2-(3-
(S)-methylpyrrolidine-
3-amino-
4
1.70
417

aminosulfonylphenyl)amino-
2-
benzenesulfonamide

4-[(2-
carboxylate

methyloxycarbonyl)pyrrolidin-
hydrochloride

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

2f (1)
2-(4-(1,1-
4-
4-(1,1-
4
1.58
457

dioxothiomorpholin-
hydroxymethylpiperidine
dioxothiomorpholin-

4-yl)phenyl)amino-4-

4-yl)-

(4-

phenylamine

hydroxymethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2g (1)
2-(3-
4-
3-
4
1.48
381

acetylaminophenyl)amino-
hydroxymethylpiperidine
aminoacetanilide

4-(4-

hydroxymethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2h (1)
4-(4-
4-
3-(1,3-oxazol-5-
4
1.78
391

hydroxymethylpiperidin-
hydroxymethylpiperidine
yl)phenylamine

1-yl)-2-(3-(1,3-

oxazol-5-

yl)phenyl)amino-7H-

pyrrolo[2,3-

d]pyrimidine

2i (1)
4-(4-
4-
3-(1H-imidazol-1-
4
1.17
404

hydroxymethylpiperidin-
hydroxymethylpiperidine
ylmethyl)phenylamine

1-yl)-2-(3-(1H-

imidazol-1-

ylmethyl)phenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2j (1)
(R)-2-(3-
(R)-3-
3-amino-
4
0.90
402

aminosulfonylphenyl)amino-
dimethylaminopyrrolidine
benzenesulfonamide

4-(3-

dimethylaminopyrrolidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2k
2-[4-(2-
4-
4-amino-1-(2-
2
2.13
431

hydroxyethylaminosulfonyl)-
methylpiperidine
hydroxyethyl)-

phenyl]amino-4-(4-

benzenesulfonamide

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2l
2-(4-(4-
4-
4-(4-
2
2.34
406

methylpiperazin-1-
methylpiperidine
methylpiperazino)-

yl)phenyl)amino-4-

phenylamine

(4-methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2m
4-(4-methylpiperidin-
4-
3-pyrrolidin-1-
2
2.50
391

1-yl)-2-(3-pyrrolidin-
methylpiperidine
ylmethylphenylamine

1-

ylmethylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2n
4-(2-
2-aza-
3-pyrrolidin-1-
2
2.26
389

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
ylmethylphenylamine

2-yl)-2-(3-
hydrochloride

pyrrolidin-1-

ylmethylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2o (1)
4-(4-
4-
4-(4-
4
1.13
422

hydroxymethylpiperidin-
hydroxymethylpiperidine
methylpiperazino)-

1-yl)-2-(4-(4-

phenylamine

methylpiperazin-1-

yl)phenyl)amino-7H-

pyrrolo[2,3-

d]pyrimidine

2p (1)
2-(3-
4-
3-
4
1.58
368

hydroxyethylphenyl)amino-
hydroxymethylpiperidine
hydroxyethylphenylamine

4-(4-

hydroxymethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2q (1)
2-(3-
4-[(2-methyl-
3-amino-
4
1.18
467

aminosulfonylphenyl)amino-
1H-imidazol-1-
benzenesulfonamide

4-(4-[(2-
yl)methyl]piperidine

methyl-1H-imidazol-

1-

yl)methyl]piperidin-

1-yl)-7H-pyrrolo[2,3-

d]pyrimidine

2r (1)
4-(4-
4-
3-amino-N-
4
1.60
417

hydroxymethylpiperidin-
hydroxymethylpiperidine
methylbenzenesulfonamide

1-yl)-2-[3-(N-

methylaminosulfonyl)-

phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2s (1)
4-(4-(3-
4-(3-
3-pyrrolidin-1-
4
1.45
435

hydroxypropylpiperidin-
hydroxypropyl)piperidine
ylmethylphenylamine

1-yl)-2-(3-

pyrrolidin-1-

ylmethylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2t (1)
(R)-2-(3-
(R)-2-
3-amino-
4
1.83
373

aminosulfonylphenyl)amino-
methylpyrrolidine
benzenesulfonamide

4-(2-

methylpyrrolidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2u (1)
(S)-2-(3-
(S)-2-methylpiperidine
3-amino-
4
2.03
387

aminosulfonylphenyl)amino-

benzenesulfonamide

4-[(2-

methyl)piperidin-1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

2v
2-(3-
1,4-
3-amino-
2
1.62
414

aminosulfonylphenyl)amino-
diazabicyclo[4.3.0]nonane
benzenesulfonamide

4-(1,4-

diazabicyclo[4.3.0]nonan-

4-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2w (1)
2-(3-
3,3-dimethylpiperidine
3-amino-
4
2.27
401

aminosulfonylphenyl)amino-

benzenesulfonamide

4-[(3,3-

dimethyl)piperidin-1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

2x (1)
(S)-4-(2-
(S)-2-
4-pyrrolidin-1-
4
1.25
393

hydroxymethylpyrrolidin-
hydroxymethylpyrrolidine
ylmethylphenylamine

1-yl)-2-(4-

pyrrolidin-1-

ylmethylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2y (1)
(R)-2-(3-
(R)-2-methylpiperidine
3-amino-
4
2.12
387

aminosulfonylphenyl)amino-

benzenesulfonamide

4-([2-

methyl]piperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2z (1)
(S)-2-[(3-
(S)-3-
N-(3-
4
1.75
393

cyclopropylcarbonyl-
hydroxypiperidine
aminophenyl)cyclo-

amino)phenyl]amino-

propanecarboxamide

4-(3-

hydroxypiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2aa (1)
(S)-4-(3-
(S)-3-
3-pyrrolidin-1-
4
1.18
393

hydroxypiperidin-1-
hydroxypiperidine
ylmethylphenylamine

yl)-2-(3-pyrrolidin-1-

ylmethylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2ab
4-(homopiperidin-1-
homopiperidine
3-pyrrolidin-1-
2
2.42
391

yl)-2-(3-pyrrolidin-1-

ylmethylphenylamine

ylmethylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2ac
4-(homopiperidin-1-
homopiperidine
4-(4-
2
2.27
406

yl)-2-[4-(4-

methylpiperazin-

methylpiperazin-1-

1-ylphenylamine

yl)phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

2ad (1)
2-[3-
4-
(3-amino-phenyl)-
4
1.47
417

(aminosulfonylmethyl)-
hydroxymethylpiperidine
methanesulfonamide

phenyl]amino-

4-(4-

hydroxymethylpiperidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2ae
4-(2-
2-aza-
4-
2
2.09
350

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
hydroxyethylphenylamine

2-yl)-2-(4-
hydrochloride

hydroxyethylphenyl)amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2af
4-(2-
2-aza-
3-
2
2.12
350

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
hydroxyethylphenylamine

2-yl)-2-(3-
hydrochloride

hydroxyethylphenyl)amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2ag (1)
(R)-4-(3-(N,N-
(R)-3-(N,N-
3-amino-N-
4
1.03
416

dimethylamino)pyrrolidin-
dimethylamino)pyrrolidine
methylbenzenesulfonamide

1-yl)-2-(3-

methylamino-

sulfonylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2ah (1)
(R)-2-(3-
(R)-3-(N,N-
3-
4
0.9
380

acetylaminophenyl)amino-
dimethylamino)pyrrolidine
aminoacetanilide

4-(3-(N,N-

dimethylamino)pyrrolidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2ai (1)
(R)-2-[3-
(R)-3-(N,N-
3-
4
1.47
414

(phenylamino)phenyl]amino-
dimethylamino)pyrrolidine
(phenylamino)phenylamine

4-(3-(N,N-

dimethylamino)pyrrolidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2aj (1)
(R)-4-(3-(N,N-
(R)-3-(N,N-
[4-(4-
4
0.92
408

dimethylamino)pyrrolidin-
dimethylamino)pyrrolidine
morpholino)phenyl]amine

1-yl)-2-[4-

(morpholin-4-

yl)phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

2ak (1)
(R)-4-(3-(N,N-
(R)-3-(N,N-
3-fluoro-4-
4
1.03
371

dimethylamino)pyrrolidin-
dimethylamino)pyrrolidine
methoxyphenylamine

1-yl)-2-(3-

fluoro-4-

methoxyphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2al
4-(2-
2-aza-
4-(morpholin-4-
2
2.23
405

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
yl)methylphenylamine

2-yl)-2-[(4-
hydrochloride

morpholin-4-

yl)methylphenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

2am
4-(2-
2-aza-
4-(1-
2
1.99
418

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
methylpiperazin-

2-yl)-2-(4-(1-
hydrochloride
4-

methylpiperazin-4-

yl)methylphenylamine

yl)methylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2an
4-(2-
2-aza-
Reference
2
2.11
377

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
example 3

2-yl)-2-[3-(N-
hydrochloride

methylacetamido)phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2ao
4-(2-
2-aza-
Reference
2
2.32
404

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
example 3a

2-yl)-2-[3-(N-
hydrochloride

methylcyclopropane-

carbonylamino)phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2ap (1), (2)
4-(4-
4-
4-(1-tert-
4
1.18
407

hydroxymethylpiperidin-
hydroxymethylpiperidine
butoxycarbonylpiperidin-

1-yl)-2-[4-

4-yl)-

(piperidin-4-yl)-

phenylamine

phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

2aq
2-(3-
Reference
3-amino-
2
1.51
453

aminosulfonylphenyl)amino-
example 4
benzenesulfonamide

4[4-

(imidazol-1-

ylmethyl)piperidin-1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

2ar
2-(3-
Reference
3-amino-
1
6.48
501

aminosulfonylphenyl)amino-
example 5
benzenesulfonamide

4-[4-[(N′-tert-

butylureido)methyl]piperidin-

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

2as
4-(3-
3-
3-amino-
2
1.24
416

acetamidopyrrolidin-
acetamidopyrrolidine
benzenesulfonamide

1-yl)-2-(3-

aminosulfonylphenyl)amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2at
2-(3-
3,3-
3-amino-
2
1.57
417

aminosulfonylphenyl)amino-
dimethylpiperidin-
benzenesulfonamide

4-(3,3-
4-ol (3)

dimethyl-4-

hydroxypiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2au
4-(1′-acetyl-[4,4′]-
1-(4,4′-
3-amino-
4
1.85
498

bipiperidin-1-yl)-2-
bipiperidin-1-
benzenesulfonamide

(3-
yl)ethanone

aminosulfonylphenyl)amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2av
4-(2-
2-aza-
4-(4-
2
2.07
404

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
methylpiperazin-

2-yl)-2-(4-[4-
hydrochloride
1-ylphenylamine

methylpiperazin-1-

yl]phenyl)amino-7H-

pyrrolo[2,3-

d]pyrimidine

2aw
4-(2-
2-aza-
4-(piperazin-1-
2
1.78
390

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
yl)phenylamine

2-yl)-2-[4-
hydrochloride

(piperazin-1-

yl)phenyl]amino-7H-

pyrrolo[2,3-

d]pyrimidine

2ax
4-(2-
2-aza-
4-(2-pyrrolidin-1-
2
2.11
419

azabicyclo[2.2.1]heptan-
bicyclo[2.2.1]heptane
yl)ethoxyaniline

2-yl)-2-[4-(2-
hydrochloride

(pyrrolidin-1-

yl)ethoxyphenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

2ay
(S)-2-(3-
(S)-3-(tert-
3-amino-
2
1.99
488

aminosulfonylphenyl)amino-
butoxycarbonylamino-
benzenesulfonamide

4-[3-(tert-
methyl)pyrrolidine

butoxycarbonylamino-

methyl)pyrrolidin-

1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

2az
trans-2-(3-
trans-4-
3-amino-
2
1.22
418

aminosulfonylphenyl)amino-
dimethylaminopyrrolidin-
benzenesulfonamide

4-(4-
3-ol (4)

dimethylamino-3-

hydroxypyrrolidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2ba
(R)-2-(3-
(R)-3-
3-amino-
4
1.85
373

aminosulfonylphenyl)amino-
methylpyrrolidine
benzenesulfonamide

4-(3-

methylpyrrolidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2bb
(R)-2-(3-
3-(R)-(N-tert-
3-amino-
2
2.14
488

aminosulfonylphenyl)amino-
butoxycarbonyl-
benzenesulfonamide

4-[3-(N-tert-
N-

butoxycarbonyl-N-
methylamino)pyrrolidine

methylamino)pyrrolidin1-

yl]-7H-

pyrrolo[2,3-

d]pyrimidine

2bc
(R)-4-[3-(N-tert-
3-(R)-(N-tert-
3-fluoro-4-
4
2.50
457

butoxycarbonyl-N-
butoxycarbonyl-
methoxyphenylamine

methylamino)pyrrolidin1-
N-

yl]-2-(3-fluoro-
methylamino)pyrrolidine

4-

methoxyphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

2bd
(R)-2-(3-
3-(R)-(N-tert-
3-amino-
2
1.98
474

aminosulfonylphenyl)amino-
butoxycarbonylamino)-
benzenesulfonamide

4-[3-(N-tert-
pyrrolidine

butoxycarbonylamino)pyrrolidin1-

yl]-7H-

pyrrolo[2,3-

d]pyrimidine

2be
(R)-4-(3-
3-(R)-
3-amino-
2
1.27
416

acetamidopyrrolidin1-
acetamidopyrrolidine
benzensulfonamide

yl)-2-(3-

aminosulfonylphenyl)amino-

7H-

pyrrolo[2,3-

d]pyrimidine

2bf
2-(3-
Reference
3-amino-
2
1.46
403

aminosulfonylphenyl)amino-
example 6
benzenesulfonamide

4-(4-

hydroxy-2-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2bg
trans-2-(3-
trans-4-
3-amino-
5
3.13
403

aminosulfonylphenyl)amino-
methylpiperidin-
benzenesulfonamide

4-(3-
3-ol (5)

hydroxy-4-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2bh
cis-2-(3-
cis-2-
3-amino-
5
3.04
403

aminosulfonylphenyl)amino-
methylpiperidin-
benzenesulfonamide

4-(3-
3-ol (6)

hydroxy-2-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2bi
cis-2-(3-
cis-6-
3-amino-
5
3.09
403

aminosulfonylphenyl)amino-
methylpiperidin-
benzenesulfonamide

4-(3-
3-ol (6)

hydroxy-6-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2bj
cis-2-(3-
cis-5-
3-amino-
5
3.22
403

aminosulfonylphenyl)amino-
methylpiperidin-
benzenesulfonamide

4-(3-
3-ol (6)

hydroxy-5-

methylpiperidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

2bk
(6S,8R)-2-(3-
Reference
3-amino-
2
1.20
555.6

aminosulfonylphenyl)amino-
example 7
benzenesulfonamide

4-(8-

hydroxy-1,4-

diazabicyclo[4.3.0]nonan-

4-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2bl
(S)-2-(3-
Reference
3-amino-
2
1.62
414.4

aminosulfonylphenyl)amino-
example 7a
benzenesulfonamide

4-(1,4-

diazabicyclo[4.3.0]nonan-

4-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2bm
(S)-2-(4-
Reference
4-
2
1.70
379.5

hydroxyethylphenyl)amino-
example 7a
hydroxyethylphenylamine

4-(1,4-

diazabicyclo[4.3.0]nonan-

4-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2bn
(6S,3S)-2-(3-
Reference
3-amino-
2
1.88
428.4

aminosulfonylphenyl)amino-
example 7b
benzenesulfonamide

4-(3-methyl-

1,4-

diazabicyclo[4.3.0]nonan-

4-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

2bo
2-(3-
2-
3-amino-
4
2.05
387.3

aminosulfonylphenyl)amino-
methylpiperidine
benzenesulfonamide

4-[(2-

methyl)piperidin-1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

2bp
2-(3-
2-
3-amino-
4
1.62
403.2

aminosulfonylphenyl)amino-
(hydroxymethyl)piperidine
benzenesulfonamide

4-[(2-

hydroxymethyl)piperidin-

1-yl]-7H-

pyrrolo[2,3-

d]pyrimidine

2bq
4-[(4-
4-
4-amino-N-(2-
4
1.67
461.3

hydroxymethyl)piperidin-
(hydroxymethyl)piperidine
methoxyethyl)-

1-yl]-2-[4-
benzenesulfonamide

(methoxyethyl)amino-

sulfonylphenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

2br
4-[(4-
4-
3-pyrrolidin-1-
4
1.18
407.3

hydroxymethyl)piperidin-
(hydroxymethyl)piperidine
ylmethylphenylamine

1-yl]-2-(3-

pyrrolidin-1-

ylmethylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

(1) First step using 1,4-dioxane instead of ethanol

(2) An additional deprotection step was necessary: over a solution of the product obtained, 4M dioxane/HCl_(g)(2 mL) were added to afford the desired product.

(3) Described in WO/2005/026145

(4) Described in WO/2007/146759

(5) Described in WO/2001/087866

(6) Described in WO/2007/122103

Example 3
(R)-2-(3-Aminosulfonylphenyl)amino-4-(3-(1-methylureido)pyrrolidin1-yl)-7H-pyrrolo[2,3-d]pyrimidine
a) (R)-2-(3-Aminosulfonylphenyl)amino-4-(3-(N-methylamino)pyrrolidin1-yl)-7H-pyrrolo[2,3-d]pyrimidine

A mixture of the compound obtained in example 2bb (390 mg, 0.8 mmol), 4M dioxane/HCl_(g)(7 mL), and methanol (3 mL) was stirred under Ar-atmosphere for 2 h at room temperature. The resulting mixture was concentrated to dryness and the residue thus obtained was partitioned between 0.2 N NaHCO₃and CHCl₃. The phases were separated and the combined organic phases were dried over Na₂SO₄and concentrated to dryness to afford 225 mg of the desired product.

LC-MS (method 2): t_R=1.27 min; m/z=388 (MH⁺).

b) Title Compound

To a solution of the compound obtained in the previous section (40 mg, 0.1 mmol) in DMF (1 mL), trimethylsilyl isocyanate (14 mg, 0.12 mmol) was added under Ar-atmosphere and the mixture was stirred at room temperature overnight. The resulting solution was concentrated to dryness, diluted with EtOAc and washed twice with NH₄Cl saturated aqueous solution. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using EtOAc/MeOH/NH₃mixtures of increasing polarity as eluent, to afford 18 mg of the desired compound (43% yield).

LC-MS (method 2): t_R=1.23 min; m/z=431 (MH⁺).

Following a similar procedure to that described in example 3, but using the corresponding starting material, the following compounds were obtained:

Reagent for step
Reagent for step
HPLC
t_R

Example
Compound name
a)
b)
method
(min)
m/z

3a
(R)-2-(3-
Example 2bb
methanesulfonyl
2
1.55
466

aminosulfonylphenyl)amino-

chloride (1)

4-[3-(N-

methylmethanesulfonylamino)pyrrolidin1-

yl]-7H-pyrrolo[2,3-

d]pyrimidine

3b
(R)-2-(3-
Example 2bh
phenyl
2
1.91
494

aminosulfonylphenyl)amino-

chloroformate (1)

4-[3-(N-

phenoxycarbonylamino)pyrrolidin1-

yl]-

7H-pyrrolo[2,3-

d]pyrimidine

3c
(R)-2-(3-
Example 2bh
methanesulfonyl
2
1.38
452

aminosulfonylphenyl)amino-

chloride

4-[3-(N-

methanesulfonylamino)pyrrolidin1-

yl]-

7H-pyrrolo[2,3-

d]pyrimidine

3d
(R)-2-(3-
Example 2bh
trimethylsilyl
2
1.15
417

aminosulfonylphenyl)amino-

isocyanate

4-(3-

ureidopyrrolidin-1-

yl)-7H-pyrrolo[2,3-

d]pyrimidine

(1) Using pyridine instead of DMF as a solvent

Example 4
(R)-2-(3-Aminosulfonylphenyl)amino-4-(3-(3-methylureido)pyrrolidin1-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of the compound obtained in example 3c (27 mg, 0.05 mmol) in pyridine (2 mL), a 2 M solution of methylamine in THF (0.27 mL, 0.54 mmol) was added under Ar-atmosphere. The resulting mixture was heated at 100° C. overnight and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using CHCl₃/MeOH/NH₃mixtures of increasing polarity as eluent, to afford the desired compound in quantitative yield.

LC-MS (method 2): t_R=1.24 min; m/z=431 (MH⁺).

Following a similar procedure to that described in example 4, but using the corresponding starting material, the following compound were obtained:

Ex-

am-

Starting
HPLC
t_R

ple
Compound name
material
method
(min)
m/z

4a
(R)-2-(3-
2,2,2-
2
1.58
499

aminosulfonylphenyl)amino-
trifluoro-

4-{3-[3-(2,2,2-
ethyl-

trifluoro)ethylureido]-
amine

pyrrolidin1-

yl}-7H-pyrrolo[2,3-

d]pyrimidine

4b
(R)-2-(3-
diethyl-
2
1.65
473

aminosulfonylphenyl)amino-
amine

4-(3-((3,3-

diethylureido)pyrrolidin1-yl)-

7H-pyrrolo[2,3-d]pyrimidine

Example 5
(S)-2-(3-Aminosulfonylphenyl)amino-4-(3-aminomethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 3 section a, but using 2ay instead of example 2bb, the product was obtained (44% yield).

LC-MS (method 2): t_R=1.08 min; m/z=388.3 (MH⁺).

Example 6
2-(3-Acetylaminosulfonylphenyl)amino-4-(4-methylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

A mixture of the compound obtained in example 1b (34 mg, 0.088 mmol), acetic anhydride (0.025 mL, 0.264 mmol) and triethylamine (0.011 mL, 0.088 mmol) in CHCl₃(2 mL) was stirred at room temperature overnight. The resulting solution was diluted with CHCl₃and washed with water and brine. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product obtained was chromatographed over silica gel using CH₂Cl₂/MeOH mixtures of increasing polarity as eluent, to afford 25 mg of the desired compound (55% yield).

LC-MS (method 2): t_R=1.71 min; m/z=429 (MH⁺).

Following a similar procedure to that described in example 6, but using the corresponding starting material, the following compound is obtained:

Starting
HPLC
t_R

Example
Compound name
material
method
(min)
m/z

6a
4-(4-methylpiperidin-
propionyl
2
1.75
443.5

1-yl)-2-(3-
chloride

propionylamino-

sulfonylphenyl)amino-

7H-pyrrolo[2,3-

d]pyrimidine

Example 7
2-(3-Acetylaminosulfonylphenyl)amino-4-(4-methylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine sodium salt

To a solution of example 6 (16 mg, 0.039 mmol) in EtOH (1.5 mL), a 0.05 M aqueous solution of NaOH in EtOH (0.78 mL) was added. The mixture was stirred at room temperature for 30 min and concentrated to dryness to afford 18 mg of the desired product (100% yield).

LC-MS (method 2): t_R=1.71 min; m/z=429 (MH⁺).

Example 8
(2S,4S)-2-(3-Aminosulfonylphenyl)amino-4-(2-hydroxymethyl-4-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine
a) (2S,4S)-2-Chloro-4-(2-methoxycarbonyl-4-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 1 section a, but using (2S,4S)-methyl-4-hydroxy-2-pyrrolidinecarboxylate instead of piperidine the desired product was obtained (61%).

LC-MS (method 2): t_R=1.19 min; m/z=297 (MH⁺).

b) (2S,4S)-2-(3-Amino-N-tert-butylsulfonylphenyl)amino-4-(2-methoxycarbonyl-4-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 2 section b, but using 3-amino-N-tert-butylbenzenesulfonamide instead of 3-fluoro-4-methoxyphenylamine, the desired product was obtained (52% yield).

LC-MS (method 2): t_R=1.78 min; m/z=489.3 (MH⁺).

c) (2S,4S)-2-(3-Amino-N-tert-butylsulfonylphenyl)amino-4-(2-hydroxymethyl-4-hydroxypyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

A solution of the compound obtained in the previous section (357 mg, 0.731 mmol) in THF (8 mL) was added to a suspension of LiAlH₄(56 mg, 1.462 mmol) in THF (4 mL) under Ar-atmosphere. The mixture was refluxed overnight, cooled and diluted with CH₂Cl₂(0.766 mL) The resulting mixture was treated with a saturated solution of sodium tartrate (0.076 mL). The organic phase was dried over Na₂SO₄and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 79 mg of the desired compound (35% yield).

LC-MS (method 2): t_R=1.67 min; m/z=461 (MH⁺).

d) Title Compound

A mixture of the compound obtained in the previous section (107 mg, 0.233 mmol), THF (2 mL) and 6N HCl_(g)(4 mL) was stirred at reflux overnight. The solvent was concentrated and the residue was diluted with EtOAc and washed with saturated aqueous NaHCO₃. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 25 mg of the desired compound (25% yield).

LC-MS (method 2): t_R=1.22 min; m/z=405 (MH⁺).

Following a similar procedure to that described in example 8 but using the corresponding starting material, the following compound is obtained:

Ex-

Reagent
Reagent

am-
Compound
for
for step
HPLC
t_R

ple
name
step a)
b)
method
(min)
m/z

8a
(R)-2-(3-
(R)-methyl
3-
4
1.42
389

aminosulfonyl-
3-
amino-

phenyl)amino-
pyrrolidine-
benzene-

4-(3-
carboxylate
sulfon-

hydroxymethy-
amide

lpyrrolidin-

1-yl)-7H-

pyrrolo[2,3-

d]pyrimidine

Example 9
2-(3-Aminosulfonylphenyl)amino-4-[3-(1-hydroxyliminoethyl)piperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine
a) 2-Chloro-4-(3-acetylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 1 section a, but using 1-(piperidin-3-yl)ethanone instead of piperidine, the desired product was obtained (39%).

LC-MS (method 2): t_R=1.75 min; m/z=279 (MH⁺).

b) 4-(3-Acetylpiperidin-1-yl)-2-(3-aminosulfonylphenyl)amino-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 2 section b, but using 3-aminobenzenesulfonamide, instead of 3-fluoro-4-methoxyphenylamine the product was obtained (37% yield).

LC-MS (method 1): t_R=6.26 min; m/z=415 (MH⁺).

c) Title Compound

To a solution of the compound obtained in previous section (96 mg, 0.233 mmol) in MeOH (3 mL) hydroxylamine hydrochloride (16.2 mg, 0.233 mmol) and sodium acetate (4 mg, 0.023 mmol) were added under Ar-atmosphere. The mixture was stirred at room temperature overnight and the resulting solution was evaporated to dryness, diluted with EtOAc and washed twice with H₂O. The combined organic phases were dried over Na₂SO₄and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 17 mg of the desired compound (13% yield).

LC-MS (method 1): t_R=6.13 min; m/z=430 (MH⁺).

Example 10
(S)-2-(3-Aminosulfonylphenyl)amino-4-(2-methoxymethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine
a) (S)-2-Chloro-4-(2-methoxymethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 1 section a, but using (S)-2-methoxymethylpyrrolidine, instead of piperidine, and 1,4-dioxane instead of EtOH, 150 mg of the desired product were obtained (83% yield).

b) (S)-2-(3-Amino-N-tert-butylsulfonylphenyl)amino-4-(2-methoxymethylpyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

c) Title Compound

To a solution of the compound obtained in the previous section (0.088 g, 0.19 mmol)) in AcN (2 mL), trifluoromethanesulfonic acid (0.16 mL) was added under Ar-atmosphere and the mixture was stirred at room temperature overnight. The resulting solution was concentrated to dryness, diluted with EtOAc and washed twice with H₂O. The organic phase was dried over Na₂SO₄and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to obtain 7 mg of the desired compound (22% yield).

LC-MS (method 4): t_R=1.77 min; m/z=403 (MH⁺).

Example 11
2-[4-(2-Hydroxyethylaminocarbonyl)phenyl]amino-4-(4-hydroxymethylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine
a) 2-(4-Ethoxycarbonylphenyl)amino-4-(4-hydroxymethylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 2 section b, but using the compound obtained in example 2c section a and ethyl 4-aminobenzoate instead of 4-(2-azabicyclo[2.2.1]heptan-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine and 3-fluoro-4-methoxyphenylamine, the desired compound was obtained.

b) 2-(4-Carboxyphenyl)amino-4-(4-hydroxymethylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 354 mg of the compound obtained in the previous section in DME (9 mL), a solution of LiOH.H₂O (188 mg) in 4.5 mL of H₂O was added. The mixture was stirred at room temperature for 40 h. and cooled to 0° C. A 1N aqueous HCl solution (4 mL) was added and the mixture was concentrated. The crude product thus obtained was chromatographed over a SCX-2 column to afford 53 mg of the desired compound.

LC-MS (method 4): t_R=1.55 min; m/z=368 (MH⁺).

c) Title Compound

To a solution of the compound obtained in the previous section (100 mg, 0.2 mmol) in DMF (3 mL), a mixture of EDC.HCl (117 mg, 0.60 mmol), HOBT (82 mg, 0.60 mmol), DIEA (87 μL, 0.60 mmol) and 2-aminoethanol (61 μL, 1.0 mmol) was added under Ar-atmosphere. The resulting mixture was stirred at room temperature overnight and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using CH₂Cl₂/MeOH/NH₃mixtures of increasing polarity as eluent, to afford 51 mg of the desired compound (62% yield).

LC-MS (method 4): t_R=1.35 min; m/z=411 (MH⁺)

HPLC
t_R

Example
Compound name
Starting material
method
(min)
m/z

11a
4-(4-
2-
4
1.53
425

hydroxymethylpiperidin-
methoxyethylamine

1-yl)-2-[4-(2-

methoxyethylaminocarbonyl)phenyl]amino-

7H-pyrrolo[2,3-

d]pyrimidine

11b
4-(4-
2-(2-aminoethyl)-1-
4
1.25
478

hydroxymethylpiperidin-
methylpyrrolidine

1-yl)-2-[(4-(2-(1-

methylpyrrolidin-2-

yl)ethyl)aminocarbonyl)phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

11c
4-(4-
4-(2-
4
1.18
480

hydroxymethylpiperidin-
aminoethyl)morpholine

1-yl)-2-[(4-(2-

(morpholin-4-

yl)ethyl)aminocarbonyl)phenyl]amino-

7H-

pyrrolo[2,3-

d]pyrimidine

Example 12
(S)-2-(3-Aminosulfonylphenyl)amino-4-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine
a) (S)-2-Chloro-4-(3-ethoxycarbonylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 1 section a, but using (S)-ethyl 3-piperidinecarboxylate instead of piperidine, the desired compound was obtained.

LC-MS (method 4): t_R=3.01 min; m/z=309 (MH⁺).

b) (S)-2-(3-Aminosulfonylphenyl)amino-4-(3-ethoxycarbonylpiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

Following a similar procedure to that described in example 2 section b, but using the compound obtained in the previous section and 3-aminobenzenesulfonamide instead of 4-(2-azabicyclo[2.2.1]heptan-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine and 3-fluoro-4-methoxyphenylamine, the desired compound was obtained.

LC-MS (method 4): t_R=2.05 min; m/z=445 (MH⁺).

c) Title Compound

To a solution of the compound obtained in the previous section (65 mg, 0.15 mmol) in THF (3 mL), a 1.4 M solution of methylmagnesium bromide in THF (0.75 mL, 1.05 mmol) was added at 0° C. The resulting mixture was stirred under Ar-atmosphere at room temperature overnight. The mixture was concentrated to dryness and the residue thus obtained was chromatographed over silica gel using CH₂Cl₂/MeOH/NH₃mixtures of increasing polarity as eluent, to afford 17 mg of the desired compound (26% yield).

LC-MS (method 4): t_R=1.78 min; m/z=431 (MH⁺)

Example 13
2-(3-Aminosulfonylphenyl)amino-4-(7-oxo-6-azabicyclo[3.2.1]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine
a) 4-(3-Carboxycyclohexylamino)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.50 g, 2.66 mmol) in THF/H₂O (1:1) (7 mL), 3-aminocyclohexane carboxylic acid (0.38 g, 2.66 mmol) and K₂CO₃(0.55 g, 3.98 mmol) were added. The reaction was stirred at 110° C. in a sealed tube for 10 h. The resulting mixture was diluted with H₂O and the phases were separated. Aqueous 1N HCl was added at 0° C. until pH=3 and extracted thrice with EtOAc/MeOH (9:1). The combined organic phases were dried over Na₂SO₄and concentrated to dryness and the crude product thus obtained was directly used in the next step.

LC-MS (method 2): t_R=0.94 min; m/z=295 (MH⁺).

a) 2-Chloro-4-(7-oxo-6-azabicyclo[3.2.1]octan-6-yl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of the product obtained in the previous section in DMF (25 mL), HBTU (1.14 g, 3.00 mmol) and DIEA (0.65 mL, 3.73 mmol) were added. The reaction was stirred under Ar-atmosphere at room temperature for 18 h. The resulting mixture was concentrated to dryness and the residue was dissolved in DMF (20 mL). DIEA (0.65 mL, 3.73 mmol) was added and the mixture was stirred overnight at 120° C. The resulting mixture was evaporated to dryness and the crude product thus obtained was chromatographed over silica gel using CHCl₃/MeOH mixtures of increasing polarity as eluent, to afford 0.15 g of the desired compound (20% yield).

LC-MS (method 2): t_R=1.95 min; m/z=277 (MH⁺).

b) Title Compound

Following a similar procedure to that described in example 2 section b, but using the compound obtained in the previous section, and 3-aminobenzenesulfonamide instead of 4-(2-azabicyclo[2.2.1]heptan-2-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine and 3-fluoro-4-methoxyphenylamine, the desired product was obtained (19% yield).

LC-MS (method 2): t_R=1.72 min; m/z=413 (MH⁺).

Example 14
Biological Assay 1
JAK3 Kinase Inhibition

In a final volume of 50 μL, 5 μL of the test product dissolved in 10% DMSO (final concentration, 0.001-10 μM), was incubated with 4 μg/mL of human JAK3 781-1124, 1 μg/mL of Poly-L-Ala, L-Glu, L-Lys, L-Tyr and ATP (0.2 μM, approximately 2×10⁵cpm of γ³³P-ATP) in HEPES buffer (60 mM, pH 7.5) with Mg²⁺chloride (3 mM), Mn²⁺chloride (3 mM), sodium orthovanadate (3 μM) and dithiothreitol (1.2 mM). The reaction was started by adding Mg²⁺[γ³³P-ATP]. After incubation for 50 min at room temperature, the reaction was quenched by the addition of 50 μL of 2% phosphoric acid solution. The reaction mixture was filtered in vacuo and washed three times with a 150 mM phosphoric acid solution. 200 μL of liquid scintillation was added before drying it and counting it.

The compounds of all examples showed more than 50% of inhibition of JAK3 activity at 10 μM in this assay.

PYRROLOPYRIMIDINE DERIVATIVES AS JAK3 INHIBITORS

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