Purine Derivatives

Abstract

Purine derivatives of Formula (I), wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as JAK3 kinase inhibitors.

Description

FIELD OF THE INVENTION

The present invention relates to a new series of purine 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 immunosuppresive agents useful for transplant rejection prevention and in the prevention or treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, systemic lupus erythematosus, type I diabetes and complications from diabetes, allergic reactions and leukemia (see e.g. O'Shea J. J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82).

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

DESCRIPTION OF THE INVENTION

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

wherein:

R₁ represents 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 R₁ can 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 SO₂ groups, and wherein R₁ can be optionally substituted with one or more R₃;

R₂ represents phenyl or a 5- or 6-membered aromatic heterocycle bonded to the purine ring 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 R₂ can 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 SO₂ groups, and wherein R₂ can be optionally substituted with one or more R₄;

R₃ and R₄ independently represent C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, halogen, —CN, —NO₂, —COR₆, —CO₂R₆, —CONR₆R₆, —OR₆, —OCOR₅, —OCONR₅R₅, —OCO₂R₅, —SR₆, —SO₂R₅, —SOR₅, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆, —NR₇CONR₆R₆, —NR₇CO₂R₅, —NR₇SO₂R₅, —C(═N—OH)R₅ or Cy₁, wherein the C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl groups can be optionally substituted with one or more R₅ and Cy₁ can be optionally substituted with one or more R₉;

R₅ represents C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl or Cy₂, wherein the C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl groups can be optionally substituted with one or more R₁₀ and Cy₂ can be optionally substituted with one or more R₁₁;

R₆ represents hydrogen or R₅;

R₇ represents hydrogen or C_1-4alkyl;

R₈ represents halogen, —ON, —NO₂, —COR₁₃, —CO₂R₁₃, —CONR₁₃R₁₃, —OR₁₃, —OCOR₁₂, —OCONR₁₂R₁₂, —OCO₂R₁₂, —SR₁₃, —SO₂R₁₂, —SOR₁₂, —SO₂NR₁₃R₁₃, —SO₂NR₇COR₁₂, —NR₁₃R₁₃, —NR₇COR₁₃, —NR₇CONR₁₃R₁₃, —NR₇CO₂R₁₂, —NR₇SO₂R₁₂, —C(═N—OH)R₁₂ or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₉ represents C_1-4alkyl that can be optionally substituted with one or more R₁₀, or R₉ represents any of the meanings described for R₁₄;

R₁₀ represents halogen, —ON, —NO₂, —COR₁₆, —CO₂R₁₆, —CONR₁₆R₁₆, —OR₁₆, —OCOR₁₅, —OCONR₁₅R₁₅, —OCO₂R₁₅, —SR₁₆, —SO₂R₁₅, —SOR₁₅, —SO₂NR₁₆R₁₆, —SO₂NR₇COR₁₅, —NR₁₆R₁₆, —NR₇COR₁₆, —NR₇CONR₁₆R₁₆, —NR₇CO₂R₁₅, —NR₇SO₂R₁₅, —C(═N—OH)R₁₅ or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₁₁ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl or any of the meanings described for R₁₄;

R₁₂ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl, Cy₃-C_1-4alkyl or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₁₃ represents hydrogen or R₁₂;

R₁₄ represents halogen, —ON, —NO₂, —COR₁₈, —CO₂R₁₈, —CONR₁₈R₁₈, —OR₁₈, —OCOR₁₇, —OCONR₁₇R₁₇, —OCO₂R₁₇, —SR₁₈, —SO₂R₁₇, —SOR₁₇, —SO₂NR₁₈R₁₈, —SO₂NR₇COR₁₇, —NR₁₈R₁₈, —NR₇COR₁₈, —NR₇CONR₁₈R₁₈, —NR₇CO₂R₁₇, —NR₇SO₂R₁₇ or —C(═N—OH)R₁₇;

R₁₅ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₁₆ represents hydrogen or R₁₅;

R₁₇ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl or cyanoC_1-4alkyl;

R₁₈ represents hydrogen or R₁₇;

or two R₁₇ groups or two R₁₈ groups on the same N atom can be bonded completing together with the N atom a saturated 5- or 6-membered 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;

Cy₁ and Cy₂ independently represent a 3- to 7-membered monocyclic or 8-to 12-membered bicyclic carbocyclic ring that can be saturated, partially unsaturated or aromatic, and which can optionally contain from 1 to 4 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 ring atoms can be optionally oxidized forming CO, SO or SO₂ groups;

Cy₃ represents a ring selected from (a)-(c):

and

R₁₉ represents 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 JAK3 kinase inhibitors and therefore can be useful for the treatment or prevention of diseases mediated by this kinase.

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

wherein:

R₁ represents 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 R₁ can 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 SO₂ groups, and wherein R₁ can be optionally substituted with one or more R₃;

R₂ represents phenyl or a 5- or 6-membered aromatic heterocycle bonded to the purine ring 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 R₂ can 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 SO₂ groups, and wherein R₂ can be optionally substituted with one or more R₄;

R₃ and R₄ independently represent C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, halogen, —CN, —NO₂, —COR_E, —CO₂R₆, —CONR₆R₆, —OR₆, —OCOR₅, —OCONR₅R₅, —OCO₂R₅, —SR₆, —SO₂R₅, —SOR₅, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆, —NR₇CONR₆R₆, —NR₇CO₂R₅, —NR₇SO₂R₅, —C(═N—OH)R₅ or Cy₁, wherein the C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl groups can be optionally substituted with one or more R₈ and Cy₁ can be optionally substituted with one or more R₉;

R₅ represents C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl or Cy₂, wherein the C_1-4alkyl, C_2-4alkenyl and C_2-4alkynyl groups can be optionally substituted with one or more R₁₀ and Cy₂ can be optionally substituted with one or more R₁₁;

R₆ represents hydrogen or R₅;

R₇ represents hydrogen or C_1-4alkyl;

R₈ represents halogen, —ON, —NO₂, —COR₁₃, —CO₂R₁₃, —CONR₁₃R₁₃, —OR₁₃, —OCOR₁₂, —OCONR₁₂R₁₂, —OCO₂R₁₂, —SR₁₃, —SO₂R₁₂, —SOR₁₂, —SO₂NR₁₃R₁₃, —SO₂NR₇COR₁₂, —NR₁₃R₁₃, —NR₇COR₁₃, —NR₇CONR₁₃R₁₃, —NR₇CO₂R₁₂, —NR₇SO₂R₁₂, —C(═N—OH)R₁₂ or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₉ represents C_1-4alkyl that can be optionally substituted with one or more R₁₀, or R₉ represents any of the meanings described for R₁₄;

R₁₀ represents halogen, —ON, —NO₂, —COR₁₆, —CO₂R₁₆, —CONR₁₆R₁₆, —OR₁₆, —OCOR₁₅, —OCONR₁₅R₁₅, —OCO₂R₁₅, —SR₁₆, —SO₂R₁₅, —SOR₁₅, —SO₂NR₁₆R₁₆, —SO₂NR₇COR₁₅, —NR₁₆R₁₆, —NR₇COR₁₆, —NR₇CONR₁₆R₁₆, —NR₇CO₂R₁₅, —NR₇SO₂R₁₅, —C(═N—OH)R₁₅ or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₁₁ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl or any of the meanings described for R₁₄;

R₁₂ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl, Cy₃-C_1-4alkyl or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₁₃ represents hydrogen or R₁₂;

R₁₄ represents halogen, —ON, —NO₂, —COR₁₈, —CO₂R₁₈, —CONR₁₈R₁₈, —OR₁₈, —OCOR₁₇, —OCONR₁₇R₁₇, —OCO₂R₁₇, —SR₁₈, —SO₂R₁₇, —SOR₁₇, —SO₂NR₁₈R₁₈, —SO₂NR₇COR₁₇, —NR₁₈R₁₈, —NR₇COR₁₈, —NR₇CONR₁₈R₁₈, —NR₇CO₂R₁₇, —NR₇SO₂R₁₇ or —C(═N—OH)R₁₇;

R₁₅ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl, cyanoC_1-4alkyl or Cy₂, wherein Cy₂ can be optionally substituted with one or more R₁₁;

R₁₆ represents hydrogen or R₁₅;

R₁₇ represents C_1-4alkyl, haloC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, hydroxyC_1-4alkyl or cyanoC_1-4alkyl;

R₁₈ represents hydrogen or R₁₇;

or two R₁₇ groups or two R₁₈ groups on the same N atom can be bonded completing together with the N atom a saturated 5- or 6-membered 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;

Cy₁ and Cy₂ independently represent a 3- to 7-membered monocyclic or 8-to 12-membered bicyclic carbocyclic ring that can be saturated, partially unsaturated or aromatic, and which can optionally contain from 1 to 4 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 ring atoms can be optionally oxidized forming CO, SO or SO₂ groups;

Cy₃ represents a ring selected from (a)-(c):

and

R₁₉ represents hydrogen or C_1-4alkyl,

for use in therapy.

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

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by 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 manufacture of a medicament for the treatment or prevention of a disease selected from transplant rejection; immune, autoimmune or inflammatory diseases; neurodegenerative diseases; and proliferative disorders. In a preferred embodiment, the disease is selected from transplant rejection and immune, autoimmune or inflammatory diseases.

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

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

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

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

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

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAKs, particularly JAK3, in a subject in need thereof, especially a human being, which comprises administering to said subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treating or preventig a disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, and proliferative disorders in a subject in need thereof, especially a human being, which comprises administering to said subject an effective amount of 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 or inflammatory diseases.

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

Another aspect of the present invention relates to a process for the preparation of a compound of formula I as defined above, which comprises:

(a) reacting a compound of formula IV with a compound of formula V

wherein R₁ and R₂ have the previously described meaning and P₁ represents an amine protecting group, followed if required by the removal of the protecting group; or(b) reacting a compound of formula X with a compound of formula III

wherein R₁ and R₂ have the previously described meaning, P₁ represents an amine protecting group, and R_a and R_b represent H or C_1-4alkyl, or can be bonded forming together with the B and O atoms a 5- or 6-membered ring that can be optionally substituted with one or more methyl groups, followed if required by the removal of the protecting group; or(c) reacting a compound of formula XV with a compound of formula XII

wherein R₄* represents —NR₆R₆ or Cy₁ bonded through a N atom to the pyridine ring, each R₂₅ independently represents hydrogen, halogen, C_1-4alkyl, C_1-4alkoxy, haloC_1-4alkoxy or —SC_1-4alky, P₁ represents an amine protecting group and R₁, Cy₁ and R₆ have the meaning previously described, followed if required by the removal of the protecting group; or(d) 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 —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.

A halogen group 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, 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 haloC_1-4alkoxy group means a group resulting from the replacement of one or more hydrogen atoms from a C_1-4alkoxy 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 trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy and nonafluorobutoxy.

A 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 Cy₃-C_1-4alkyl group means a group resulting from the replacement of one hydrogen atom from a C_1-4alkyl group with one Cy₃ group. Examples include, among others, the groups (morpholin-4-yl)methyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 4-(morpholin-4-yl)butyl, (piperazin-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-ethylpiperazin-1-yl)methyl, (4-propylpiperazin-1-yl)methyl, (4-butylpiperazin-1-yl)methyl, (1,1-dioxothiomorpholin-4-yl)methyl, 2-(1,1-dioxotiomorpholin-4-yl)ethyl, 3-(1,1-dioxothiomorpholin-4-yl)propyl and 4-(1,1-dioxothiomorpholin-4-yl)butyl.

A Cy₂, C_1-4alkyl group means a group resulting from the replacement of one hydrogen atom from a C_1-4alkyl group with one Cy₂, group as defined below.

The term Cy₁ or Cy₂ refers to a 3- to 7-membered monocyclic or a 8- to 12-membered bicyclic carbocyclic ring that can be saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms selected from N, S and O. When Cy₁ or Cy₂ are saturated or partially unsaturated, one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO₂ groups. Cy₁ and Cy₂ can be optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, the substituents can be the same or different and can be placed on any available position. Cy₁ and Cy₂ can be bonded to the rest of the molecule through any available carbon or nitrogen atom. Examples of Cy₁ and Cy₂ include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxyranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, azepinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, cycloheptanonyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2(1H)-pyridonyl, 2(1H)-pyrazinonyl, 2(1H)-pyrimidinonyl, 3(2H)-pyridazinonyl, azetidinonyl, imidazolidinonyl, oxazolidinonyl, 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, 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.

In a compound of formula I R₁ and R₂ represent a phenyl group or a 5- or 6-membered aromatic heterocycle which is bonded through a C atom to the NH group, in the case of R₁, and to the purine ring, in the case of R₂. Both the phenyl group and the 5- or 6-membered aromatic heterocycle can be optionally fused to a 5- or 6-membered carbocyclic or heterocyclic ring that can be saturated, partially unsaturated or aromatic. The R₁ and R₂ groups can thus be either monocyclic or bicyclic and can contain from 1 to 4 heteroatoms in total selected from N, O and S. When the second ring, that is, the fused 5- or 6-membered carbocyclic or heterocyclic ring, is saturated or partially unsaturated, one or more C or S atoms of said ring can be optionally oxidized forming CO, SO or SO₂ groups. R₁ can be optionally substituted with one or more R₃ and R₂ can be optionally substituted with one or more R₄, as indicated above in the definition of a compound of formula I. Each R₃ and each R₄ is independently selected from the list of possible meanings for said groups indicated in the definition of a compound of formula I. If present, the substituents on R₁ or R₂ can be placed in any available position. Examples of R₁ and R₂ 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, 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, 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.

In the above definitions of Cy₁, Cy₂, R₁ and R₂, 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 possible positions of attachment are included, unless any limitation is mentioned in the definition of the corresponding group, for example that the ring is bonded through a C atom in R₁ and R₂, in which case such limitation applies. Thus for example, in the definitions for Cy₁ and Cy₂, which do not include any limitation with regard to the position of attachment, 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 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 in the definition of a substituent two or more groups with the same numbering are indicated (e.g. —NR₇CONR₆R₆, —NR₁₆R₁₆, —CONR₁₈R₁₈, 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.

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 R₁ represents phenyl or pyridyl, which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein R₁ can 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 SO₂ groups, and wherein R₁ can be optionally substituted with one or more R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl, pyridyl or a ring of formula R_1a,

wherein in ring A X₁, X₂ and X₃ are 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 SO₂ groups, and wherein the phenyl, pyridyl and R_1a groups can be optionally substituted with one or more R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl, 3-pyridyl, 4-pyridyl or a ring of formula R_1a, each of which can be optionally substituted with one or more R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl, pyridyl, benzo[1,3]dioxolyl or benzooxazolyl, each of which can be optionally substituted with one or more R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl, 3-pyridyl, 4-pyridyl, 5-benzo[1,3]dioxolyl or 6-benzooxazolyl, each of which can be optionally substituted with one or more R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl optionally substituted with one or more R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl substituted with one or more R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl substituted with one, two or three R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl substituted with one or two R₃.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ represents phenyl substituted with one or two R₃, which are placed at positions 3, 4 and/or 5 of the phenyl ring.

In another embodiment, the invention relates to the compounds of formula I wherein each R₃ independently represents C_1-4alkyl, halogen, —CN, —COR₆, —CO₂R₆, —CONR₆R₆, —OR₆, —SR₆, —SO₂R₅, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆, —NR₇CONR₆R₆, —NR₇SO₂R₅ or Cy₁, wherein the C_1-4alkyl group can be optionally substituted with one or more R₈ and Cy₁ can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein each R₃ independently represents C_1-4alkyl, halogen, —CN, —OR₆, —SO₂R₅, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆, —NR₇SO₂R₅ or Cy₁, wherein the C_1-4alkyl group can be optionally substituted with one or more R₈ and Cy₁ can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein each R₃ independently represents C_1-4alkyl, halogen, haloC_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —CN, —OR₆, —SO₂R₅, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆, —NR₇SO₂R₅ or Cy₁, wherein Cy₁ can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁ in R₃ is Cy_1a and Cy_1a represents 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 ring atoms can be optionally oxidized forming CO, SO or SO₂ groups, wherein said Cy_1a can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁ in R₃ is Cy_1c and Cy_1c represents 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 SO₂ groups, and wherein said Cy_1c can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁ in R₃ represents a ring selected from (i)-(iii):

wherein R_9a represents hydrogen or C_1-4alkyl, and R_9b represents hydrogen, C_1-4alkyl or hydroxy.

In another embodiment, the invention relates to the compounds of formula I wherein each R₃ independently represents C_1-4alkyl, halogen, —OR₆, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or Cy_1a, wherein the C_1-4alkyl group can be optionally substituted with one or more R₈ and Cy_1a can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein each R₃ independently represents C_1-4alkyl, halogen, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —OR₆, Cy_2aC_1-4alkyl, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉, and wherein Cy_2a represents 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 SO₂ groups, and wherein said Cy_2a can be optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I wherein each R₃ independently represents C_1-4alkyl, halogen, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —OR₆, Cy_2aC_1-4alkyl, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or a ring of formula (i)-(iii), wherein Cy_2a can be optionally substituted with one or more R₁₁.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ in R₃ represents hydrogen or R₅ and R₅ represents C_1-4alkyl optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ in R₃ represents hydrogen or R₅ and R₅ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl.

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

R₁ represents phenyl substituted with one or more R₃;

each R₃ independently represents C_1-4alkyl, halogen, haloC_1-4alkyl, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —CN, —OR₆, —SO₂R₅, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆, —NR₇SO₂R₅ or Cy_1a, wherein Cy_1a can be optionally substituted with one or more R₉; and

Cy_1a represents 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 ring atoms can be optionally oxidized forming CO, SO or SO₂ groups.

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

R₁ represents a ring of formula R_1b:

one of R₂₁, R₂₂ and R₂₃ represents hydroxyC_1-4alkyl, —CN, —OR₆, —SO₂NR₆R₆, —NR₇COR₆, —NR₇SO₂R₅ or Cy_1a, wherein Cy_1a can be optionally substituted with one or more R₉; and

the remainder of R₂₁, R₂₂ and R₂₃ as well as R₂₀ and R₂₄ are independently selected from hydrogen, C_1-4alkyl, halogen and C_1-4alkoxy.

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

R₁ represents phenyl substituted with one or more, preferably one or two R₃; and

each R₃ independently represents C_1-4alkyl, halogen, —OR₆, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or Cy_1a, wherein the C_1-4alkyl group can be optionally substituted with one or more R₈ and Cy_1a can be optionally substituted with one or more R₉.

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

R₁ represents phenyl substituted with one or more, preferably one or two

R₃; and

each R₃ independently represents C_1-4alkyl, halogen, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —OR₆, Cy_2aC_1-4alkyl, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉, and wherein Cy_2a can be optionally substituted with one or more R₁₁.

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

R₁ represents phenyl substituted with one or two R₃, which are placed at positions 3, 4 and/or 5 of the phenyl ring; and

each R₃ independently represents C_1-4alkyl, halogen, hydroxyC_1-4alkyl,

C_1-4alkoxyC_1-4alkyl, —OR₆, Cy_2aC_1-4alkyl, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉, and wherein Cy_2a can be optionally substituted with one or more R₁₁.

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

R₁ represents phenyl substituted with one or more, preferably one or two R₃; and

each R₃ independently represents C_1-4alkyl, halogen, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —OR₆, Cy_2aC_1-4alkyl, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or a ring of formula (i)-(iii), wherein Cy_2a can be optionally substituted with one or more R₁₁.

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

R₁ represents phenyl substituted with one or two R₃, which are placed at positions 3, 4 and/or 5 of the phenyl ring; and

each R₃ independently represents C_1-4alkyl, halogen, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —OR₆, Cy_2aC_1-4alkyl, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆ or a ring of formula (i)-(iii), wherein Cy_2a can be optionally substituted with one or more R₁₁.

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

R₁ represents a ring of formula R_1c:

and

R₃ represents C_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₇COR₆ or Cy_1c, wherein the C_1-4alkyl group can be optionally substituted with one or more R₈ and Cy_1c can be optionally substituted with one or more R₉.

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

R₁ represents a ring of formula R_1c:

and

R₃ represents hydroxyC_1-4alkyl, Cy_2aC_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆, —SO₂NR₇COR₆, —NR₇COR₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉ and Cy_2a can be optionally substituted with one or more R₁₁.

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

R₁ represents a ring of formula R_1c:

R₃ represents hydroxyC_1-4alkyl, Cy_2aC_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆, —SO₂NR₇COR₆, —NR₇COR₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉ and Cy_2a can be optionally substituted with one or more R₁₁;

R₅ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl; and

R₆ represents hydrogen or R₅.

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

R₁ represents a ring of formula R_1c:

and

R₃ represents —SO₂NR₆R₆, —NR₇COR₆ or Cy_2aC_1-4alkyl, wherein Cy_2a can be optionally substituted with one or more R₁₁.

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

R₁ represents a ring of formula R_1c:

R₃ represents —SO₂NR₆R₆, —NR₇COR₆ or Cy_2aC_1-4alkyl, wherein Cy_2a can be optionally substituted with one or more R₁₁; and

R₆ represents hydrogen or C_1-4alkyl optionally substituted with one or more R₁₀.

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

R₁ represents a ring of formula R_1c:

R₃ represents —SO₂NR₆R₆, —NR₇COR₆ or Cy_2aC_1-4alkyl, wherein Cy_2a can be optionally substituted with one or more R₁₁; and

R₆ represents hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl.

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

R₁ represents a ring of formula R_1c:

R₃ represents —SO₂NR₆R₆, —NR₇COR₆ or Cy_2aC_1-4alkyl, wherein Cy_2a can be optionally substituted with one or more R₁₁; and

R₆ represents hydrogen or C_1-4alkyl.

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

R₁ represents a ring of formula R_1d:

and

R₃ represents C_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆ or Cy_1c, wherein the C_1-4alkyl group can be optionally subtituted with one or more R₈ and Cy_1c can be optionally substituted with one or more R₉.

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

R₁ represents a ring of formula R_1d:

and

R₃ represents hydroxyC_1-4alkyl, Cy_2aC_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉ and wherein Cy_2a can be optionally substituted with one or more R₁₁.

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

R₁ represents a ring of formula R_1d:

R₃ represents hydroxyC_1-4alkyl, Cy_2aC_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆ or Cy_1c,

wherein Cy_1c can be optionally substituted with one or more R₉ and wherein Cy_2a can be optionally substituted with one or more R₁₁; and

R₆ represents hydrogen or C_1-4alkyl optionally substituted with one or more R₁₀.

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

R₁ represents a ring of formula R_1d:

R₃ represents hydroxyC_1-4alkyl, Cy_2aC_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆ or Cy_1c,

wherein Cy_1c can be optionally substituted with one or more R₉ and wherein Cy_2a can be optionally substituted with one or more R₁₁; and

R₆ represents hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl.

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

R₁ represents a ring of formula R_1d:

R₃ represents hydroxyC_1-4alkyl, Cy_2aC_1-4alkyl, —NR₆R₆, —SO₂NR₆R₆ or a ring of formula (i)-(iii), wherein Cy_2a can be optionally substituted with one or more R₁₁;

R₆ represents hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl;

R_9a represents hydrogen or C_1-4alkyl; and

R_9b represents hydrogen, C_1-4alkyl or hydroxy.

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

R₁ represents a ring of formula R_1d:

and

R₃ represents —SO₂NR₆R₆ or Cy_1c optionally substituted with one or more R₉.

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

R₁ represents a ring of formula R_1d:

R₃ represents —SO₂NR₆R₆ or Cy_1c optionally substituted with one or more R₉; and

R₆ represents hydrogen or C_1-4alkyl optionally substituted with one or more R₁₀.

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

R₁ represents a ring of formula R_1d:

and

R₃ represents Cy_1c optionally substituted with one or more R₉.

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

R₁ represents a ring of formula R_1d:

R₃ represents a ring of formula (i)-(iii)

R_9a represents hydrogen or C_1-4alkyl; and

R_9b represents hydrogen, C_1-4alkyl or hydroxy.

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

R₁ represents a ring of formula R_1e:

R₂₆ represents halogen or —SO₂NR₆R₆; and

R₂₇ represents C_1-4alkyl, C_1-4alkoxyalkyl or —OR₆.

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

R₁ represents a ring of formula R_1e:

R₂₆ represents halogen or —SO₂NR₆R₆;

R₂₇ represents C_1-4alkyl, C_1-4alkoxyC_1-4alkyl or —OR₆; and

R₆ represents hydrogen, C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl.

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

R₁ represents a ring of formula R_1e:

R₂₆ represents halogen or —SO₂NR₆R₆;

R₂₇ represents C_1-4alkyl C_1-4alkoxyC_1-4alkyl or —OR₆; and

R₆ represents hydrogen or C_1-4alkyl.

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

R₁ represents a group selected from R_1c and R_1d:

R₃ in R_1c represents —SO₂NR₆R₆, —NR₇COR₆ or Cy_2aC_1-4alkyl, wherein Cy_2a can be optionally substituted with one or more R₁₁; and

R₃ in R_1d represents —SO₂NR₆R₆ or Cy_1c optionally substituted with one or more R₉.

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

R₁ represents a group selected from R_1c and R_1d:

R₃ in R_1c represents —SO₂NR₆R₆, —NR₇COR₆ or Cy_2aC_1-4alkyl, wherein Cy_2a can be optionally substituted with one or more R₁₁;

R₃ in R_1d represents —SO₂NR₆R₆ or Cy_1c optionally substituted with one or more R₉; and

R₆ represents hydrogen or C_1-4alkyl optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents phenyl or a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein R₂ can contain from 1 to 4 heteroatoms selected from N, O and S, wherein the adjacent atoms to the C atom at the position of attachment to the purine ring are C atoms, wherein one or more C or S atoms of the 5- or 6-membered fused ring can be optionally oxidized forming CO, SO or SO₂ groups, and wherein R₂ can be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents phenyl, pyridyl, indolyl or thienyl, which can all be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents phenyl, 3-pyridyl, 5-indolyl or 3-thienyl which can all be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents phenyl optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents phenyl substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein R₂ contains 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 SO₂ groups, and wherein R₂ can be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, which can be optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein R₂ contains from 1 to 4 heteroatoms selected from N, O and S, wherein the adjacent atoms to the C atom at the position of attachment to the purine ring are C atoms, wherein one or more C or S atoms of the 5- or 6-membered fused ring can be optionally oxidized forming CO, SO or SO₂ groups, and wherein R₂ can be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, which can be optionally fused to a 5- or 6-membered aromatic carbocyclic or heterocyclic ring, wherein R₂ contains from 1 to 4 heteroatoms selected from N, O and S, wherein the adjacent atoms to the C atom at the position of attachment to the purine ring are C atoms, and wherein R₂ can be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, wherein R₂ contains 1 or 2 heteroatoms selected from N, O and S, and wherein R₂ can be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, wherein R₂ contains 1 or 2 heteroatoms selected from N, O and S, wherein the adjacent atoms to the C atom at the position of attachment to the purine ring are C atoms, and wherein R₂ can be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents 3-pyridyl, 5-indolyl, 3-pyrrolyl, 3-thienyl or 4-pyrazolyl, which can be optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 3-pyridyl optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 4-pyrazolyl optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 3-thienyl optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 5-indolyl optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 3-pyrrolyl optionally substituted with one or more R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ is optionally substituted with one or two R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 3-pyridyl substituted with one or two R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 4-pyrazolyl substituted with one or two R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 3-thienyl substituted with one or two R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 5-indolyl substituted with one or two R₄.

In another embodiment, the invention relates to the compounds of formula wherein R₂ represents 3-pyrrolyl substituted with one or two R₄.

In another embodiment, the invention relates to the compounds of formula wherein each R₄ independently represents C_1-4alkyl, halogen, —CN, —COR₆, —CO₂R₆, —CONR₆R₆, —OR₆, —SR₆, —SO₂R₅, —SO₂NR₆R₆, —SO₂NR₇COR₅, —NR₆R₆, —NR₇COR₆, —NR₇CONR₆R₆, —NR₇SO₂R₅ or Cy₁, wherein the C_1-4alkyl group can be optionally substituted with one or more R₈ and Cy₁ can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein each R₄ independently represents C_1-4alkyl, halogen, —CN, —CONR₆R₆, —OR₆, —SR₆, —SO₂R₆, —SO₂NR₆R₆, —NR₆R₆, —NR₇COR₆ or Cy₁, wherein Cy₁ can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁ in R₄ is Cy_1b and Cy_1b represents a 3- to 7-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 ring atoms can be optionally oxidized forming CO, SO or SO₂ groups, wherein said Cy_1b can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁ in R₄ is Cy_1d and Cy_1d represents a 3- to 7-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms selected from N, S and O with the proviso that at least it contains 1 N atom, wherein said ring is bonded to the rest of the molecule through a N atom, and wherein one or more C or S ring atoms can be optionally oxidized forming CO, SO or SO₂ groups, wherein said Cy_1d can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein Cy₁ in R₄ is Cy_1c and Cy_1c represents 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 SO₂ groups, and wherein said Cy_1c can be optionally substituted with one or more R₉.

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

each R₄ independently represents C_1-4alkyl, halogen, —CN, —CONR₆R₆, —OR₆, —SR₆, —SO₂R₆, —SO₂NR₆R₆, —NR₆R₆, —NR₇COR₆ or Cy_1b, wherein Cy_1b can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein each R₄ independently represents C_1-4alkyl, halogen, —CONR₆R₆, —SR₆, —SOR₆, —SO₂R₆, —NR₆R₆, —NR₇SO₂R₅, —NR₇CONR₆R₆ or Cy_1d, wherein the C_1-4alkyl group can be optionally substituted with one or more R₈ and Cy_1d can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein each R₄ independently represents C_1-4alkyl, halogen, hydroxyC_1-4alkyl, C_1-4alkoxyC_1-4alkyl, —CONR₆R₆, —SR₆, —SOR₅, —SO₂R₅, —NR₆R₆, —NR₇SO₂R₅, —NR₇CONR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ in R₄ represents hydrogen or R₅ and R₅ represents C_1-4alkyl optionally substituted with one or more R₁₀.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ in R₄ represents hydrogen or R₅ and R₅ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl.

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

R₂ represents phenyl, pyridyl, indolyl or thienyl which can be optionally substituted with one or more R₄; and

R₄ represents C_1-4alkyl, halogen, —CN, —CONR₆R₆, —OR₆, —SR₆, —SO₂R₅, —SO₂NR₆R₆, —NR₆R₆, —NR₇COR₆ or Cy_1b, wherein Cy_1b can be optionally substituted with one or more R₉.

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

R₂ represents phenyl, pyridyl, indolyl or thienyl which can be optionally substituted with one or more R₄; and

R₄ represents C_1-4alkyl, halogen, —CN, —CONR₆R₆, —OR₆, —SR₆, —SO₂R₅, —SO₂NR₆R₆, —NR₆R₆ or —NR₇COR₆.

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

R₂ represents a group of formula R_2a:

R₄ represents —OR₆, —NR₆R₆ or Cy_1b, wherein Cy_1b can be optionally substituted with one or more R₉;

X represents CR₂₅ or N; and

each R₂₅ independently represents hydrogen, halogen, C_1-4alkyl, C_1-4alkoxy, haloC_1-4alkoxy or —SC_1-4alkyl.

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

R₂ represents a group of formula R_2a:

R₄ represents —OR₆, —NR₆R₆ or Cy_1b, wherein Cy_1b can be optionally substituted with one or more R₉;

X represents N; and

each R₂₅ independently represents hydrogen, halogen, C_1-4alkyl, C_1-4alkoxy, haloC_1-4alkoxy or —SC_1-4alkyl.

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

R₂ represents a group of formula:

and

each R₂₅ independently represents hydrogen, halogen or C_1-4alkyl.

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

R₂ represents a group of formula:

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆ or Cy_1d, wherein Cy_1d can be optionally substituted with one or more R₉; and

each R₂₅ independently represents hydrogen, halogen or C_1-4alkyl.

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

R₂ represents a group of formula:

and

R₄ represents —NR₆R₆ or Cy_1d, wherein Cy_1d can be optionally substituted with one or more R₉.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉; and

each R₂₅ independently represents hydrogen, halogen or C_1-4alkyl.

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

R₂ represents a group of formula:

and

R₄ represents —NR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉;

R₆ represents C_1-4alkyl optionally substituted with one or more R₁₀; and

each R₂₅ independently represents hydrogen, halogen or C_1-4alkyl.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉; and

R₆ represents C_1-4alkyl optionally substituted with one or more R₁₀.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉;

R₆ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl;

R₉ represents C_1-4alkyl, —OR₁₈, —CONR₁₈R₁₈ or —COR₁₈; and

each R₂₅ independently represents hydrogen, halogen or C_1-4alkyl.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆ or Cy_1c, wherein Cy_1c can be optionally substituted with one or more R₉;

R₆ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl; and

R₉ represents C_1-4alkyl, —OR₁₈, —CONR₁₈R₁₈ or —COR₁₈.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆;

R₆ represents C_1-4alkyl optionally substituted with one or more R₁₀; and

each R₂₅ independently represents hydrogen, halogen or C_1-4alkyl.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆; and

R₆ represents C_1-4alkyl optionally substituted with one or more R₁₀.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆;

R₆ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl; and

each R₂₅ independently represents hydrogen, halogen or C_1-4alkyl.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆; and

R₆ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a group of formula:

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

R₂ represents a group of formula:

R₄ represents C_1-4alkyl optionally substituted with one or more R₈.

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

R₂ represents a group of formula:

and

R₄ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a group of formula:

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

R₂ represents a group of formula:

and

R₄ represents —CONR₆R₆, —SR₆, —SOR₅, or —SO₂R₅.

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

R₂ represents a group of formula:

R₄ represents —CONR₆R₆, —SR₆, —SOR₅, or —SO₂R₅;

R₅ represents C_1-4alkyl optionally substituted with one or more R₁₀; and

R₆ represents hydrogen or R₅.

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

R₂ represents a group of formula:

R₄ represents —CONR₆R₆, —SR₆, —SOR₅, or —SO₂R₅;

R₅ represents C_1-4alkyl, haloC_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl; and

R₆ represents hydrogen or R₅.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ represents a group of formula:

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

R₂ represents a group of formula:

and

R₄ represents —NR₆R₆, —NR₇SO₂R₅, or —NR₇CONR₆R₆.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆, —NR₇SO₂R₅, or —NR₇CONR₆R₆;

R₅ represents C_1-4alkyl optionally substituted with one or more R₁₀; and

R₆ represents hydrogen or R₅.

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

R₂ represents a group of formula:

R₄ represents —NR₆R₆, —NR₇SO₂R₅, or —NR₇CONR₆R₆;

R₅ represents C_1-4alkyl, hydroxyC_1-4alkyl or C_1-4alkoxyC_1-4alkyl; and

R₆ represents hydrogen or R₅.

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 27.

In another embodiment, the invention relates to a compound of formula I selected from the list of compounds described in examples 1 to 26a.

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 used for therapeutic purposes. The term pharmaceutically acceptable salt refers to 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 a 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 by conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction or removal are well known in the art (see for example Greene T. W. and Wuts P. G. M, “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3^rd edition, 1999). As an example, as protecting groups of an amino function the tetrahydropyranyl (THP) 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 three steps by the method described in Scheme 1:

wherein R₁ and R₂ have the meaning previously described in relation with a compound of formula I; P₁ represents an amine protecting group, such as for example tetrahydropyranyl (THP); and R_a and R_b represent H or C_1-4alkyl, or can be bonded forming together with the B and O atoms a 5- or 6-membered ring that can be optionally substituted with one or more methyl groups.

In a first step (step a), a compound of formula II is reacted with a compound of formula III under the conditions reported in the literature for Suzuki couplings to give a compound of formula IV. For example, the reaction can be carried out in the presence of a base, such as Na₂CO₃, NaOH, Cs₂CO₃, CsF or Ba(OH)₂, and a palladium catalyst, such as Pd(PPh₃)₄, Pd₂(dba)₃ or Pd(OAc)₂, in a solvent, such as dimethoxyethane, toluene, N,N-dimethylformamide, tetrahydrofuran or dioxane, optionally in the presence of water, and heating, preferably at around 90° C.

In step b a compound of formula IV is reacted with an amine of formula V in the presence of a base, such as potassium tert-butoxide, Cs₂CO₃, LiHMDS, K₂CO₃ or K₂PO₃, in the presence of a phosphine, such as BINAP or 4,5-bis(diphenylphosphine)-9,9-dimethyl-9H-xanthene (Xantphos), and of a palladium catalyst, such as Pd₂(dba)₃ or Pd(OAc)₂, in a solvent such as toluene, dioxane or tetrahydrofuran, and heating, preferably at around 100° C., to give a compound of formula VI.

Finally, the protecting group of a compound of formula VI is cleavaged under the standard conditions described in the literature to give a compound I. For example, in case THP is used as P₁, the cleavage is performed by treating compound VI with a 4M dioxane/HCl_(g) mixture at room temperature.

Alternatively, the compounds of formula I can also be obtained using the method described in Scheme 2:

wherein R₁, R₂, P₁, R_a and R_b have the meaning previously described.

Step a is carried out by reacting VII with an amine of formula V in a solvent, such as 2-methoxyethanol or n-butanol, heating, preferably at around 120° C., to give a compound of formula VIII.

Thereafter a compound of formula VIII is converted into a compound of formula IX in the presence of a chlorinating agent, such as POCl₃ or dichlorophenylphosphoric acid, and a base such as N,N-dimethylaniline, and heating, preferably at reflux.

In a third step, the amino group of a compound of formula IX is protected with an amine protecting group P₁, such as THP, under standard conditions, to give a compound of formula X. If P₁ is THP, the reaction is carried out in the presence of an acid, such as p-toluensulfonic acid, pyridinium p-toluensulfonate, Amberlyst® or HCl, in a solvent, such as ethyl acetate, and heating, preferably at around 50° C.

The conversion of X into a compound of formula VI by reaction with a compound III is carried out in the same conditions described in step a of Scheme 1.

Finally, a compound of formula VI is deprotected following the method described in step c of Scheme 1, to give a compound of formula I.

Alternatively, a compound of formula I wherein R₂=6-R₄*-pyridin-3-yl and R₄*=—NR₆R₆ or Cy₁ bonded through a N atom to the pyridine ring (compounds Ia) can be also obtained by the method described in Scheme 3:

wherein R₄* represents —NR₆R₆ or Cy₁ bonded through a N atom to the pyridine ring, each R₂₅ independently represents hydrogen, halogen, C_1-4alkyl, C_1-4alkoxy, haloC_1-4alkoxy or —SC_1-4alky, and P₁, R₁, Cy₁, R_a, and R_b have the meaning previously described.

In a first step, the compound of formula II is allowed to react with a compound of formula IIIa following a similar procedure to that described for step a of Scheme 1 to give a compound of formula XI.

The compound of formula XI thus obtained is allowed to react with an amine of formula XII, in a solvent such as n-butanol, in the presence of a base such as diisopropylethylamine, and heating, preferably at around 120° C., to give a compound of formula XIII.

The compound of formula XIII thus obtained is then allowed to react with an amine of formula V following the procedure described in step b of Scheme 1 to give a compound of formula XIV.

Finally a compound of formula XIV is deprotected to give a compound of formula Ia following the procedure described in step c of Scheme 1.

Alternatively, a compound of formula Ia can be obtained from a compound of formula XI in three steps, as shown in Scheme 4:

wherein P₁, R₁, R₄* and R₂₅ have the meaning previously described.

In a first step, a compound of formula XI is allowed to react with an amine of formula V following the procedure described in step b of Scheme 1 to yield a compound of formula XV.

Next, a compound of formula XV is allowed to react with an amine of formula XII following a similar procedure to that described in step b of Scheme 3, to give a compound of formula XIV.

And, finally, the amino protecting group of a compound of formula XIV is cleavaged using the method described in step c of Scheme 1, to give a compound of formula Ia.

The compounds of formula II can be prepared from 2,6-dichloropurine following any of the methods described in the literature for protecting amino groups.

The compounds of formula III and IIIa are commercially available or can be prepared by well-known methods described in the literature.

The compounds of formula III with a cyclic structure (IIIb) can be prepared from a compound of formula XVI following the procedure shown in Scheme 5:

wherein R₂ has the meaning previously described.

The reaction is carried out by reacting a compound of formula XVI with bis(pinacolato)diboron and [1,1′-bis(diphenylphosphine)ferrocene]-dichloropalladium in the presence of a base, such as potassium acetate, in a solvent, such as N,N-dimethylformamide or dioxane, and heating, preferably at around 90° C., to give a compound of formula IIIb.

The compounds of formula V, VII, XII and XVI 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 R₁ or R₂ groups and include, for example:

the reduction of a nitro group to give an amino group, for example by treatment with hydrogen, hydrazine or formic acid in the presence of a suitable catalyst such as Pd/C; or by treatment with sodium borohydride in the presence of 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 ketone by treatment with a reducing agent such as sodium borohydride;

the reduction of a carboxylic acid or a carboxylic acid derivative to an alcohol by treatment with a reducing agent such as diisobutylaluminium hydride or 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 halogen into an amine by reaction with an amine, optionally in the presence of a suitable solvent, and preferably heating; and

the conversion of a primary amide into a —CN group 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 or prevent diseases in which JAKs, particularly JAK3, play a role in mammals, including human beings. These diseases include, but are not limited to, transplant rejection; immune, autoimmune or 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 prevented or 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 or inflammatory diseases that can be treated or prevented with the compounds of the present invention include among others, rheumatic diseases (e.g. rheumatoid arthritis and psoriatic arthritis), autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis and inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), scleroderma, type I diabetes and complications from diabetes, type B hepatitis, type C hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, suppression of HIV replication, infertility of autoimmune origin, autoimmune thyroid disease (Grave's disease), interstitial cystitis, and mast cell-mediated allergic reactions such as asthma, angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis (see e.g. Sorbera 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 0.2006, 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 or prevented 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 or prevented with the compounds of the present invention include, among others, leukemias, lymphomas, glioblastoma multiforme, colon carcinoma, as well as thromboembolic and allergic complications associated with these diseases (see e.g. Sudbeck 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 27. 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 or prevention 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 27. 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, flavouring and colouring agents.

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

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

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

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

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

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

The following examples illustrate the scope of the invention.

EXAMPLES

The following abbreviations have been used in the examples:

AcN: acetonitrileAcOH: acetic acidBINAP: 2,2′-bis(diphenylphosphine)-1,1′-binaphthyln-BuOH: 1-butanolCDI: 1,1′-carbonyldiimidazoled. doubletdd: double doublet

DIEA: N,N-diisopropylethylamine

DMAP: 4-(dimethylamino)pyridineDME: 1,2-dimethoxyethane

DMF: N,N-dimethylformamide

EDC: N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimideEtOAc: ethyl acetateEtOH: ethanolHBTU: O-Benzotriazol-1-yl-N,N,N′,N′,-tetramethyluronium hexafluorophosphateHOBT: 1-hydroxybenzotriazoleHPLC: high performance liquid chromatographyLC-MS: liquid chromatography-mass spectroscopym: multipletMeOH: methanol

NMM: N-methylmorpholine

NMR: nuclear magnetic resonancePd(PPh₃)₄: tetrakis(triphenylphosphine) palladium (0)Pd₂(dba)₃: tris(dibenzylidenacetone)dipalladium(0)s: singletTEA: triethylamineTHF: tetrahydrofuraneTMS: tetramethylsylanet_R: retention timeX-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=NH₄HCO₃ 10 mM, gradient: 0 min A 10%; 10 min A 90%; 15 min A 90%; 15.01 min A 10%.Method 2: Column X-bridge, MS C18 2.5 μm (50 mm×2.1 mm), temperature: 50° C., flow: 0.50 mL/min, eluent: A=NH₄HCO₃ 10 mM, B=AcN, C=H₂O, gradient: 0 min A 10%, B 10%; 4 min A 10%, B 85%; 4.75 min A 10%, B 85%; 4.76 min A 10%, B 10%.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 Acquity HPLC BEH C18 1.7 μm (2.1×50 mm), temperature: 40° C., flow: 0.50 mL/min, eluent: A=AcN, B=NH₄HCO₃ 10 mM, gradient: 0 min A 10%; 0.25 min A 10%; 3.00 min A 90%; 3.75 min A 90%.

Reference Example 1

2,6-Dichloro-9-(tetrahydropyran-2-yl)-9H-purine

To a suspension of 2,6-dichloropurine (2.00 g, 10.58 mmol) in EtOAc (36 mL) under Ar-atmosphere, 3,4-dihydro-2H-pyrane (2.40 mL, 26.40 mmol) and p-toluensulfonic acid (0.30 g, 1.59 mmol) were added. The resulting mixture was stirred at 57° C. for 4 h. It was allowed to reach room temperature. EtOAc was evaporated. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 2.30 g of the title compound (80% yield).

LC-MS (method 1): t_R=6.79 min; m/z=271 (MH⁻).

Reference Example 2

2-Chloro-6-(6-fluoropyridin-3-yl)-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of reference example 1 (0.40 g, 1.46 mmol) in DME (14 mL) under Ar-atmosphere, 2-fluoro-5-pyridylboronic acid (0.20 g, 1.46 mmol), Pd(PPh₃)₄ (0.17 g, 0.14 mmol) and a solution of Na₂CO₃ (0.31 g, 2.92 mmol) in H₂O (1.46 mL) were added. The mixture was heated at 90° C. overnight. After cooling, it was diluted with EtOAc and washed thrice with H₂O. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0.16 g of the title compound (33% yield).

LC-MS (method 1): t_R=8.32 min; m/z=334 (MH⁺).

Reference Example 3

2-[4-(tert-Butoxycarbonylamino)piperidin-1-yl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine

a) 5-Bromo-2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]pyridine

To a suspension of 2,5-dibromopyridine (3.43 g, 14.50 mmol) and DIEA (3.78 mL, 21.70 mmol) in n-BuOH (35 mL), 4-(tert-butoxycarbonylamino)piperidine (3.19 g, 0.06 mmol) was added. The mixture was heated for 48 h at 120° C., cooled and concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 2.83 g of the desired compound (55% yield).

¹H NMR (300 MHZ, CDCl₃) 8 (TMS): 8.17 (d, J=3.0 Hz, 1H), 7.50 (dd, J=8.8 J=3.0 Hz, 1H), 6.55 (d, J=8.8 Hz, 1H, 1H), 4.45 (broad s, 1H), 4.14 (m, 2H), 3.75 (m, 1H), 2.96 (m, 2H), 2.00 (m, 2H), 1.44 (s, 9H), 1.42 (m, 2H).

b) Title Compound

To a solution of the compound obtained in the previous section (2.83 g, 7.97 mmol) in DMF (91 mL), bis(pinacolato)diboron (4.05 g, 15.90 mmol), potassium acetate (3.90 g, 39.80 mmol) and [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium (II) (0.09 g, 0.11 mmol) were added. The reaction mixture was heated at 90° C. overnight. It was cooled until room temperature. DMF was evaporated, the residue was taken up in EtOAc and washed twice with H₂O. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford the desired compound in a quantitative yield.

LC-MS (method 2) t_R=3.18 min; m/z=404.5 (MH⁻).

Reference Example 4

2-[4-(4-Acetyl-[1,4]diazepan-1-yl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

a) 1-Acetyl-4-(4-bromophenyl)-[1,4]diazepan

To a solution of 1,4-dibromobenzene (3.30 g, 14 mmol) in toluene (44 mL) under Ar-atmosphere, sodium tert-butoxide (1.88 g, 19.60 mol), BINAP (0.17 g, 0.28 mmol), Pd₂(dba)₃ (0.13 g, 0.14 mmol) and 1-acetylhomopiperazine (2 g, 14 mmol) were added at room temperature. The reaction mixture was heated at 80° C. overnight. The resulting mixture was cooled, diluted with MeOH and filtered over Celite®. The filtrate was concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 3.42 g of the desired compound (82% yield).

LC-MS (method 1): t_R=7.08 min; m/z=299 (MH⁺).

b) Title Compound

Following a similar procedure to that described in reference example 3 section b, but using the compound obtained in the previous section instead of 5-bromo-2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]pyridine, the desired compound was obtained (56% yield).

LC-MS (method 1): t_R=7.59 min; m/z=345 (MH⁺).

Following a similar procedure to that described in reference example 4, but using in each case the corresponding starting materials, the following compound was obtained:

Reference		Starting	HPLC	tR
example	Compound name	material	method	(min)	m/z
4a	2-{4-[3-(hydroxy-	3-hydroxy-	1	8.46	318
	methyl)piperidin-1-	methyl-
	yl]phenyl}-4,4,5,5-	piperidine
	tetramethyl-	hydrochloride
	[1,3,2]dioxa-
	borolane

Reference Example 5

2-[4-(4-tert-Butoxycarbonyl-[1,4]diazepan-1-yl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

Following a similar procedure to that described in reference example 4, but using 1-tert-butoxycarbonylhomopiperazine instead of 1-acetylhomopiperazine, the desired compound was obtained (16% yield).

LC-MS (method 1): t_R=10.97 min; m/z=403 (MH⁺).

Reference Example 6

2-{4-[((4-tert-Butoxycarbonyl)piperazin-1-yl)sulfonyl]phenyl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

a) 4-Bromo-1-[((4-tert-butoxycarbonyl)piperazin-1-yl)sulfonyl]benzene

To a solution of 4-bromobenzenesulfonyl chloride (10 g, 39.13 mmol) in pyridine (120 mL), DMAP (1 mg) and 1-tert-butoxycarbonylpiperazine (7.20 g, 39.13 mmol) were added. The mixture was stirred at 60° C. for 18 h. It was cooled until room temperature and evaporated. The residue was washed with a saturated aqueous solution of NaHCO₃ and extracted thrice with EtOAc. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 8.50 g of the desired compound (53% yield).

b) Title Compound

Following a similar procedure to that described in reference example 3 section b, but using the compound obtained in the previous section instead of 5-bromo-2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]pyridine, the desired compound was obtained (63% yield).

LC-MS (method 1): t_R=6.64 min; m/z=369 (MH⁻).

Reference Example 7

3-Amino-N-(2-hydroxyethyl)benzenesulfonamide

a) N-(2-hydroxyethyl)-3-nitrobenzenesulfonamide

To a solution of 3-nitrobenzenesulfonyl chloride (0.50 g, 2.25 mmol) in THF (5 mL), 2-aminoethanol (1.83 mL, 30.38 mmol) was added. The mixture was stirred at room temperature for 18 h. It was diluted with EtOAc and washed thrice with 0.5 N HCl. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product thus obtained was directly used in the next step.

b) Title Compound

To a solution of the compound obtained in the previous section (0.64 g, 2.60 mmol) in MeOH (15 mL) under Ar-atmosphere, 10% Pd/C (64 mg) was added at room temperature. The resulting mixture was stirred under H₂ overnight, 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 0.39 g of the desired compound (69% yield).

LC-MS (method 1): t_R=2.21 min; m/z=217 (MH⁺).

Reference Example 8

[4-(3-Hydroxypiperidin-1-yl)phenyl]amine

a) 4-(3-Hydroxypiperidin-1-yl)nitrobenzene

To a solution of 4-fluoronitrobenzene (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 evaporated. The crude product thus 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

Following a similar procedure to that described in reference example 7 section b, but using the compound obtained in the previous section, the desired compound was obtained in quantitative yield.

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

Following a similar procedure to that described in reference example 8, but using in each case the corresponding starting materials, the following compounds were obtained:

Reference			HPLC	tR
Example	Compound name	Starting material	method	(min)	m/z
8a	[4-(3-tert-	3-tert-	1	5.41	308
	butoxycarbonylaminopyrrolidin-	butoxycarbonylaminopyrrolidine
	1-yl)phenyl]amine
8b	[4-(3-hydroxypyrrolidin-1-	3-	1	2.53	179
	yl)phenyl]amine	hydroxypyrrolidine
8c	[4-(3-tert-	3-tert-	1	6.67	292
	butoxycarbonylaminopiperidin-1-	butoxycarbonylaminopiperidine
	yl)phenyl]amine
8d	[4-(3-(S)-hydroxypiperidin-1-	3-(S)-	1	5.94	223
	yl)phenyl]amine	hydroxypiperidine
		hydrochloride (1)
8e	[4-(3-(R)-Hydroxypiperidin-1-	3-(R)-	1	5.94	223
	yl)phenyl]amine	hydroxypiperidine
		hydrochloride (1)
8f	[4-(cis-3,5-dimethylpiperazin-1-	cis-2,6-	5	0.56	206
	yl)phenyl]amine	dimethylpiperazine
(1) Step b was performed as described below in reference example 10 section b.

Reference Example 9

2-{4-[(S)-3-hydroxypiperidin-1-yl]phenyl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

a) 4-Bromo-1-(3-(S)-hydroxypiperidin-1-yl)benzene

To a solution of reference example 8d (0.37 g, 1.92 mmol) in 8.2 mL HBr 48%, a solution of NaNO₂ (0.133 g, 1.92 mmol) in 1.4 mL of H₂O was slowly added at 0° C. The mixture was stirred for 15 minutes and added to a solution of CuBr (0.151 g, 1.06 mmol) in 2.7 mL HBr 48%. The resulting mixture was stirred and refluxed for 2 h. The suspension thus obtained was partitioned between 2N NaOH and ethyl acetate. The organic layer was washed with aqueous NaCl, dried over Na₂SO₄ and concentrated to dryness. The desired compound was obtained (0.387 g, 84%).

b) Title Compound

Following a similar procedure to that described in reference example 3 section b, but using the compound obtained in the previous section instead of 5-bromo-2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]pyridine, the desired compound was obtained (71% yield).

LC-MS (method 1): t_R=8.02 min; m/z=304 (MH⁺).

Reference Example 10

3-(4-Aminophenyl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrazole

a) 3-(4-Nitrophenyl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-pyrazole

To a solution of 3-(4-nitrophenyl)pyrazole (200 mg, 1.06 mmol) in CHCl₃ (3 mL) and DIEA (0.55 mL, 3.18 mmol) under Ar-atmosphere, 2-(trimethylsilyl)-ethoxymethyl chloride (282 μL, 1.59 mmol) was added at 0° C. The resulting mixture was stirred at room temperature overnight. Water was added and the phases were separated. The aqueous layer was extracted twice with CHCl₃. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford the desired compound in quantitative yield.

LC-MS: (method 1): t_R=10.51 min; m/z=320 (MH⁺)

b) Title Compound

To a solution of the compound obtained in the previous section (350 mg, 1.08 mmol) and NiCl₂.6H₂O (104 mg, 044 mmol) in MeOH/THF (27 mL/14 mL), NaBH₄ (175 mg, 4.62 mmol) was added. The resulting mixture was stirred for 1 h at room temperature. The mixture was partitioned between 1N NaOH and ethyl acetate, and the organic layer was washed with aqueous NaCl and dried over Na₂SO₄. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford the desired compound in quantitative yield.

LC-MS (method 1): t_R=8.54 min; m/z=290 (MH⁺).

Reference Example 11

2-[2-Methoxycarbonyl-1-(4-toluoyl)sulfonylpyrrole-4-yl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

a) 4-Iodo-2-methyloxycarbonyl-1-(4-toluoyl)sulfonylpyrrole

To a solution of 4-iodo-2-methoxycarbonylpyrrole (4.576 g, 18.3 mmol) in 50 mL dichloromethane was added triethylamine (5.7 mL, 40.10 mmol), N,N-dimethylaminopyridine (0.245 g, 2.00 mmol), and p-toluoylsulfonyl chloride (3.823 g, 20.05 mmol). The mixture was stirred at room temperature overnight. The solution was consecutively washed with 1N HCl, NaHCO₃ saturated aqueous solution, and NaCl saturated solution. The organic layer was dried over Na₂SO₄ and concentrated to dryness. The resulting crude product was recrystallized in tert-buthylmethylether to obtain 4.562 g (62% yield) of the title compound as a yellow solid.

b) Title Compound

To a solution of the compound obtained in the previous section (1.00 g, 2.47 mmol) in DMF (30 mL), bis(pinacolato)diboron (1.25 g, 4.92 mmol), potassium acetate (1.21 g, 12.34 mmol) and [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium (II) (0.20 g, 0.245 mmol) were added. The reaction mixture was heated at 95° C. overnight under an Ar-atmosphere. The mixture was cooled to room temperature, the solvent was evaporated, and the residue was triturated with 200 mL diethyl ether. The resulting suspension was filtered and evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0.86 g of the desired compound (86% yield).

LC-MS (method 5) t_R=2.95 min; m/z=405 (MH⁺).

Reference Example 12

4-(2-Hydroxy-2-methylpropyl)phenylamine

a) Ethyl 4-benzyloxycarbonylaminophenylacetate

To a solution of ethyl 4-aminophenylacetate (1.00 g, 5.5 mmol) and Na₂CO₃ (0.77 g, 7.2 mmol) in H₂O:THF (10 mL:3 mL), benzyl chloroformiate (0.8 mL, 5.5 mmol) was added. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with dichloromethane (50 mL) and partitioned between H₂O and dichloromethane. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 1.1 g of the desired compound.

b) Benzyl 4-(2-hydroxy-2-methylpropyl)phenylcarbamate

To a solution of the compound obtained in the previous section (1.1 g, 3.537 mmol) in THF (30 mL) at 0° C., a solution of methylmagnesium bromide (12.2 mL, 3M in diethyl ether) was added. The resulting mixture was stirred for 1 h at room temperature and the resulting suspension was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0.87 g of the desired compound (82% yield).

c) Title Compound

Following a similar procedure to that described in reference example 7 section b, but using the compound obtained in the previous section, the desired compound was obtained in quantitative yield.

LC-MS (method 5): t_R=1.19 min; m/z=166 (MH⁺).

Reference Example 13

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 Na₂SO₄ and 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

Following a similar procedure to that described in reference example 7 section b, but using the compound obtained in the previous section, the desired compound was obtained (65% yield).

LC-MS (method 5): t_R=1.02 min; m/z=165 (MH⁺).

Following a similar procedure to that described in reference example 13, but using in each case the corresponding starting materials, the following compounds were obtained:

Refer-
ence		reagent for	HPLC	tR
example	Compound name	step a)	method	(min)	m/z
13a	N-(3-aminophenyl)-N-	Isobutyryl	5	1.89	193
	isopropylacetamide	chloride
13b	N-(3-aminophenyl)-N-	Cyclopropane	5	1.38	191
	cyclopropylacetamide	carbonyl
		chloride

Reference Example 14

2-[1-(Methanesulfonyl)-1H-indol-5-yl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

a) 5-Bromo-1-(methanesulfonyl)-1H-indole

To a solution of 5-bromoindole (1 g, 5.1 mmol) in THF (10 mL) under Ar-atmosphere, methanesulfonyl chloride (0.88 mL, 12.75 mmol), and TEA (2.23 mL, 15.3 mmol) were added. The mixture was stirred at room temperature overnight. The resulting mixture was evaporated and the crude product thus obtained was directly used in the next step.

LC-MS (method 4): t_R=3.30 min; m/z=276 (MH⁺).

b) Title Compound

Following a similar procedure to that described in reference example 3 section b, but using the compound obtained in the previous section instead of 5-bromo-2-[4-(tent-butoxycarbonylamino)piperidin-1-yl]pyridine, the desired compound was obtained (56% yield).

LC-MS (method 4): t_R=3.68 min; m/z=322 (MH⁺).

Example 1

6-[6-(4-Aminopiperidin-1-yl)pyridin-3-yl]-2-[4-(4-morpholino)phenyl]amino-9H-purine

a) 6-[6-[4-(tert-Butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl]-2-chloro-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using the compound obtained in reference example 3 instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained (93% yield).

LC-MS (method 1): t_R=9.72 min; m/z=514 (MH⁺).

b) 6-{6-[4-(tert-Butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl}-2-[4-(4-morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section (70 mg, 0.136 mmol) in toluene (1.75 mL) under Ar-atmosphere, sodium tert-butoxide (18 mg, 0.190 mmol), BINAP (7 mg, 0.010 mmol), Pd₂(dba)₃ (16 mg, 0.005 mmol) and [4-(4-morpholino)phenyl]amine (36 mg, 0.200 mmol) were added at room temperature. The reaction mixture was heated at 100° C. overnight. It was diluted with EtOAc and washed thrice with H₂O. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using Hexane/EtOAc mixtures of increasing polarity as eluent, to afford 63 mg of the desired compound (71% yield).

LC-MS (method 1): t_R=9.52 min; m/z=656 (MH⁺)

c) Title Compound

In a flask were mixed, under Ar-atmosphere, the compound obtained in the previous section (63 mg, 0.09 mmol) and a mixture of 4M dioxane/HCl_(g) (3 mL). It was stirred at room temperature overnight and concentrated to dryness. The resulting residue was washed with a 1N NaOH and extracted with CHCl₃. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 26 mg of the desired compound (58% yield).

LC-MS (method 1): t_R=4.95 min; m/z=472 (MH⁺).

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

Exam-		Reagent	Reagent for	HPLC	tR
ple	Compound name	for step a)	step b)	method	(min)	m/z
1a	6-[6-(4-aminopiperidin-1-	Reference	(4-	1	4.72	465
	yl)pyridin-3-yl]-2-(4-	Example 3	methanesulfonylphenyl)amine
	methanesulfonylphenyl)amino-
	9H-purine
1b	2-(4-	Reference	N-(4-	1	4.41	444
	acetamidophenyl)amino-6-	Example 3	aminophenyl)acetamide
	[6-(4-aminopiperidin-1-
	yl)pyridin-3-yl]-9H-purine
1c	2-(4-acetylphenyl)amino-6-	Reference	4′-	1	5.23	429
	[6-(4-aminopiperidin-1-	Example 3	aminoacetophenone
	yl)pyridin-3-yl]-9H-purine
1d	6-[6-(4-aminopiperidin-1-	Reference	(4-	1	6.21	433
	yl)pyridin-3-yl]-2-(4-	Example 3	methylsulfanylphenyl)amine
	methylsulfanylphenyl)amino-
	9H-purine
1e	6-[4-(4-acetyl-	Reference	2-aminothiazole	1	5.56	435
	[1,4]diazepan-1-yl)phenyl]-	Example 4
	2-(2-thiazolyl)amino-9H-
	purine
1f	6-[6-(4-aminopiperidin-1-	Reference	4-	1	5.42	431
	yl)pyridin-3-yl]-2-(4-	Example 3	aminobenzylic
	methoxymethylphenyl)amino-		alcohol
	9H-purine
1g	6-[6-(4-aminopiperidin-1-	Reference	4-aminophenol	1	4.49	403
	yl)pyridin-3-yl]-2-(4-	Example 3
	hydroxyphenyl)amino-9H-
	purine
1h	6-[6-(4-aminopiperidin-1-	Reference	(4-	1	7.00	519
	yl)pyridin-3-yl]-2-(4-	Example 3	trifluoromethanesulfonylphenyl)amine
	trifluoromethanesulfonylphenyl)amino-
	9H-purine
1i	6-[6-(4-aminopiperidin-1-	Reference	4-	1	5.55	412
	yl)pyridin-3-yl]-2-(4-	Example 3	aminobenzonitrile
	cyanophenyl)amino-9H-
	purine
1j	6-[6-(4-aminopiperidin-1-	Reference	[3-(1-	1	6.63	470
	yl)pyridin-3-yl]-2-[3-(1-	Example 3	piperidinyl)phenyl]amine
	piperidinyl)phenyl]amino-
	9H-purine
1k	6-[6-(4-aminopiperidin-1-	Reference	[4-(1-	3	3.41	470
	yl)pyridin-3-yl]-2-[4-(1-	Example 3	piperidinyl)phenyl]amine
	piperidinyl)phenyl]amino-
	9H-purine
1l	6-[6-(4-aminopiperidin-1-	Reference	4-	1	6.59	491
	yl)pyridin-3-yl]-2-(4-	Example 3	aminobenzophenone
	benzoylphenyl)amino-9H-
	purine
1m	6-[6-(4-aminopiperidin-1-	Reference	2-(4-	1	4.71	431
	yl)pyridin-3-yl]-2-[4-(2-	Example 3	aminophenyl)ethanol
	hydroxyethyl)phenyl]amino-
	9H-purine
1n	6-[6-(4-aminopiperidin-1-	Reference	[4-(4-	3	2.80	485
	yl)pyridin-3-yl]-2-[4-(4-	Example 3	methylpiperazin-
	methylpiperazin-1-		1-
	yl)phenyl]amino-9H-purine		yl)phenyl]amine
1o	6-[6-(4-aminopiperidin-1-	Reference	(3-	1	4.34	465
	yl)pyridin-3-yl]-2-(3-	Example 3	methanesulfonylphenyl)amine
	methanesulfonylphenyl)amino-
	9H-purine
1p	6-[6-(4-aminopiperidin-1-	Reference	[3-(4-	1	5.79	464
	yl)pyridin-3-yl]-2-[3-(4-	Example 3	pyridyl)phenyl]amine
	pyridyl)phenyl]amino-9H-
	purine
1q	2-(3-	Reference	N-(3-	1	4.67	444
	acetamidophenyl)amino-6-	Example 3	aminophenyl)acetamide
	[6-(4-aminopiperidin-1-
	yl)pyridin-3-yl]-9H-purine
1r	6-[6-(4-aminopiperidin-1-	Reference	N-(3-	1	4.81	480
	yl)pyridin-3-yl]-2-(3-	Example 3	aminophenyl)methylsulfonamide
	methylsulfonamidophenyl)amino-
	9H-purine
1s	6-[6-(4-aminopiperidin-1-	Reference	3-amino-N-tert-	1	4.50	466
	yl)pyridin-3-yl]-2-(3-	Example 3	butylbenzenesulfonamide
	aminosulfonylphenyl)amino-
	9H-purine
1t	6-[6-(4-aminopiperidin-1-	Reference	4-amino-N-tert-	1	4.39	466
	yl)pyridin-3-yl]-2-(4-	Example 3	butylbenzenesulfonamide
	aminosulfonylphenyl)amino-
	9H-purine
1u	6-[6-(4-aminopiperidin-1-	Reference	(3-	1	6.23	433
	yl)pyridin-3-yl]-2-(3-	Example 3	methylsulfanylphenyl)amine
	methylsulfanylphenyl)amino-
	9H-purine
1v	6-[6-(4-aminopiperidin-1-	Reference	3-	1	6.66	491
	yl)pyridin-3-yl]-2-(3-	Example 3	aminobenzophenone
	benzoylphenyl)amino-9H-
	purine
1w	6-[6-(4-aminopiperidin-1-	Reference	(3-	1	7.36	493
	yl)pyridin-3-yl]-2-(3-	Example 3	benzyloxyphenyl)amine
	benzyloxyphenyl)amino-
	9H-purine
1x	6-[6-(4-aminopiperidin-1-	Reference	(3-	1	6.76	478
	yl)pyridin-3-yl]-2-(3-	Example 3	phenylaminophenyl)amine
	phenylaminophenyl)amino-
	9H-purine
1y	6-[6-(4-aminopiperidin-1-	Reference	[4-(1-	3	2.50	471
	yl)pyridin-3-yl]-2-[4-(1-	Example 3	piperazinyl)phenyl]amine
	piperazinyl)phenyl]amino-
	9H-purine
1z	6-[6-(4-aminopiperidin-1-	Reference	[3-(1-	1	5.86	471
	yl)pyridin-3-yl]-2-[3-(1-	Example 3	piperazinyl)phenyl]amine
	piperazinyl)phenyl]amino-
	9H-purine
1aa	6-[6-(4-aminopiperidin-1-	Reference	(3,4,5-	1	5.30	477
	yl)pyridin-3-yl]-2-(3,4,5-	Example 3	trimethoxyphenyl)amine
	trimethoxyphenyl)amino-
	9H-purine
1ab	6-[6-(4-aminopiperidin-1-	Reference	(3,4-	1	5.08	447
	yl)pyridin-3-yl]-2-(3,4-	Example 3	dimethoxyphenyl)amine
	dimethoxyphenyl)amino-
	9H-purine
1ac	6-[6-(4-aminopiperidin-1-	Reference	4-amino-N,N-	1	5.54	494
	yl)pyridin-3-yl]-2-[3-(N,N-	Example 3	dimethylaminobenzenesulfonamide
	dimethylaminosulfonyl)phenyl]amino-
	9H-purine
1ad	6-[6-(4-aminopiperidin-1-	Reference	Reference	1	4.58	510
	yl)pyridin-3-yl]-2-{3-[N-(2-	Example 3	Example 7
	hydroxyethyl)aminosulfonyl]phenyl}-
	amino-9H-purine
1ae	6-[6-(4-aminopiperidin-1-	Reference	3-amino-N-	1	4.98	480
	yl)pyridin-3-yl]-2-[3-(N-	Example 3	methylbenzene
	methylaminosulfonyl)phenyl]amino-		sulfonamide
	9H-purine
1af	6-[6-(4-aminopiperidin-1-	Reference	4-amino-N-	1	4.91	480
	yl)pyridin-3-yl]-2-[4-(N-	Example 3	methylbenzene
	methylaminosulfonyl)phenyl]amino-		sulfonamide
	9H-purine
1ag	6-[6-(4-aminopiperidin-1-	Reference	(3,5-	1	5.81	447
	yl)pyridin-3-yl]-2-(3,5-	Example 3	dimethoxyphenyl)amine
	dimethoxyphenyl)amino-
	9H-purine
1ah	6-[6-(4-aminopiperidin-1-	Reference	[4-(1,1-	1	4.83	520
	yl)pyridin-3-yl]-2-[4-(1,1-	Example 3	dioxothiomorpholin-
	dioxothiomorpholin-4-		4-
	yl)phenyl]amino-9H-purine		yl)phenyl]amine
1ai	6-[6-(4-aminopiperidin-1-	Reference	[4-(N,N-	1	6.62	458
	yl)pyridin-3-yl]-2-[4-(N,N-	Example 3	diethylamino)phenyl]amine
	diethylamino)phenyl]amino-
	9H-purine
1aj	6-[6-(4-aminopiperidin-1-	Reference	4-amino-N-(2-	1	4.49	510
	yl)pyridin-3-yl]-2-{4-[N-(2-	Example 3	hydroxyethyl)benzenesulfonamide
	hydroxyethyl)aminosulfonyl]phenyl}-
	amino-9H-purine
1ak	6-[6-(4-aminopiperidin-1-	Reference	3-	1	5.85	412
	yl)pyridin-3-yl]-2-(3-	Example 3	aminobenzonitrile
	cyanophenyl)amino-9H-
	purine
1al	2-(4-	5-	3-amino-N-tert-	4	2.13	406
	aminosulfonylphenyl)amino-	indolylboronic	butylbenzenesulfonamide
	6-(1H-indol-5-yl)-9H-	acid
	purine
1am	6-[6-(4-aminopiperidin-1-	Reference	(3-	1	7.34	477
	yl)pyridin-3-yl]-2-(3-	Example 3	benzylphenyl)amine
	bencylphenyl)amino-9H-
	purine
1an	6-[6-(4-aminopiperidin-1-	Reference	Reference	1	4.88	486
	yl)pyridin-3-yl]-2-[4-(3-	Example 3	Example 8
	hydroxypiperidin-1-
	yl)phenyl]amino-9H-purine
1ao	2-(3-acetylphenyl)amino-6-	Reference	3′-	1	5.37	429
	[6-(4-aminopiperidin-1-	Example 3	aminoacetophenone
	yl)pyridin-3-yl]-9H-purine
1ap	6-[4-(4-acetyl-	Reference	(3,4-	1	6.69	472
	[1,4]diazepan-1-yl)phenyl]-	Example 4	methylendioxyphenyl)amine
	2-(3,4-
	methylendioxyphenyl)amino-
	9H-purine
1aq	6-[4-(4-acetyl-	Reference	N-tert-	1	5.41	511
	[1,4]diazepan-1-yl)phenyl]-	Example 4	butoxycarbonyl-
	2-[4-(piperidin-3-		3-(4-
	yl)phenyl]amino-9H-purine		aminophenyl)piperidine
1ar	6-[4-(4-acetyl-	Reference	Reference	1	5.26	512
	[1,4]diazepan-1-yl)phenyl]-	Example 4	Example 8a
	2-[4-(3-aminopyrrolidin-1-
	yl)phenyl]amino-9H-purine
1as	6-[4-([1,4]diazpan-1-	Reference	[4-(4-	1	5.67	471
	yl)phenyl]-2-[4-(4-	Example 5	morpholino)phenyl]amine
	morpholino)phenyl]amino-
	9H-purine
1at	6-[4-(4-acetyl-	Reference	[4-(4-	1	5.91	513
	[1,4]diazepan-1-yl)phenyl]-	Example 4	morpholino)phenyl]amine
	2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
1au	6-[4-(4-acetyl-	Reference	Reference	1	5.62	527
	[1,4]diazepan-1-yl)phenyl]-	Example 4	Example 8
	2-[4-(3-hydroxypiperidin-1-
	yl)phenyl]amino-9H-purine
1av	2-(3-acetylphenyl)amino-6-	3-	3′-	4	2.90	360
	(3-methoxyphenyl)-9H-	methoxyphenylboronic	aminoacetophenone
	purine	acid
1aw	6-[4-(4-acetyl-	Reference	3-	1	5.21	429
	[1,4]diazepan-1-yl)phenyl]-	Example 4	aminopyridine
	2-(3-pyridyl)amino-9H-
	purine
1ax	6-[4-(4-acetyl-	Reference	4-	1	5.10	429
	[1,4]diazepan-1-yl)phenyl]-	Example 4	aminopyridine
	2-(4-pyridyl)amino-9H-
	purine
1ay	2-(4-	3-	4-amino-N-tert-	4	3.85	435
	aminosulfonylphenyl)amino-	trifluoromethylphenyl	butylbenzenesulfonamide
	6-(3-	boronic
	trifluoromethylphenyl)-9H-	acid
	purine
1az	2-(4-	3-	4-amino-N-tert-	4	2.33	397
	aminosulfonylphenyl)amino-	methoxyphenylboronic	butylbenzenesulfonamide
	6-(3-methoxyphenyl)-9H-	acid
	purine
1ba	2-(4-	3-	4-amino-N-tert-	4	2.68	401
	aminosulfonylphenyl)amino-	chlorophenylboronic	butylbenzenesulfonamide
	6-(3-chlorophenyl)-9H-	acid
	purine
1bb	6-[6-(4-aminopiperidin-1-	Reference	6-amino-2-	1	4.93	442
	yl)pyridin-3-yl]-2-(2-	Example 3	methylbenzooxazol
	methylbenzooxazol-6-
	yl]amino-9H-purine
1bc	6-[4-(N-	6-[4-(N-	3-amino-N-tert-	4	1.92	424
	acetyl)aminophenyl]-2-(3-	acetyl)aminophenyl]boronic	butylbenzenesulfonamide
	aminosulfonylphenyl)amino-	acid
	9H-purine
1bd	2-[4-(3-hydroxypyrrolidin-1-	3-	Reference	4	2.12	403
	yl)phenyl]amino-6-(3-	methoxyphenylboronic	Example 8b
	methoxyphenyl)-9H-purine	acid
1be	2-(3-	3-	(3-	4	3.42	409
	phenylaminophenyl)amino-	methoxyphenylboronic	phenylaminophenyl)amine
	6-(3-methoxyphenyl)-9H-	acid
	purine
1bf	2-[4-(3-aminopyrrolidin-1-	3-	Reference	4	1.72	402
	yl)phenyl]amino-6-(3-	methoxyphenylboronic	Example 8a
	methoxyphenyl)-9H-purine	acid
1bg	2-[4-(3-hydroxypiperidin-1-	3-	Reference	4	1.73	417
	yl)phenyl]amino-6-(3-	methoxyphenylboronic	Example 8
	methoxyphenyl)-9H-purine	acid
1bh	2-(3-	3-	(3-	4	3.88	447
	phenylaminophenyl)amino-	trifluoromethylphenyl	phenylaminophenyl)amine
	6-(3-trifluoromethylphenyl)-	boronic
	9H-purine	acid
1bi	2-(3-	3-	(3-	4	3.37	385
	phenylaminophenyl)amino-	thiophenboronic	phenylaminophenyl)amine
	6-(thien-3-yl)-9H-purine	acid
1bj	2-(3-	3-	3-amino-N-tert-	4	2.38	397
	aminosulfonylphenyl)amino-	methoxyphenylboronic	butylbenzenesulfonamide
	6-(3-methoxyphenyl)-9H-	acid
	purine
1bk	2-(3-	3-	3-amino-N-tert-	4	2.87	435
	aminosulfonylphenyl)amino-	trifluoromethylphenyl	butylbenzenesulfonamide
	6-(3-	boronic
	trifluoromethylphenyl)-9H-	acid
	purine
1bl	6-(1H-indol-5-yl)-2-(3-	5-	(3-	4	3.05	418
	phenylaminophenyl)amino-	indolylboronic	phenylaminophenyl)amine
	9H-purine	acid
1bm	2-(3-	3-	3-amino-N-tert-	4	2.25	373
	aminosulfonylphenyl)amino-	thiophenboronic	butylbenzenesulfonamide
	6-(thien-3-yl)-9H-purine	acid
1bn	6-(2,5-difluorophenyl)-2-(3-	2,5-	(3-	4	3.22	415
	phenylaminophenyl)amino-	difluorophenyl	phenylaminophenyl)amine
	9H-purine	boronic
		acid
1bo	6-(3-	3-	(3-	4	3.15	457
	methanesulfonylphenyl)-2-	methanesulfonylphenylboronic	phenylaminophenyl)amine
	(3-	acid
	phenylaminophenyl)amino-
	9H-purine
1bp	6-[4-(N-	6-[4-(N-	(3-	4	2.85	436
	acetyl)aminophenyl]-2-(3-	acetyl)aminophenyl]boronic	phenylaminophenyl)amine
	phenylaminophenyl)amino-	acid
	9H-purine
1bq	2-(3-	3-	3-amino-N-tert-	4	2.12	445
	aminosulfonylphenyl)amino-	methanesulfonylphenylboronic	butylbenzenesulfonamide
	6-(3-	acid
	methanesulfonylphenyl)-
	9H-purine
1br	2-(3-	Reference	3-amino-N-tert-	1	5.44	466
	Aminosufonylphenyl)amino-	example 9	butylbenzenesulfonamide
	6-{4-[(S)-3-
	hydroxypiperidin-1-
	yl]phenyl}-9H-purine
1bs	2-[3-	4-	3-	5	1.29	424
	(aminosulfonyl)phenyl]amino-	(methylaminocarbonyl)phenyl	aminobenzenesulfonamide (1)
	6-(4-	boronic
	(methylaminocarbonyl)phenyl)-	acid
	9H-purine
1bt	2-[3-	4-	N-(3-	5	1.48	428
	(acetylamino)phenyl]amino-	(cyclopropylaminocarbonyl)phenyl	aminophenyl)acetamide (1)
	6-(4-	boronic
	(cyclopropylaminocarbonyl)phenyl)-	acid
	9H-purine
1bu	2-[3-	3-	N-(3-	5	1.31	388
	(acetylamino)phenyl]amino-	carbamoylphenylboronic	aminophenyl)acetamide (1)
	6-(3-carbamoyl)phenyl-	acid
	9H-purine
1bv	2-[3-	3-	3-	5	1.26	410
	(aminosulfonyl)phenyl]amino-	carbamoylphenylboronic	aminobenzenesulfonamide (1)
	6-(3-carbamoyl)phenyl-	acid
	9H-purine
1bw	6-(3-carbamoyl)phenyl-2-	3-	[4-(4-	5	1.47	416
	[4-(4-	carbamoylphenylboronic	morpholino)phenyl]amine (1)
	morpholino)phenyl]amino-	acid
	9H-purine
1bx	6-(3-carbamoyl)phenyl-2-	3-	4-(2-	5	1.33	375
	[4-(2-	carbamoylphenylboronic	hydroxyethyl)phenylamine (1)
	hydroxyethyl)phenyl]amino-	acid
	9H-purine
1by	6-(3-carbamoyl)phenyl-2-	3-	Reference	5	1.23	454
	[4-(2-	carbamoylphenylboronic	Example 7 (1)
	hydroxyethyl)sulfonylphenyl]amino-	acid
	9H-purine
1bz	2-[4-(2-	3-	Reference	5	1.61	417
	hydroxyethyl)sulfonylphenyl]amino-	thiopheneboronic	Example 7 (1)
	6-(thien-3-yl)-9H-	acid
	purine
1ca	6-(3-carbamoyl)phenyl-2-	3-	[4-(4-	5	1.37	429
	[4-(4-methylpiperazin-1-	carbamoylphenylboronic	methylpiperazin-
	yl)phenyl]amino-9H-purine	acid	1-
			yl)phenyl]amine (1)
1cb	6-(4-acetylamino)phenyl-2-	4-	2-methyl-5-	4	2.05	438
	(4-methyl-3-	(acetylamino)phenyl	aminobenzenesulfonamide
	aminosulfonylphenyl)amino-	boronic
	9H-purine	acid
1cc	6-(4-acetylamino)phenyl-2-	4-	5-amino-2-	4	1.87	454
	(4-methoxy-3-	(acetylamino)phenyl	methoxybenzene
	aminosulfonylphenyl)amino-	boronic	sulfonamide
	9H-purine	acid
1cd	6-(4-acetylamino)phenyl-2-	4-	3-amino-N-	4	2.15	438
	(3-	(acetylamino)phenyl	methylbenzene
	methylaminosulfonylphenyl)amino-	boronic	sulfonamide
	9H-purine	acid
1ce	6-(3-carbamoyl)phenyl-2-	3-	3-(pyrrolidin-1-	5	1.35	451
	[3-(pyrrolidin-1-	carbamoylphenylboronic	ylmethyl)aniline (1)
	ylmethyl)phenyl]amino-9H-	acid
	purine
1cf	6-(3-	3-	5-amino-2-	4	2.12	475
	methanesulfonyl)phenyl-2-	(methanesulfonyl)phenylboronic	methoxybenzenesulfonamide (1)
	(4-methoxy-3-	acid
	aminosulfonylbenzene)amino-
	9H-purine
1cg	2-(3-	4-N-	3-	5	1.74	410
	Aminosufonylphenyl)amino-	(dimethylamino)phenyl	aminobenzenesulfonamide (1)
	6-(4-	boronic
	dimethylaminophenyl)-9H-	acid
	purine
1ch	2-[3-	3-	N-(3-	5	1.90	391
	(acetylamino)phenyl]amino	(methylsulfanyl)phenylboronic	aminophenyl)acetamide
	6-(3-	acid
	methylsulfanylphenyl)-9H-
	purine
1ci	2-[4-(3-(R)-	3-	Reference	1	7.16	433
	hydroxypiperidin-1-	(methylsulfanyl)phenylboronic	Example 8e (1)
	yl)phenyl]amino-6-(3-	acid
	methylsulfanylphenyl)-9H-
	purine
1cj	2-(3-	4-	3-	1	6.72	413
	aminosulfonyl)phenylamino-	(methylsulfanyl)phenylboronic	aminobenzenesulfonamide (1)
	6-(4-	acid
	methylsulfanylphenyl)-9H-
	purine
1ck	2-[3-	3-	N-(3-	5	1.45	423
	(acetylamino)phenyl]amino	(Methanesulfonyl)phenylboronic	aminophenyl)acetamide (1)
	6-(4-	acid
	methanesulfonyl)phenyl-
	9H-purine
1cl	2-[(4-piperidin-3-	3-	4-(N-tert-	4	1.72	377
	yl)phenyl]amino-6-(thien-3-	thiopheneboronic	butoxycarbonylpiperidin-
	yl)-9H-purine	acid	3-
			yl)phenylamine
1cm	2-(4-	3-	2-(4-	4	2.37	338
	hydroxyethylphenyl)amino-	thiopheneboronic	aminophenyl)ethanol
	6-(thien-3-yl)-9H-purine	acid
1cn	6-[4-(N-	4-(N-	3,4-	4	2.15	405
	acetyl)aminophenyl]-2-	acetyl)aminophenylboronic	dimethoxyphenylamine
	(3,4-	acid
	dimethoxyphenyl)amino-
	9H-purine
1co	2-[3-	3-	N-(3-	4	2.23	423
	(acetylamino)phenyl]amino-	(methanesulfonyl)phenylboronic	aminophenyl)acetamide
	(3-	acid
	methanesulfonyl)phenyl-
	9H-purine
1cp	2-(3-hydroxyphenyl)amino-	3-	3-	4	2.27	382
	6-(3-	(methanesulfonyl)phenylboronic	hydroxyaniline
	methanesulfonyl)phenyl-	acid
	9H-purine
1cq	2-[4-(1,1-	3-	[4-(1,1-	4	2.33	499
	dioxothiomorpholin-4-	(methanesulfonyl)phenylboronic	dioxothiomorpholin-
	yl)phenyl]amino-6-(3-	acid	4-
	methanesulfonyl)phenyl-		yl)phenyl]amine
	9H-purine
1cr	2-(3,4-	3-	3,4-	4	2.48	426
	dimethoxyphenyl)amino-6-	(methanesulfonyl)phenylboronic	dimethoxyphenylamine
	(3-	acid
	methanesulfonyl)phenyl-
	9H-purine
1cs	6-[4-(N-	4-(N-	[4-(1,1-	4	2.07	478
	acetyl)amino]phenyl-2-[4-	acetyl)aminophenylboronic	dioxothiomorpholin-
	(1,1-dioxothiomorpholin-4-	acid	4-
	yl) phenyl]amino-9H-purine		yl)phenyl]amine
1ct	2-[(4-	3-	2-(4-	2	2.22	410
	hydroxyethyl)phenyl)]amino-	(methanesulfonyl)phenylboronic	aminophenyl)ethanol
	6-(3-	acid
	methanesulfonyl)phenyl-
	9H-purine
1cu	6-(3-	3-	3-	4	2.93	411
	methanesulfonyl)phenyl-2-	(methanesulfonyl)phenylboronic	nitrophenylamine
	(3-nitrophenyl)amino-9H-	acid
	purine
1cv	6-[4-	4-	[4-(4-	5	2.00	416
	(dimethylamino)]phenyl-2-	(dimethylamino)phenylboronic	morpholino)phenyl]amine
	[4-(4-	acid
	morpholino)phenyl]amino-
	9H-purine
1cw	2-[(3-	3-	Ethyl-3-	4	3.02	438
	ethoxycarbonyl)phenyl]amino-	(methanesulfonyl)phenylboronic	aminobenzoate
	6-(3-	acid
	methanesulfonyl)phenyl-
	9H-purine
1cx	6-(4-N-	N-tert-	[4-(4-	4	1.90	402
	methylamio)phenyl-2-[4-	butoxycarbonyl-	morpholino)phenyl]amine
	(4-	N-
	morpholino)phenyl]amino-	methylamine-
	9H-purine	4-
		(4,4,5,5-
		tetramethyl-
		1,3,2-
		dioxoborolan-
		2-
		yl)aniline
1cy	2-(3-	4-	3-	5	1.13	410
	aminosufonylphenyl)amino-	carbamoylphenylboronic	aminobenzenesulfonamide (1)
	6-(4-carbamoylphenyl)	acid
	9H-purine
1cz	2-[(3-fluoro-4-	3-	3-fluoro-4-	4	2.77	414
	methoxy)phenyl]amino-6-	(methanesulfonyl)phenylboronic	methoxyaniline (1)
	(3-	acid
	methanesulfonyl)phenyl-
	9H-purine
1da	6-(3-	3-	4-[4-tert-	4	1.63	449
	methanesulfonyl)phenyl-2-	(methanesulfonyl)phenylboronic	butoxycarbonylpiperazin-
	[(4-piperazin-1-	acid	1-
	yl)phenyl]amino-9H-purine		yl]phenylamine
1db	6-[4-(N-	4-(N-	3-(pyrrolidin-1-	4	1.53	428
	acetyl)amino]phenyl-2-[(3-	acetyl)aminophenylboronic	ylmethyl)aniline (1)
	pyrrolidin-1-ylmethyl)phenyl]amino-	acid
	9H-purine
1dc	6-(3-	3-	3-(pyrrolidin-1-	4	1.63	449
	methanesulfonyl)phenyl-2-	(methanesulfonyl)phenylboronic	ylmethyl)aniline (1)
	[(3-pyrrolidin-1-	acid
	ylmethyl)phenyl]amino-9H-
	purine
1dd	6-(3-	3-	N-tert-	4	1.42	435
	methanesulfonyl)phenyl-2-	(methanesulfonyl)phenylboronic	butoxycarbonyl-
	[3-(2-	acid	2-(3-
	pyrrolidinyl)phenyl]amino-		aminophenyl)pyrrolidine (1)
	9H-purine
1de	2-(3-	Reference	3-	4	2.55	484
	aminosufonylphenyl)amino-	Example	aminobenzenesulfonamide (1)
	6-[1-(methanesulfonyl)-	14
	1H-indol-5-yl]-9H-purine
(1) In section b, wo equivalents of K2CO3 were used instead of NaOtBu, 0.1 equivalents of X-Phos were used instead of BINAP, and tert-butanol was used instead of toluene.

Example 2

6-[6-(4-Acetyl[1,4]diazepan-1-yl)pyridin-3-yl]-2-[4-(4-morpholino)phenyl]amino-9H-purine

a) 6-[6-(4-Acetyl[1,4]diazepan-1-yl)pyridin-3-yl]-2-chloro-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of reference example 2 (0.30 g, 0.89 mmol) and DIEA (0.47 mL, 2.69 mmol) in n-BuOH (25 mL), N-acetylhomopiperazine (0.51 g, 3.59 mmol) was added. The mixture was heated for 18 h at 120° C., it was allowed to cool, and was concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0.26 g of the desired compound (63% yield).

LC-MS (method 1): t_R=7.24 min; m/z=456 (MH⁺).

b) 6-[6-(4-Acetyl[1,4]diazepan-1-yl)pyridin-3-yl]-2-[4-(4-morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 1 section b, but using the compound obtained in the previous section, the desired compound was obtained (76% yield).

LC-MS (method 2): t_R=2.55 min; m/z=598 (MH⁺).

c) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section, the title compound of the example was obtained (53% yield).

LC-MS (method 1): t_R=4.34 min; m/z=514 (MH⁺).

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

		reagent for step	reagent for	HPLC	tR
Example	Compound name	a)	step b)	method	(min)	m/z
2a	6-[6-(3-hydroxypiperidin-1-	3-	(3-	1	7.45	479
	yl)pyridin-3-yl]-2-(3-	hydroxypiperidine	phenylaminophenyl)amine
	phenylaminophenyl)amino-	hydrochloride
	9H-purine
2b	6-[6-(4-	N-	(3-	1	7.07	520
	acetyl[1,4]diazepan-1-	acetylhomopiperazine	phenylaminophenyl)amine
	yl)pyridin-3-yl]-2-(3-
	phenylaminophenyl)amino-
	9H-purine
2c	6-[6-(4-	N-	Reference	1	5.35	528
	acetyl[1,4]diazepan-1-	acetylhomopiperazine	Example 8
	yl)pyridin-3-yl]-2-[4-(3-
	hydroxypiperidin-1-
	yl)phenyl]amino-9H-purine
2d	6-[6-(4-	N-	(3-	1	6.69	473
	acetyl[1,4]diazepan-1-	acetylhomopiperazine	ethoxyphenyl)amine
	yl)pyridin-3-yl]-2-(3-
	ethoxyphenyl)amino-9H-
	purine
2e	2-[4-(3-hydroxypiperidin-1-	3-	Reference	3	3.58	487
	yl)phenyl]amino-6-[6-(3-	hydroxypiperidine	Example 8
	hydroxypiperidin-1-	hydrochloride
	yl)pyridin-3-yl]-9H-purine
2f	6-[6-(3-hydroxypiperidin-1-	3-	[4-(4-	3	4.20	473
	yl)pyridin-3-yl]-2-[4-(4-	hydroxypiperidine	morpholino)phenyl]amine
	morpholino)phenyl]amino-	hydrochloride
	9H-purine
2g	6-[6-(3-aminopiperidin-1-	3-N-tert-	[4-(4-	3	3.90	472
	yl)pyridin-3-yl]-2-[4-(4-	butoxycarbonylaminopiperidine	morpholino)phenyl]amine
	morpholino)phenyl]amino-
	9H-purine
2h	6-[6-(3-aminopiperidin-1-	3-N-tert-	(3-	1	6.52	431
	yl)pyridin-3-yl]-2-(3-	butoxycarbonylaminopiperidine	ethoxyphenyl)amine
	ethoxyphenyl)amino-9H-
	purine
2i	6-[6-(3-aminopiperidin-1-	3-N-tert-	(3-	1	7.13	478
	yl)pyridin-3-yl]-2-(3-	butoxycarbonylaminopiperidine	phenylaminophenyl)amine
	phenylaminophenyl)amino-
	9H-purine
2j	6-[6-(3-aminopiperidin-1-	3-N-tert-	Reference	1	5.16	486
	yl)pyridin-3-yl]-2-[4-(3-	butoxycarbonylaminopiperidine	Example 8
	hydroxypiperidin-1-
	yl)phenyl]amino-9H-purine
2k	6-[6-(4-	N-	3-amino-N-	1	4.93	508
	acetyl[1,4]diazepan-1-	acetylhomopiperazine	tert-
	yl)pyridin-3-yl]-2-(3-		butylbenzenesulfonamide
	aminosulfonylphenyl)amino-
	9H-purine
2l	2-(3-ethoxyphenyl)amino-	N-tert-	(3-	1	6.18	417
	6-[6-(piperazin-1-	butoxycarbonylpiperazine	ethoxyphenyl)amine
	yl)pyridin-3-yl]-9H-purine
2m	2-(3-	N-tert-	3-amino-N-	1	4.27	452
	aminosulfonylphenyl)amino-	butoxycarbonylpiperazine	tert-
	6-[6-(piperazin-1-		butylbenzenesulfonamide
	yl)pyridin-3-yl]-9H-purine
2n	2-(3-	N-tert-	(3-	1	6.81	464
	phenylaminophenyl)amino-	butoxycarbonylpiperazine	phenylaminophenyl)amine
	6-[6-(piperazin-1-
	yl)pyridin-3-yl]-9H-purine
2o	6-[6-(4-methylpiperazin-1-	N-	[4-(4-	4	1.37	472
	yl)pyridin-3-yl]-2-[4-(4-	methylpiperazine	morpholino)phenyl]amine
	morpholino)phenyl]amino-
	9H-purine
2p	6-(6-	cyclohexylamine	[4-(4-	4	1.90	471
	cyclohexylaminopyridin-3-		morpholino)phenyl]amine
	yl)-2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
2q	2-[4-(4-	N-tert-	[4-(4-	4	1.35	458
	morpholino)phenyl]amino-	butoxycarbonylpiperazine	morpholino)phenyl]amine
	6-[6-(piperazin-1-
	yl)pyridin-3-yl]-9H-purine
2r	2-(3-	N-	3-	5	1.90	439
	aminosufonylphenyl)amino-	methylpropylamine	aminobenzenesulfonamide (1)
	6-[6-(N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
2s	2-(3-	N-	N-(3-	5	1.89	417
	acetylaminophenyl)amino-	methylpropylamine	aminophenyl)acetamide
	6-[6-(N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
2t	2-(3-	4-	N-(3-	4	1.5	445
	acetylaminophenyl)amino-	hydroxypiperidine (2)	aminophenyl)acetamide
	6-[6-(4-hydroxypiperidin-1-
	yl)pyridin-3-yl]-9H-purine
2u	2-(3-acetylphenyl)amino-	4-	3′-	4	1.75	430
	6-[6-(4-hydroxypiperidin-1-	hydroxypiperidine (2)	aminoacetophenone (1)
	yl)pyridin-3-yl]-9H-purine
2v	2-(3-	4-	3-	4	1.47	467
	aminosufonylphenyl)amino-	hydroxypiperidine (2)	aminobenzenesulfonamide (1)
	6-[6-(4-hydroxypiperidin-
	1-yl)pyridin-3-yl]-9H-
	purine
2w	6-[6-(3-hydroxypiperidin-1-	3-	Reference	4	167	454
	yl)pyridin-3-yl]-2-[4-	hydroxypiperidine	Example 10 (3)
	(pyrazol-3-	hydrochloride
	yl)phenyl]amino-9H-purine
(1) Two equivalents of K2CO3 were used instead of NaOtBu, 0.1 equivalents of X-Phos were used instead of BINAP, and tert-buthanol was used instead of toluene.
(2) Using ethanol, instead of n-butanol.
(3) An additional deprotection step was necessary: over a solution of the product obtained in section c (1 eq) in THF (10 mL) 4.8 eq. of a 1M solution of TBAF were added. The reaction was refluxed for 5 h and the mixture thus obtained was partitioned between H2O and dichloromethane. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product thus obtained was chromatographed over silica gelusing CHCl3:MeOH:NH3 mixtures of increasing polarity as eluent, to afford the desired compound.

Example 3

6-[6-(4-Acetylpiperazin-1-yl)pyridin-3-yl]-2-(3-phenylaminophenyl)amino-9H-purine

To a solution of example 2n (24.90 mg, 0.05 mmol) in CH₂Cl₂ (0.50 mL) and TEA (11.22 μL, 0.08 mmol) under Ar-atmosphere, acetic anhydride (5.58 μL, 0.06 mmol) was added at 0° C. The resulting mixture was stirred at room temperature for 1 h. Water was added and the phases were separated. The aqueous layer was extracted twice with CH₂Cl₂. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using 10% EtOAc/MeOH as eluent, to afford 16.4 mg of the title compound of the example (60% yield).

LC-MS (method 1): t_R=6.82 min; m/z=506 (MH⁺).

Following a similar procedure to that described in example 3, but using in each case the corresponding starting materials, these compounds were obtained:

		Starting	HPLC
Example	Compound name	material	method	tR (min)	m/z
3a	6-[6-(4-acetylpiperazin-1-yl)pyridin-3-yl]-2-	Example	1	6.40	459
	(3-ethoxyphenyl)amino-9H-purine	2l
3b	6-[6-(4-acetylpiperazin-1-yl)pyridin-3-yl]-2-	Example	1	4.75	494
	(3-aminosulfonylphenyl)amino-9H-purine	2m

Example 4

6-[6-(4-Aminopiperidin-1-yl)pyridin-3-yl]-2-[3-(4-morpholino)phenyl]amino-9H-purine

a) 6-Hydroxy-2-[3-(4-morpholino)phenyl]amino-9H-purine

To a solution of 2-bromohypoxanthine (0.50 g, 2.32 mmol) in 2-methoxyethanol (6 mL) and H₂O (5 mL), [3-(4-morpholino)phenyl]amine (0.86 g, 4.87 mmol) was added. The mixture was heated for 18 h at 120° C. It was cooled and H₂O (20 mL) was added. A white solid precipitated which was separated by filtration and dried under vacuum. 0.71 g of the desired compound was obtained (99% yield).

LC-MS (method 1): t_R=3.62 min; m/z=313 (MH⁺).

b) 6-Chloro-2-[3-(4-morpholino)phenyl]amino-9H-purine

In a flask were mixed, under Ar-atmosphere, the compound obtained in the previous section (0.71 g, 2.30 mmol), POCl₃ (5.5 mL) and N,N-dimethylaniline (0.70 mL). The mixture was refluxed for 1 h. It was cooled and, at 0° C., the mixture was poured over H₂O. Sodium acetate was added until pH=4. A white solid precipitated which was separated by filtration and dried in a vacuum heater. 0.46 g of the desired compound was obtained (61% yield).

LC-MS (method 2): t_R=2.13 min; m/z=331 (MH⁺).

c) 6-Chloro-2-[3-(4-morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 1, but using the compound obtained in the previous section, 0.41 g of the desired compound was obtained (71% yield).

LC-MS (method 1): t_R=7.34 min; m/z=415 (MH⁺).

d) 6-[6-[4-(tert-Butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl]-2-[3-(4-morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 1 section a, but using the compound obtained in the previous section, the desired compound was obtained (50% yield).

LC-MS (method 1): t_R=7.67 min; m/z=656 (MH⁺).

e) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section, the title compound of the example was obtained (8% yield).

LC-MS (method 1): t_R=5.52 min; m/z=472 (MH⁺).

Following a similar procedure to that described in example 4, but using in each case the corresponding starting materials, these compounds were obtained:

		reagent for	reagent for step	HPLC	tR
Example	Compound name	step a)	b)	method	(min)	m/z
4a	2-(3-ethoxyphenyl)amino-6-	(3-	3-pyridylboronic	1	6.48	333
	(3-pyridyl)-9H-purine	methoxyphenyl)amine	acid
4b	6-[6-(4-aminopiperidin-1-	aniline	Reference	1	5.51	387
	yl)pyridin-3-yl]-2-		Example 3
	phenylamino-9H-purine
4c	2-(3-methoxyphenyl)amino-	(3-	4-	4	3.60	386
	6-(4-trifluoromethylphenyl)-	methoxyphenyl)amine	trifluoromethylphenylboronic
	9H-purine		acid
4d	6-(3-methoxyphenyl)-2-(3-	(3-	3-	4	3.05	348
	methoxyphenyl)amino-9H-	methoxyphenyl)amine	methoxyphenylboronic
	purine		acid
4e	6-[4-(piperazin-1-	aniline	Reference	1	6.43	436
	sulfonyl)phenyl]-2-		Example 6
	phenylamino-9H-purine
4f	6-(3-methoxyphenyl)-2-[4-	[4-(4-	3-methoxyphenylboronic	4	2.32	403
	(4-	morpholino)phenyl]amine	acid
	morpholino)phenyl]amino-
	9H-purine
4g	6-(5-bromo-2-fluorophenyl)-	[4-(4-	5-bromo-2-	1	7.15	471
	2-[4-(4-	morpholino)phenyl]amine	fluorophenylboronic
	morpholino)phenyl]amino-		acid
	9H-purine
4h	6-(1H-indol-5-yl)-2-[4-(4-	[4-(4-	5-indolylboronic	4	2.00	412
	morpholino)phenyl]amino-	morpholino)phenyl]amine	acid
	9H-purine
4i	6-(3-chlorophenyl)-2-[4-(4-	[4-(4-	3-	4	2.78	407
	morpholino)phenyl]amino-	morpholino)phenyl]amine	chlorophenylboronic
	9H-purine		acid
4j	6-(3-acetylphenyl)-2-[4-(4-	[4-(4-	3-	4	2.25	415
	morpholino)phenyl]amino-	morpholino)phenyl]amine	acetylphenylboronic
	9H-purine		acid
4k	6-(3-cyanophenyl)-2-[4-(4-	[4-(4-	3-	4	2.38	398
	morpholino)phenyl]amino-	morpholino)phenyl]amine	cyanophenylboronic
	9H-purine		acid
4l	2-[4-(4-	[4-(4-	3-	4	2.18	379
	morpholino)phenyl]amino-	morpholino)phenyl]amine	thiophenboronic
	6-(thien-3-yl)-9H-purine		acid
4m	6-[4-(N-	[4-(4-	6-[4-(N-	4	1.82	430
	acetyl)aminophenyl]-2-[4-	morpholino)phenyl]amine	acetyl)aminophenyl]boronic
	(4-		acid
	morpholino)phenyl]amino-
	9H-purine
4n	6-(3-chloro-4-fluorophenyl)-	[4-(4-	3-chloro-4-	4	2.93	425
	2-[4-(4-	morpholino)phenyl]amine	fluorophenylboronic
	morpholino)phenyl]amino-		acid
	9H-purine
4o	6-(5-fluoro-2-	[4-(4-	5-fluoro-2-	4	2.02	421
	methoxyphenyl)-2-[4-(4-	morpholino)phenyl]amine	methoxyphenylboronic
	morpholino)phenyl]amino-		acid
	9H-purine
4p	6-(2,5-difluorophenyl)-2-[4-	[4-(4-	2,5-	4	2.10	409
	(4-	morpholino)phenyl]amine	difluorophenylboronic
	morpholino)phenyl]amino-		acid
	9H-purine
4q	6-(3-fluoro-4-	[4-(4-	3-fluoro-4-	4	2.47	421
	methoxyphenyl)-2-[4-(4-	morpholino)phenyl]amine	methoxyphenylboronic
	morpholino)phenyl]amino-		acid
	9H-purine
4r	6-[6-(4-aminopiperidin-1-	(3-	Reference	1	5.99	431
	yl)pyridin-3-yl]-2-(3-	ethoxyphenyl)amine	Example 3
	ethoxyphenyl)amino-9H-
	purine
4s	6-(3-	[4-(4-	3-	4	2.02	451
	methanesulfonylphenyl)-2-	morpholino)phenyl]amine	methanesulfonylphenylboronic
	[4-(4-		acid
	morpholino)phenyl]amino-
	9H-purine
4t	6-(2-chloro-5-	[4-(4-	2-chloro-5-	4	2.27	421
	methylphenyl)-2-[4-(4-	morpholino)phenyl]amine	methylphenylboronic
	morpholino)phenyl]amino-		acid
	9H-purine
4u	6-[4-(N-	[4-(4-	4-(N-	4	2.17	458
	isobutyryl)aminophenyl]-2-	morpholino)phenyl]amine	isobutyryl)aminophenylboronic
	[4-(4-		acid
	morpholino)phenyl]amino-
	9H-purine
4v	6-[4-(N-	[4-(4-	4-(N-	4	2.47	492
	benzoyl)aminophenyl]-2-[4-	morpholino)phenyl]amine	benzoyl)aminophenyl
	(4-		boronic acid
	morpholino)phenyl]amino-
	9H-purine
4w	6-(3-bromophenyl)-2-[4-(4-	[4-(4-	3-	1	8.05	451
	morpholino)phenyl]amino-	morpholino)phenyl]amine	bromophenylboronic
	9H-purine		acid

Example 5

2-(4-Aminosulfonylphenyl)amino-6-[6-(piperidin-4-yl)aminopyridin-3-yl]-9H-purine

a) 2-(4-tert-Butylaminosulfonylphenyl)amino-6-(6-fluoropyridin-3-yl)-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 1 section b, but using reference example 2 and 4-tert-butylaminosulfonylaniline, the desired compound was obtained (90% yield).

LC-MS (method 1): t_R=8.86 min; m/z=526 (MH⁺).

b) 2-(4-tert-Butylaminosulfonylphenyl)amino-6-[6-[1-(tert-butoxycarbonyl)piperidin-4-yl]aminopyridin-3-yl]-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 2 section a, but using the compound obtained in the previous section and 4-amino-1-tert-butoxycarbonylpiperidine, the desired compound was obtained (86% yield).

LC-MS (method 1): t_R=9.81 min; m/z=706 (MH⁺).

c) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section, the title compound of the example was obtained (31% yield).

LC-MS (method 1): t_R=4.28 min; m/z=466 (MH⁺).

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

		reagent for	reagent for	HPLC	tR
Example	Compound name	step a)	step b)	method	(min)	m/z
5a	2-[4-(4-	[4-(4-	morpholine	4	1.72	459
	morpholino)phenyl]amino-6-	morpholino)phenyl]amine
	[6-(morpholin-4-yl)pyridin-3-
	yl]-9H-purine
5b	2-[4-(1,1-	[4-(1,1-	3-	4	1.65	521
	dioxothiomorpholin-4-	dioxothiomorpholin-	hydroxypiperidine
	yl)phenyl]amino-6-[6-(3-	4-	hydrochloride
	hydroxypiperidin-1-	yl)phenyl]amine
	yl)pyridin-3-yl]-9H-purine
5c	2-[4-(4-	[4-(4-	piperidine	4	1.80	457
	morpholino)phenyl]amino-6-	morpholino)phenyl]amine
	[6-(piperidin-1-yl)pyridin-3-
	yl]-9H-purine
5d	6-[6-(3-hydroxypyrrolidin-1-	[4-(4-	3-	4	1.40	459
	yl)pyridin-3-yl]-2-[4-(4-	morpholino)phenyl]amine	hydroxypyrrolidine
	morpholino)phenyl]amino-
	9H-purine
5e	6-[6-(2-	[4-(4-	2-aminoethanol	4	1.32	433
	hydroxyethyl)aminopyridin-	morpholino)phenyl]amine
	3-yl]-2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
5f	6-[6-(3-	[4-(4-	3-	4	1.36	447
	hydroxypropyl)aminopyridin-	morpholino)phenyl]amine	aminopropanol
	3-yl]-2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
5g	6-[6-(3-	[4-(4-	3-	4	1.25	486
	dimethylaminopyrrolidin-1-	morpholino)phenyl]amine	dimethylaminopyrrolidine
	yl)pyridin-3-yl]-2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
5h	6-[6-(3-hydroxypiperidin-1-	3-	3-	4	2.48	480
	yl)pyridin-3-yl]-2-(3-	phenoxyaniline	hydroxypiperidine
	phenoxyphenyl)amino-9H-		hydrochloride
	purine
5i	2-[4-(3-aminopiperidin-1-	Reference	3-	4	1.30	486
	yl)phenyl]amino-6-[6-(3-	Example 8c	hydroxypiperidine
	hydroxypiperidin-1-		hydrochloride
	yl)pyridin-3-yl]-9H-purine
5j	6-[6-(3-aminopyrrolidin-1-	[4-(4-	3-tert-	4	1.15	458
	yl)pyridin-3-yl]-2-[4-(4-	morpholino)phenyl]amine	butoxycarbonyl
	morpholino)phenyl]amino-		aminopyrrolidine
	9H-purine
5k	6-[6-(2-	[4-(4-	ethylendiamine	4	1.14	432
	aminoethyl)aminopyridin-3-	morpholino)phenyl]amine
	yl]-2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
5l	6-[6-(4-hydroxipiperidin-1-	[4-(4-	4-	4	1.47	473
	yl)pyridin-3-yl]-2-[4-(4-	morpholino)phenyl]amine	hydroxypiperidine
	morpholino)phenyl]amino-		hydrochloride
	9H-purine
5m	6-[6-(4-	[4-(4-	4-	4	1.25	486
	aminomethylpiperidin-1-	morpholino)phenyl]amine	aminomethylpiperidine
	yl)pyridin-3-yl]-2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
5n	2-[4-(4-	[4-(4-	3-	4	1.19	472
	morpholino)phenyl]amino-6-	morpholino)phenyl]amine	(aminomethyl)-
	[6-(pyrrolidin-3-		1-tert-
	ylmethyl)aminopyridin-3-yl]-		butoxycarbonyl
	9H-purine		pyrrolidine
5o	6-[6-(3-hydroxypiperidin-1-	3-methoxy-5-	3-	4	2.42	486
	yl)pyridin-3-yl]-2-(3-	trifluoromethylaniline	hydroxypiperidine
	methoxy-5-		hydrochloride
	trifluorophenyl)amino-9H-
	purine
5p	6-(6-methoxypyridin-3-yl)-2-	[4-(4-	N-	5	1.79	404
	[4-(4-	morpholino)phenyl]amine	methylpropylamine (1)
	morpholino)phenyl]amino-
	9H-purine
5q	2-[3-(2-	3-(2-	N-	5	2.03	404
	hydroxyethyl)phenyl]amino-	hydroxyethyl)phenylamine (2)	methylpropylamine
	6-[6-(N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5r	2-(3-	3-amino-N-	(S)-3-	1	5.15	467
	aminosufonylphenyl)amino-	tert-	hydroxypiperidine
	6-[6-(3-(S)-hydroxypiperidin-	butylbenzene	hydrochloride
	1-yl)pyridin-3-yl]-9H-purine	sulfonamide
5s	2-(3-	3-amino-N-	(R)-3-	1	5.14	467
	aminosulfonylphenyl)amino-	tert-	hydroxypiperidine
	6-[6-(3-(R)-hydroxypiperidin-	butylbenzene	hydrochloride
	1-yl)pyridin-3-yl]-9H-purine	sulfonamide
5t	6-[6-(3-acetylpiperidin-1-	3-amino-N-	3-	1	6.10	493
	yl)pyridin-3-yl]-2-(3-	tert-	acetylpiperidine
	aminosulfonylphenyl)amino-	butylbenzene	hydrochloride
	9H-purine	sulfonamide
5u	6-[(6-N-	[4-(4-	N-	5	2.16	445
	methylpropylamino)pyridin-	morpholino)phenyl]amine (3)	methylpropylamine
	3-yl]-2-[4-(4-
	morpholino)phenyl]amino-
	9H-purine
5v	2-[4-(4-methylpiperazin-1-	[4-(4-	N-	5	2.01	458
	yl)phenyl]amino-6-[(6-N-	methylpiperazin-	methylpropylamine
	methylpropylamino)pyridin-	1-
	3-yl]-9H-purine	yl)phenyl]amine
5w	2-[4-(3-hydroxypiperidin-1-	Reference	N-	5	2.03	460
	yl)phenyl]amino-6-[(6-N-	Example 8	methylpropylamine
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5x	6-[(6-N-	N-tert-	N-	5	1.78	443
	methylpropylamino)pyridin-	butoxycarbonyl-	methylpropylamine
	3-yl]-2-[4-(piperidin-3-	3-(4-
	yl)phenyl]amino-9H-purine	aminophenyl)piperidine
5y	2-[(4-	4-(2-	N-	5	1.97	404
	hydroxyethyl)phenyl]amino-	hydroxyethyl)phenylamine	methylpropylamine
	6-[6-(N-
	methypropylamino)pyridin-3-
	yl]-9H-purine
5z	2-[4-(N-diethylamino)phenyl]amino-	N,N-diethyl-	N-	5	2.7	431
	6-(6-N-	1,4-	methylpropylamine
	methylpropylamino)pyridin-	phenylenediamine
	3-yl]-9H-purine
5aa	6-(6-N-	3-(pyrrolidin-	N-	5	2.1	443
	methylpropylamino)pyridin-	1-	methylpropylamine
	3-yl]-2-[(3-pyrrolidinyl-1-	ylmethyl)aniline
	ylmethyl)phenyl]amino-9H-
	purine
5ab	2-(3-	N-(3-	N-	5	2.21	445
	isobutyroylaminophenyl)amino-	aminophenyl)isobutyramide	methylpropylamine
	6-[(6-N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5ac	2-[4-(2-	Reference	N-	5	1.84	483
	hydroxyethyl)aminosulfonylphenyl]amino-	Example 7	methylpropylamine
	6-[(6-N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5ad	6-[6-(3-(R)-hydroxypiperidin-	[4-(4-	(R)-3-	5	1.65	473
	1-yl)pyridin-3-yl]-2-(4-	morpholino)phenyl]amine	hydroxypiperidine
	morpholino)phenyl]amino-		hydrochloride
	9H-purine
5ae	6-[6-(3-(S)-hydroxypiperidin-	[4-(4-	(S)-3-	5	1.65	473
	1-yl)pyridin-3-yl]-2-(4-	morpholino)phenyl]amine	hydroxypiperidine
	morpholino)phenyl]amino-		hydrochloride
	9H-purine
5af	2-[4-(4-methylpiperazin-1-	[4-(4-	(R)-2-	5	1.99	470
	yl)phenyl]amino-6-[6-(2-(R)-	methylpiperazin-	methylpyrrolidine
	methylpyrrolidin-1-yl)pyridin-	1-
	3-yl]-9H-purine	yl)phenyl]amine
5ag	2-[4-(4-methylpiperazin-1-	[4-(4-	(S)-2-	5	1.99	470
	yl)phenyl]amino-6-[6-(2-(S)-	methylpiperazin-	methylpyrrolidine
	methylpyrrolidin-1-yl)pyridin-	1-
	3-yl]-9H-purine	yl)phenyl]amine
5ah	2-[4-(4-methylpiperazin-1-	[4-(4-	(S)-2-	5	2.22	484
	yl)phenyl]amino-6-[6-(2-(S)-	methylpiperazin-	methylpiperidine
	methylpiperidin-1-yl)pyridin-	1-
	3-yl]-9H-purine	yl)phenyl]amine
5ai	2-[4-(4-methylpiperazin-1-	[4-(4-	(R)-2-	5	2.22	484
	yl)phenyl]amino-6-[6-(2-(R)-	methylpiperazin-	methylpiperidine
	methylpiperidin-1-yl)pyridin-	1-
	3-yl]-9H-purine	yl)phenyl]amine
5aj	6-(6-N-	[4-(4-	N,N-	5	1.68	430
	dimethylamino)pyridin-3-yl]-	methylpiperazin-	dimethylamine
	2-[4-(4-methylpiperazin-1-	1-
	yl)phenyl]amino-9H-purine	yl)phenyl]amine
5ak	6-[6-(2-	[4-(4-	N-(2-	5	1.72	475
	methoxyethyl)methylaminopyridin-	methylpiperazin-	methoxyethyl)methylamine
	3-yl]-2-[4-(4-	1-
	methylpiperazin-1-	yl)phenyl]amine
	yl)phenyl]amino-9H-purine
5al	2-[(4-	4-(2-	N-(2-	5	1.68	420
	hydroxyethyl)phenyl]amino-	hydroxyethyl)phenylamine	methoxyethyl)methylamine
	6-[6-(2-
	methoxyethyl)methylaminopyridin-
	3-yl]-9H-purine
5am	2-[(3-	3-(2-	N-(2-	5	1.74	421
	hydroxyethyl)phenyl]amino-	hydroxyethyl)phenylamine	methoxyethyl)methylamine
	6-[6-(2-
	methoxyethyl)methylaminopyridin-
	3-yl]-9H-purine
5an	6-[6-(2-	4-(pyrrolidin-	N-(2-	5	1.60	457
	methoxyethyl)methylaminopyridin-	1-	methoxyethyl)methylamine
	3-yl]-2-[4-(pyrrolidin-1-	ylmethyl)aniline
	ylmethyl)phenyl]amino-9H-
	purine
5ao	6-[6-(2-	[4-(piperazin-	N-(2-	5	1.42	460
	methoxyethyl)methylaminopyridin-	1-	methoxyethyl)methylamine
	3-yl]-2-[4-(piperazin-1-	yl)phenyl]amine
	yl)phenyl]amino-9H-purine
5ap	2-[4-(2-hydroxy-2-	Reference	N-	5	2.18	433
	methylpropyl)]phenylamino-	Example 12	methylpropylamine
	6-[(6-N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5aq	2[4-(cis-3,5-	Reference	N-	5	1.85	472
	dimethylpiperazin-1-	Example 8f (3)	methylpropylamine
	yl)phenyl]amino-6-[(6-N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5ar	2-(N-methyl-3-	Reference	N-	5	2.04	431
	acetylaminophenyl)amino-6-	Example 13 (3)	methylpropylamine
	[(6-N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5as	2-(N-methyl-3-	Reference	N-	5	2.25	457
	isobutyroylaminophenyl)amino-	Example 13a (3)	methylpropylamine
	6-[(6-N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
5at	2-(N-methyl-3-	Reference	N-	5	2.31	459
	cyclopropylcarbonylaminophenyl)amino-	Example 13b (3)	methylpropylamine
	6-[(6-N-
	methylpropylamino)pyridin-
	3-yl]-9H-purine
(1) Methanol was added at deprotection step 5c to improve solubility
(2) Cesium carbonate was used instead of NaOtBu.
(3) Two equivalents of K2CO3 were used instead of NaOtBu, 0.1 equivalents of X-Phos were used instead of BINAP, and tert-buthanol was used instead of toluene.

Example 6

2-(4-Aminosulfonylphenyl)amino-6-(6-hydroxypyridin-3-yl)-9H-purine

In a flask were mixed, under Ar-atmosphere, the compound obtained in example 5 section a (70 mg, 0.13 mmol) and a mixture of 4M dioxane/HCl_(g) (5 mL) with dioxane (4 mL). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was washed with a saturated NaHCO₃ aqueous solution and extracted thrice with EtOAc. The phases were separated and the organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was purified by HPLC to afford 11 mg of the title compound of the example (21% yield).

LC-MS (method 1): t_R=3.93 min; m/z=384 (MH⁺).

Example 7

2-(4-Aminocarbonylphenyl)amino-6-[6-(4-aminopiperidin-1-yl)pyridin-3-yl]-9H-purine

a) 6-[6-[4-(tert-Butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl]-2-(4-ethoxycarbonylphenyl)amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 1 section b, but using ethyl 4-aminobenzoate instead of [4-(4-morpholino)phenyl]amine, the desired compound was obtained (34% yield).

LC-MS (method 1): t_R=10.54 min; m/z=643 (MH⁺).

b) 6-[6-[4-(tert-Butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl]-2-(4-carboxyphenyl)amino-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section (93 mg, 0.14 mmol) in EtOH (2 mL), a solution of KOH (54 mg, 0.96 mmol) in H₂O (2 mL) was added. The reaction mixture was stirred at 90° C. for 72 h. It was cooled until room temperature. The residue was washed with H₂O and extracted with EtOAc. The aqueous layer was cooled to 0° C. and adjusted to pH=4 by the addition of 1N HCl and it was extracted thrice with EtOAc. The combined organic phases were dried over anhydrous MgSO₄ and concentrated to dryness, to afford 60 mg (67% yield) of the desired compound.

LC-MS (method 2): t_R=2.27 min; m/z=615 (MH⁺).

c) 2-(4-Aminocarbonylphenyl)amino-6-[6-[4-(tert-butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl]-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section (60 mg, 0.09 mmol) in DMF (1.5 mL) under Ar-atmosphere, EDC.HCl (23 mg, 0.10 mmol), HOBT (13 mg, 0.09 mmol), NMM (43 μL, 0.36 mmol) and finally a 30% aqueous NH₃ solution (43 μL, 0.97 mmol) were added. The resulting mixture was stirred at room temperature overnight and concentrated to dryness. The resulting residue was diluted in a mixture EtOAc/H₂O (1:1), the phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 46 mg of the desired compound (76% yield).

LC-MS (method 2): t_R=2.69 min; m/z=614 (MH⁺). 699/64

d) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section, the title compound of the example was obtained (53% yield).

LC-MS (method 1): t_R=4.22 min; m/z=430 (MH⁺).

Example 8

6-[3-(N-Isobutyl-N-acetylamino)phenyl]-2-[4-(4-morpholino)phenyl]amino-9H-purine

a) N-Isobutyl-3-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)aniline

To a solution of 3-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)aniline (250 mg, 1.14 mmol) in CH₂Cl₂ (1 mL) under Ar-atmosphere, a solution of isobutyraldehyde (103 μL, 1.14 mmol) in CH₂Cl₂ (2 mL) was added. The resulting mixture was cooled to 0° C. and sodium triacetoxyborohydride (483 mg, 2.28 mmol) was added. The resulting mixture was stirred at room temperature overnight and diluted with EtOAc. It was treated with 0.2M NaHCO₃. The phases were separated and the aqueous phase extracted thrice with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 280 mg of the title compound (89% yield).

LC-MS (method 1): t_R=6.32 min; m/z=276 (MH⁺).

b) 2-Chloro-6-[3-(N-isobutylamino)phenyl]-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using the compound obtained in the previous section instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained (63% yield).

LC-MS (method 1): t_R=10.55 min; m/z=386 (MH⁺).

c) 2-Chloro-6-[3-(N-isobutyl-N-acetylamino)phenyl]-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section (57 mg, 0.14 mmol) in CH₂Cl₂ (2 mL) under Ar-atmosphere, acetyl chloride (16 μL, 0.22 mmol) and DIEA (77 μL, 0.45 mmol) were added. The resulting mixture was stirred at room temperature overnight and concentrated to dryness. The resulting residue was diluted in a mixture of EtOAc/H₂O (1:1), the phases were separated and the aqueous phase extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was chromatographed over silica gel using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 30 mg of the desired compound (47% yield).

LC-MS (method 1): t_R=9.52 min; m/z=428 (MH⁺).

d) 6-[3-(N-Isobutyl-N-acetylamino)phenyl]-2-[4-(4-morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 1 section b, but starting from the compound obtained in the previous section, the desired compound was obtained (25% yield).

LC-MS (method 1): t_R=9.18 min; m/z=570 (MH⁺).

e) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section, the title compound of the example was obtained (11% yield).

LC-MS (method 1): t_R=7.03 min; m/z=486 (MH⁺).

Example 9

2-(3-Aminophenyl)amino-6-[6-(4-aminopiperidin-1-yl)pyridin-3-yl]-9H-purine

a) 6-{6-[4-(tert-Butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl}-2-(3-nitrophenyl)amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 1 section b, but using 3-nitroaniline instead of [4-(4-morpholino)phenyl]amine, the desired compound was obtained (56% yield).

LC-MS (method 2): t_R=3.45 min; m/z=616 (MH⁺).

b) 2-(3-Aminophenyl)amino-6-{6-[4-(tert-butoxycarbonyl)aminopiperidin-1-yl]pyridin-3-yl}-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 7 section b, but starting from the compound obtained in the previous section, the desired compound was obtained (59% yield).

LC-MS (method 1): t_R=8.82 min; m/z=586 (MH⁺).

c) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section, the title compound of the example was obtained (31% yield).

LC-MS (method 1): t_R=4.54 min; m/z=402 (MH⁺).

Example 10

2-[4-(4-Morpholino)phenyl]amino-6-[6-(piperidin-3-ylamino)pyridin-3-yl]-9H-purine

a) 2-[4-(4-morpholino)phenyl]amino-6-[6-[1-(tert-butoxycarbonyl)piperidin-3-ylamino]pyridin-3-yl]-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 2 section a, but using the compound obtained in example 5a section a, and 3-amino-1-(tert-butoxycarbonyl)piperidine, 0.027 g of the desired compound was obtained (20% yield).

b) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section. In this case, the crude product obtained was chromatographed over a SCX-2 column instead of silica gel using MeOH—NH₃(MeOH) mixtures of increasing polarity as eluent. The title compound of the example was obtained (88% yield).

LC-MS (method 4): t_R=1.28 min; m/z=472 (MH⁺).

Following a similar procedure to that described in example 10, but using in each case the corresponding starting materials, these compounds were obtained:

		reagent for	HPLC	tR
Example	Compound name	step a)	method	(min)	m/z
10a	2-[4-(4-morpholino)phenyl]amino-6-[6-	N-	4	1.55	431
	(N-propylamino)pyridin-3-yl]-9H-	propylamine
	purine
10b	6-[6-(N-dimethylamino)pyridin-3-yl]-2-	N-	4	1.40	417
	[4-(4-morpholino)phenyl]amino-9H-	dimethylamine
	purine	hydrochloride
10c	6-[6-([1,4]diazepan-1-yl)pyridin-3-yl]-	N-tert-	4	1.28	472
	2-[4-(4-morpholino)phenyl]amino-9H-	butoxycarbonylhomopiperazine
	purine
10d	6-[6-(3-methoxycarbonylpyrrolidin-1-	Methyl	4	1.61	501
	yl)pyridin-3-yl]-2-[4-(4-	pyrrolidine-3-
	morpholino)phenyl]amino-9H-purine	carboxylate
10e	6-[6-(N-ethylmethylamino)pyridin-3-	N-	4	1.52	431
	yl]-2-[4-(4-morpholino)phenyl]amino-	ethylmethylamine
	9H-purine
10f	6-[6-(N-butylmethylamino)pyridin-3-	N-	4	1.88	459
	yl]-2-[4-(4-morpholino)phenyl]amino-	butylmethylamine
	9H-purine
10g	6-[6-N-((2-	2-	4	1.32	447
	hydroxyethyl)methylamino)pyridin-3-	(methylamino)ethanol
	yl]-2-[4-(4-morpholino)phenyl]amino-
	9H-purine
10h	6-[6-(N-diethylamino)pyridin-3-yl]-2-[4-	N-	4	1.64	445
	(4-morpholino)phenyl]amino-9H-	diethylamine
	purine
10i	6-[6-(N-benzylmethylamino)pyridin-3-	N-	4	2.19	493
	yl]-2-[4-(4-morpholino)phenyl]amino-	benzylmethyl
	9H-purine	amine
10j	6-[6-[(2-hydroxy-2-	2-	4	1.90	523
	phenylethyl)methylamino]pyridin-3-yl]-	(methylamino)-
	2-[4-(4-morpholino)phenyl]amino-9H-	1-
	purine	phenylethanol
10k	6-[6-(N-isobutylmethylamino)pyridin-3-	N-	4	1.88	459
	yl]-2-[4-(4-morpholino)phenyl]amino-	isobutymethyll
	9H-purine	amine
10l	6-[6-(N-butylethylamino)pyridin-3-yl]-	N-	4	2.03	473
	2-[4-(4-morpholino)phenyl]amino-9H-	butylethylamine
	purine
10m	6-[6-((2-	2-	4	1.61	475
	hydroxyethyl)propylamino)pyridin-3-	(propylamino)ethanol
	yl]-2-[4-(4-morpholino)phenyl]amino-
	9H-purine
10n	6-[6-(2-	N-(2-	4	1.55	461
	methoxyethyl)methylaminopyridin-3-	methoxyethyl)methylamine
	yl]-2-[4-(4-morpholino)phenyl]amino-
	9H-purine
10o	6-[6-(2-	1-	4	1.43	461
	hydroxypropyl)methylaminopyridin-3-	(methylamino)propan-
	yl]-2-[4-(4-morpholino)phenyl]amino-	2-ol
	9H-purine
10p	6-[6-(N-ethylpropylamino)pyridin-3-yl]-	N-	4	1.83	459
	2-[4-(4-morpholino)phenyl]amino-9H-	ethylpropylamine
	purine
10q	6-[6-[N-methyl-(prop-2-	N-	4	1.94	441
	ynyl)amino]pyridin-3-yl]-2-[4-(4-	methylpropar
	morpholino)phenyl]amino-9H-purine	gylamine
10r	6-[6-(N-methylamino)pyridin-3-yl]-2-[4-	N-	4	1.38	403
	(4-morpholino)phenyl]amino-9H-	methylamine
	purine	hydrochloride

Example 11

6-[6-(3-Methylaminocarbonylpyrrolidin-1-yl)pyridin-3-yl]-2-[4-(4-morpholino)phenyl]amino-9H-purine

a) 6-[6-(3-Carboxypyrrolidin-1-yl)pyridin-3-yl]-2-[4-(4-morpholino)phenyl]amino-9H-purine

Following a similar procedure to that described in example 7 section b, but using the compound obtained in example 10d, the title compound was obtained quantitatively.

b) Title Compound

Following a similar procedure to that described in example 7 section c, but using the compound obtained in the previous section, and N-methylamine hydrochloride instead of 30% aqueous NH₃ solution, the title compound of the example was obtained (20% yield).

LC-MS (method 4): t_R=1.37 min; m/z=500 (MH⁺).

Example 12

2-(3-Aminosulfonylphenyl)amino-6-{(4-[3-(hydroxymethyl)piperidin-1-yl]phenyl}-9H-purine

a) 2-Chloro-6-{4-[3-(hydroxymethyl)piperidin-1-yl]phenyl}-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using the compound obtained in reference example 4a instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained (39% yield).

LC-MS (method 5): t_R=2.47 min; m/z=428 (MH⁺).

b) 2-[3-(N-tert-Butyl)aminosulfonylphenyl]amino-6-{4-[3-(hydroxymethyl)piperidin-1-yl]phenyl}-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section (150 mg, 0.351 mmol) in tert-butanol (4 mL) under Ar-atmosphere, potassium carbonate (106 mg, 0.768 mmol), X-Phos (17 mg, 0.036 mmol), Pd₂(dba)₃ (16 mg, 0.017 mmol) and 3-amino-N-tert-butylbenzenesulfonamide (160 mg, 0.701 mmol) were added at room temperature. The mixture was purgued under Ar-atmosphere and heated at 100° C. overnight. The reaction crude was filtered through a plug of Celite®, washed with methanol and evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 99 mg of the desired compound (46% yield).

LC-MS (method 5): t_R=2.53 min; m/z=620 (MH⁺)

c) Title Compound

The compound obtained in the previous section (60 mg, 0.097 mmol) and a mixture of THF/6N HCl_(aq) (3 mL) was stirred at reflux temperature for 4 h under Ar-atmosphere. Afterwards, the mixture was concentrated to dryness and the residue was partitioned and the mixture was concentrated to dryness. The residue was partitioned between 0.2N NaHCO₃ and CH₂Cl₂. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 22 mg of the desired compound (48% yield).

LC-MS (method 1): t_R=5.83 min; m/z=480 (MH⁺).

Following a similar procedure to that described in example 12, but using the corresponding starting materials, the following compound was obtained:

				HPLC	tR
Example	Compound name	a) step reagent	b) step reagent	method	(min)	m/z
12a	2-(3-	3-	3-amino-N-tert-	5	1.84	413
	aminosufonylphenyl)amino-	(methylsulfanyl)phenylboronic	butylbenzenesulfonamide
	6-(3-	acid
	methylsulfanyl)phenyl-
	9H-purine

Example 13

2-(3-Aminosulfonylphenyl)amino-6-[3-(methylsulfinyl)phenyl]-9H-purine

To a solution of the compound of example 12a (50 mg, 0.121 mmol) in 4 mL of a 1:1 mixture of acetic acid and methanol, was added under an Ar-atmosphere 0.04 mL of 30% H₂O₂ and the resulting mixture was stirred at room temperature overnight. The crude product obtained was evaporated to dryness and chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 21 mg of the desired compound (41% yield).

LC-MS (method 5): t_R=1.27 min; m/z=429 (MH⁺).

Following a similar procedure to that described in example 13, but using the corresponding starting materials, the following compound was obtained:

		Starting	HPLC	tR
Example	Compound name	Material	method	(min)	m/z
13a	2-(3-acetylaminophenyl)-	Example	5	1.37	407
	amino-6-[3-	1ch
	(methylsulfinyl)phenyl]-
	9H-purine

Example 14

2-(3-Aminosulfonylphenyl)amino-6-[4-(ethylaminocarbonyloxy)phenyl]-9H-purine

a) 2-Chloro-6-(4-hydroxyphenyl)-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using 4-hydroxyphenyl boronic acid instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained (21% yield).

LC-MS (method 5): t_R=2.11 min; m/z=329 (MH⁻).

b) 2-Chloro-6-(4-ethylaminocarbonyloxy)phenyl-9-(tetrahydropyran-2-yl)-9H-purine

A mixture of the compound obtained in the previous section (125 mg, 0.378 mmol), ethyl isocyanate (0.030 mL, 0.380 mmol) and 3 mL of DMF was stirred at 80° C. overnight. The resulting solution was evaporated to dryness and chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 33 mg of the desired compound (22% yield).

LC-MS (method 5): t_R=2.36 min; m/z=402 (MH⁺)

c) 2-(3-Aminosulfonylphenyl)amino-6-(4-ethylaminocarbonyloxy)phenyl-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 12 section b, but using the compound obtained in the previous section and 3-aminobenzenesulfonamide instead of 3-amino-N-tert-butylbenzenesulfonamide, the desired compound was obtained.

LC-MS (method 5): t_R=1.40 min; m/z=538 (MH⁺).

d) Title Compound

A mixture of the compound obtained in the previous section (68 mg, 0.126 mmol), 4M dioxane/HCl_(g) (5 mL) and 1 mL of methanol was stirred at room temperature under Ar-atmosphere overnight. The solution was concentrated to dryness and the crude product thus obtained was chromatographed over silica gel using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 27 mg of the desired compound (47% yield).

LC-MS (method 1): t_R=3.83 min; m/z=454 (MH⁺).

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

		reagent for	reagent for	HPLC	tR
Example	Compound name	step a)	step c)	method	(min)	m/z
14a	2-[3-	4-	3-	5	1.43	453
	aminosulfonylphenyl]amino-	aminophenylboronic	aminobenzenesulfonamide
	6-[4-	acid
	(ethylaminocarbonylamino)phenyl]-
	9H-purine

Example 15

2-[3-(Aminosulfonyl)phenyl]amino-6-[4-(methanesulfonylamino)phenyl]-9H-purine

a) 6-(4-Aminophenyl)-2-chloro-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained (33% yield).

LC-MS (method 5): t_R=2.15 min; m/z=330 (MH⁺).

b) 2-Chloro-6-[4-(methanesulfonylamino)phenyl]-9-(tetrahydropyran-2-yl)-9H-purine

To a mixture of the compound obtained in the previous section (170 mg, 0.52 mmol), a catalytic amount of DMAP, diisopropyethylamine (0.181 mL, 1.04 mmol) and 4 mL dichloromethane, methanesulfonyl chloride (40.3 4, 0.52 mmol) was added and the resulting mixture was stirred at room temperature overnight. The resulting solution was partitioned between H₂O and dichloromethane and the organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 14 mg of the desired compound (7% yield).

LC-MS (method 5): t_R=2.07 min; m/z=408 (MH⁺)

c) 2-(3-Aminosulfonylphenyl)amino-6-[4-(methanesulfonylamino)phenyl]-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 12 section b, but using the compound obtained in the previous section and 3-aminobenzenesulfonamide instead of 3-amino-N-tert-butylbenzenesulfonamide, the desired compound was obtained.

LC-MS (method 5): t_R=1.78 min; m/z=544 (MH⁺).

d) Title Compound

Following a similar procedure to that described in example 14 section d, but using the compound obtained in the previous section, the title compound of the example was obtained (26% yield).

LC-MS (method 5): t_R=1.28 min; m/z=460 (MH⁺).

Following a similar procedure to that described in example 15, but using in each case the corresponding starting materials, these compounds were obtained:

	Compound	reagent	reagent	reagent for	HPLC	tR
Example	name	for step a)	for step b)	step c)	method	(min)	m/z
15a	2-(3-	4-(4,4,5,5-	isobutyril	3-amino-N-	5	1.58	452
	aminosulfonylphenyl)amino-	tetramethyl-	chloride	tert-
	6-[4-(N-	1,3,2-		butylbenzene
	isobutirylamino)phenyl]-	dioxaborolan-		sulfonamide
	9H-purine	2-
		yl)aniline
15b	6-[4-(N-	N-methyl-	propionyl	[4-(4-	4	2.13	458
	methylpropionylamino)phenyl]-	4-(4,4,5,5-	chloride	morpholino)phenyl]amine
	2-[4-(4-	tetramethyl-
	morpholino)phenyl]amino-	1,3,2-
	9H-purine	dioxaborolan-
		2-
		yl)aniline
15c	6-[4-(N-	N-methyl-	methanesulfonyl	[4-(4-	4	2.15	480
	methylmethanesulfonylamino)-	4-(4,4,5,5-	chloride	morpholino)phenyl]amine
	phenyl]-2-	tetramethyl-
	[4-(4-	1,3,2-
	morpholino)phenyl]amino-	dioxaborolan-
	9H-purine	2-
		yl)aniline
15d	2-[4-(4-	N-tert-	propionyl	[4-(4-	4	1.64	471
	methylpiperazin-	butoxycarbonyl-	chloride	methylpiperazin-
	1-	N-		1-
	yl)phenyl]amino-	methyl-4-		yl)phenyl]amine
	6-[4-(N-	(4,4,5,5-
	methylpropionylamino)phenyl]-	tetramethyl-
	9H-	1,3,2-
	purine	dioxaborolan-
		2-
		yl)aniline (1)
15e	6-[4-(N-	N-tert-	methanesulfonyl	[4-(4-	4	1.63	493
	methylmethanesulfonylamino)-	butoxycarbonyl-	chloride	methylpiperazin-
	phenyl]-2-	N-		1-
	[4-(4-	methyl-4-		yl)phenyl]amine
	methylpiperazin-	(4,4,5,5-
	1-	tetramethyl-
	yl)phenyl]amino-	1,3,2-
	9H-purine	dioxaborolan-
		2-
		yl)aniline (1)
(1) Step d was performed after step a

Example 16

6-[6-(N-Methylmethanesulfonylamino)pyridin-3-yl]-2-[4-(4-morpholino)phenyl]amino-9H-purine

a) 6-[6-(N-Methylmethansulfonylamino)pyridin-3-yl]-2-[4-(4-morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 15 section b, but using the compound obtained in example 10r section b, the desired compound was obtained.

b) Title Compound

Following a similar procedure to that described in example 14 section d, but using the compound obtained in the previous section, the title compound of the example was obtained.

LC-MS (method 4): t_R=2.15 min; m/z=481 (MH⁺).

Example 17

2-[3-(N-Acetyl)aminosulfonylphenyl]amino-6-[6-(methylpropylamino)pyridin-3-yl]-9H-purine

A mixture of the compound of example 2r (115 mg, 0.26 mmol), N,N-dimethyaminopyridine (catalytic amount), acetic anhydride (0.025 mL, 0.26 mmol) and pyridine (4 mL) was stirred at room temperature overnight. The resulting solution was evaporated to dryness and chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 17 mg of the desired compound (13% yield).

LC-MS (method 5): t_R=1.49 min; m/z=481 (MH⁺).

Example 18

2-(3-Aminosulfonylphenyl)amino-6-[6-(3-hydroxypiperidin-1-yl)pyridin-3-yl]-9H-purine

a) 6-[6-[3-(tert-Butyldimethylsilyloxy)piperidin-1-yl]pyridin-3-yl]-2-chloro-9-(tetrahydropyran-2-yl)-9H-purine

A mixture of the compound obtained in example 2a section a (1.84 g, 4.42 mmol), imidazole (752 mg, 11.05 mmol), tert-butyldimethylsilyl chloride and DMF (50 mL) was stirred at room temperature overnight. The resulting solution was diluted with dichloromethane (250 mL) and was partitioned between H₂O and dichloromethane. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The crude product thus obtained was chromatographed over silica gel using EtOAc/MeOHI mixtures of increasing polarity as eluent, to afford the desired compound in quantitative yield.

b) 6-[6-[3-(tert-Butyldimethylsilyloxy)piperidin-1-yl]pyridin-3-yl]-2-(3-tert-butylaminosulfonylphenyl)amino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 12 section b, but using the compound obtained in the previous section instead of 2-chloro-6-{4-[3-(hydroxymethyl)piperidin-1-yl]phenyl}-9-(tetrahydropyran-2-yl)-9H-purine, the title compound was obtained.

c) 2-(3-tert-Butylaminosulfonylphenyl)amino-6-[6-(3-hydroxypiperidin-1-yl)pyridin-3-yl]-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section (136 mg, 0.19 mmol) and 3.8 mL of THF, tetrabutylammonium fluoride hydrate (148 mg, 056 mmol) was added. The mixture was stirred for 3 h at room temperature and the resulting suspension was evaporated to dryness and chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 82 mg of the desired compound (72% yield).

d) Title Compound

Following a similar procedure to that described in example 12 section c, but using the compound obtained in the previous section, the title compound was obtained.

LC-MS (method 4): t_R=1.45 min; m/z=467 (MH⁺).

Following a similar procedure to that described in example 18, but using in each case the corresponding starting materials, these compounds were obtained:

			HPLC
Example	Compound name	reagent for step b)	method	tR (min)	m/z
18a	6-[6-(3-hydroxypiperidin-	3-amino-N-	4	1.61	481
	1-yl)pyridin-3-yl]-2-(3-	methylbenzenesulfonamide
	methylaminosulfonylbenzene)amino-
	9H-purine
18b	2-[4-(3-aminopyrrolidin-	Reference Example	4	1.19	472
	1-yl)phenyl]amino-6-[6-	8a
	(3-hydroxypiperidin-1-
	yl)pyridin-3-yl]-9H-purine

Example 19

6-(6-Butoxypyridin-3-yl)-2-[4-(4-morpholino)phenyl]amino-9H-purine

a) 6-(6-Butoxypyridin-3-yl)-2-[4-(4-morpholino)phenyl]amino 9-(tetrahydropyran-2-yl)-9H-purine

A mixture of the compound obtained in example 5a section a (100 mg, 0.21 mmol) and potassium tert-butoxyde (56 mg, 0.5 mmol) in n-BuOH (2 mL) was irradiated in a monomode microwave at 160° C. for 10 min (160 W). The resulting crude product was evaporated to dryness and was partitioned between H₂O and dichloromethane. The organic phase was dried over Na₂SO₄ and concentrated to dryness and the crude product thus obtained was chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 54 mg of the desired compound.

b) Title Compound

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

LC-MS (method 4): t_R=2.97 min; m/z=446 (MH⁺).

Following a similar procedure to that described in example 19, but using the corresponding starting materials, the following compound was obtained:

		reagent for	HPLC	tR
Example	Compound name	step b)	method	(min)	m/z
19a	6-[6-(2-hydroxy)-	ethylene glycol	4	1.70	434
	ethoxypyridin-
	3-yl]-2-[4-(4-
	morpholino)-
	phenyl]amino-9H-
	purine

Example 20

2-(3-Aminosulfonylphenyl)amino-6-(2-carboxypyrrole-4-yl)-9H-purine

a) 2-Chloro-9-(tetrahydropyran-2-yl)-6-[2-(methoxycarbonyl)-1-(4-toluoyl)sulfonyl-pyrrole-4-yl]-9H-purine

Following a similar procedure to that described in reference example 2, but using the compound obtained in reference example 11 instead of 2-fluoro-5-pyridylboronic acid, and using K₂CO₃ instead of Na₂CO₃, the desired compound was obtained (60% yield).

LC-MS (method 5): t_R=3.02 min; m/z=516 (MH⁺).

b) 2-(3-Aminosulfonyl)phenylamino-9-(tetrahydropyran-2-yl)-6-[1-(4-toluoyl)sulfonyl-2-(methoxycarbonyl)pyrrole-4-yl]-9H-purine

Following a similar procedure to that described in example 12 section b, but using the compound obtained in the previous section instead of 2-chloro-6-{4-[3-(hydroxymethyl)piperidin-1-yl]phenyl}-9-(tetrahydropyran-2-yl)-9H-purine and 3-aminobenzenesulfonamide instead of 3-amino-N-tert-butylbenzenesulfonamide, the desired compound was obtained (72% yield).

LC-MS (method 5): t_R=2.60 min; m/z=652 (MH⁺).

c) Title Compound

A solution of the compound obtained in the previous section (0.54 g, 0.83 mmol) in 30 mL methanol and 25 mL 1N NaOH was heated at 80° C. during 2 h. A solution of 6N HCl was added dropwise until acidic pH and the solution extracted three times with ethyl acetate. The organic layer was dried over Na₂SO₄ and evaporated to dryness. The crude product thus obtained was filtered over silica gel using CHCl₃/MeOH/acetic acid/DMF mixtures as eluent, the solution was evaporated and dried, to afford the title compound (17% yield).

LC-MS (method 5): t_R=0.82 min; m/z=400 (MH⁺).

Example 21

2-(3-Aminophenyl)amino-6-(3-methanesulfonyl)phenyl-9H-purine

a) 2-(3-Aminophenyl)amino-6-(3-methanesulfonyl)phenyl-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 7 section b, but using the compound obtained in 1cu section b, the desired compound was obtained in quantitative yield.

b) Title Compound

Following a similar procedure to that described in example 1 section c, but using the compound obtained in the previous section, the title compound of the example was obtained (5% yield).

LC-MS (method 4): t_R=1.82 min; m/z=381 (MH⁺).

Example 22

6-(3-Methylsulfanylphenyl)-2-[4-(4-morpholino)phenyl]amino-9H-purine

a) 2-Chloro-6-[(3-methylsulfanyl)phenyl]-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using 3-(methylsulfanyl)phenylboronic acid instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained (72% yield).

LC-MS (method 5): t_R=2.18 min; m/z=419 (MH⁺).

b) 2-Chloro-6-[(3-methylsulfinyl)phenyl]-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section in dichloromethane (2 mL) 197 mg of m-chloroperbenzoic acid (77%) was added. The mixture was stirred overnight at room temperature and then the solvent was evaporated. The crude product thus obtained was purified over silica gel using hexane/EtOAc mixtures of increasing polarity, to afford 195 mg of the title compound (70% yield).

LC-MS (method 5): t_R=1.95 min; m/z=377 (MH⁺).

c) 6-[(3-Methylsulfinyl)phenyl]-2-[4-(4-morpholino)phenyl]amino-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in the previous section (97 mg, 0.258 mmol) in tert-butanol (5 mL), K₂CO₃ (157 mg, 0.567 mmol), X-Phos (25 mg, 0.0258 mmol), Pd₂(dba)₃ (24 mg, 0.0129 mmol) and [4-(4-morpholino)phenyl]amine (184 mg, 1.034 mmol) were added at room temperature and the mixture was stirred under Ar-atmosphere at 90° C. overnight. The crude product obtained was filtered over Celite® and concentrated to dryness.

LC-MS (method 5): t_R=1.99 min; m/z=519 (MH⁺).

d) Title Compound

The crude product obtained in the previous section (0.258 mmol) and a mixture of 4M dioxane/HCl_(g) (3 mL) was stirred at room temperature under Ar-atmosphere overnight. The solvent was concentrated and the crude product obtained was chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford the desired compound (7% yield).

LC-MS (method 5): t_R=2.18 min; m/z=419 (MH⁺).

Example 23

2-(3-Aminosulfonyl)phenylamino-6-(4-pyrazolyl)-9H-purine

a) 2-Chloro-6-(1-tert-butoxycarbonylpyrazol-4-yl)-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using 2-(1-tert-butoxycarbonyl)pyrazol-4-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained.

LC-MS (method 5): t_R=1.70 min; m/z=303 (MH⁻).

b) 2-[(3-Aminosulfonyl)phenyl]amino-6-(4-pyrazolyl)-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in example 22 section c, but using the compound obtained in the previous section, and 3-aminobenzenesulfonamide instead of [4-(4-morpholino)phenyl]amine, the desired compound was obtained.

LC-MS (method 1): t_R=5.63 min; m/z=441 (MH⁺).

c) Title Compound

The compound obtained in the previous section was mixed with Dowex 50w×8 (440 mg) in methanol (4 mL) and DMSO (1 mL) and the mixture was stirred overnight at room temperature. The suspension was filtered and washed with NH₄OH/MeOH (25%) and methanol. Evaporation of the solvent yielded the desired product.

LC-MS (method 1): t_R=4.01 min; m/z=357 (MH⁺).

Following a similar procedure to that described in example 23, but using in each case the corresponding starting materials, the following compounds were obtained:

		reagent for	reagent for	HPLC	tR
Example	Compound name	step a)	step b)	method	(min)	m/z
23a	2-[(3-	1-methyl-4-	3-	5	1.18	371
	aminosulfonyl)phenyl]amino-	(4,4,5,5-	aminobenzenesulfonamide
	6-(1-methyl-4-	tetramethyl-
	pyrazolyl)-9H-purine	1,3,2-
		dioxaborolan-2-
		yl)-1H-pyrazole
23b	2-[(3-	3-furanboronic	3-	5	5.38	357
	aminosulfonyl)phenyl]amino-	acid	aminobenzenesulfonamide
	6-(3-furanyl)-9H-
	purine
23c	2-[(3-	1-(triisopropyl-	3-	5	1.18	356
	aminosulfonyl)phenyl]amino-	silyl)-1H-	aminobenzenesulfonamide
	6-(3-pyrrolyl)-9H-	pyrrole-3-
	purine	boronic acid

Example 24

6-[1-(Aminocarbonyldimethylmethyl)pyrazol-4-yl]-2-(3-aminosulfonyl)phenylamino-9H-purine

a) 2-Chloro-6-[1-(ethoxycarbonyldimethylmethyl)pyrazol-4-yl]-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of the compound obtained in example 23, section a in DMF (16 mL), cooled to 0° C., 171 mg (3.938 mmol) of NaH and ethyl-2-bromoisobutyrate (0.442 mL, 2.953 mmol) were added. The mixture was stirred for 3 h at room temperature. The resulting suspension was diluted with a mixture of tert-butylmethyl ether (100 mL), water (20 mL) and NH₄Cl saturated solution (5 mL). The two phases were separated and the aqueous phase was extracted with tert-butylmethyl ether. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness to afford the desired product.

b) 6-[1-(Carboxydimethylmethyl)pyrazol-4-yl]-2-chloro-9-(tetrahydropyran-2-yl)-9H-purine

To a solution of 378 mg of the compound obtained in the previous section in THF (2 mL), a solution of LiOH.H₂O (75 mg) in 2 mL of water was added. The mixture was stirred overnight at room temperature. The crude product was cooled to 0° C. and 2 mL HCl 1N, 2.5 mL of water and 50 mL of EtOAc were added. The phases were separated and the aqueous phase extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness, to afford. 347 mg of the desired product.

LC-MS (method 5): t_R=1.41 min; m/z=391 (MH⁺).

c) 6-[1-(Aminocarbonyldimethylmethyl)pyrazol-4-yl]-2-chloro-9-(tetrahydropyran-2-yl)-9H-purine

A mixture of the product obtained in the previous section (144 mg, 0.346 mmol) and CU (100 mg, 0.554 mmol) in 8 mL of DMF was stirred for 3 h at room temperature. Then, triethylamine (0.217 mL, 1.55 mmol) and ammonium chloride (56 mg, 1.04 mmol) were added and the mixture was stirred overnight at room temperature. The resulting suspension was diluted in EtOAc and washed with 1N HCl, water, 1N NaOH and brine. The organic phase was dried over Na₂SO₄ and concentrated to dryness, to afford 112 mg of the desired product.

LC-MS (method 5): t_R=1.82 min; m/z=390 (MH⁺).

d) 6-[1-(Aminocarbonyldimethylmethyl)pyrazol-4-yl]-2-(3-aminosulfonyl)phenylamino-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in 22 section c, but using the compound obtained in the previous section, and 3-aminobenzenesulfonamide instead of [4-(4-morpholino)phenyl]amine, the desired compound was obtained.

LC-MS (method 5): t_R=1.66 min; m/z=526 (MH⁺).

e) Title Compound

A mixture of the compound obtained in the previous section and 4M dioxane/HCl_(g) (2 mL) was stirred at room temperature overnight. The suspension was concentrated to dryness and the crude product thus obtained was chromatographed over silica gel using CHCl₃/MeOH mixtures of increasing polarity as eluent, to afford the desired compound.

LC-MS (method 5): t_R=1.24 min; m/z=442 (MH⁺).

Following a similar procedure to that described in example 24, but using in each case the corresponding starting materials, the following compound was obtained:

			HPLC
Example	Compound name	reagent for step d)	method	tR (min)	m/z
24a	6-[1-	[4-(4-	5	1.32	461
	(aminocarbonyldimethylmethyl)pyrazol-	methylpiperazin-1-
	4-yl]-2-[4-(4-	yl)phenyl]amine
	methylpiperazin-1-
	yl)phenyl]amino-9H-purine

Example 25

2-(3-Aminosulfonyl)phenylamino-6-[3-(2,2,2-trifluoroethyl)aminocarbonylphenyl]-9H-purine

a) 6-(3-Carboxy)phenyl-2-chloro-6-(3-carboxy)phenyl-9-(tetrahydropyran-2-yl)-9H-purine

Following a similar procedure to that described in reference example 2, but using 3-carboxyphenylboronic acid instead of 2-fluoro-5-pyridylboronic acid, the desired compound was obtained (90% yield).

b) 2-Chloro-9-(tetrahydropyran-2-yl)-6-[3-(2,2,2-trifluoroethyl)aminocarbonylphenyl]-9H-purine

A mixture of the compound obtained in the previous section (420 mg, 1.17 mmol), DIEA (0.92 mL, 5.26 mmol), 2,2,2-trifluoroethylamine hydrochloride (476 mg, 3.51 mmol) and HBTU (533 mg, 1.40 mmol) were stirred at room temperature in 30 mL DMF overnight. The mixture was evaporated to dryness and chromatographed over silica gel using Hexane/Ethyl Acetate mixtures of increasing polarity as eluent, to afford the desired compound (26%).

LC-MS (method 5): t_R=2.46 min; m/z=440 (MH⁺).

c) 2-(3-Aminosulfonyl)phenylamino-9-(tetrahydropyran-2-yl)-6-[3-(2,2,2-trifluoroethyl)aminocarbonylphenyl]-9H-purine

Following a similar procedure to that described in 12 section b, but using the compound obtained in the previous section, and 3-aminobenzenesulfonamide instead of 3-amino-N-tert-butylbenzenesulfonamide, the desired compound was obtained.

LC-MS (method 5): t_R=2.14 min; m/z=576 (MH⁺).

d) Title Compound

A mixture of the compound obtained in the previous section (0.305 mmol) and 4M dioxane/HCl_(g) (5.2 mL) was stirred at room temperature under Ar-atmosphere overnight. The solution was concentrated to dryness and the crude product thus obtained was chromatographed over silica gel using CHCl₃/MeOH/NH₃ mixtures of increasing polarity as eluent, to afford 77 mg of the desired compound (51% yield).

LC-MS (method 5): t_R=1.71 min; m/z=492 (MH⁺).

Example 26

2-(3-Aminosulfonylphenyl)amino-6-(2-methylaminocarbonylpyrrole-4-yl)-9H-purine

A mixture of the compound obtained in example 20 (20 mg, 0.041 mmol), HBTU (19 mg, 0.050 mmol), and methylamine solution 2.0M in THF (0.1 mL, 0.207 mmol) were stirred in 1 mL of DMF at room temperature overnight. The resulting mixture was evaporated to dryness and purified over preparative HPLC. The title compound was obtained (3%).

LC-MS (method 5): t_R=1.71 min; m/z=492 (MH⁺).

Following a similar procedure to that described in example 26, but using the corresponding starting material, the following compound was obtained:

			HPLC
Example	Compound name	reagent	method	tR (min)	m/z
26a	2-(3-	Ethylamine (2.0M in	5	1.35	427
	aminosulfonylphenyl)amino-6-	THF)
	(2-ethylaminocarbonylpyrrole-4-
	yl)-9H-purine

Example 27

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 2×10⁵ cpm 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 dithiotreitol (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.

Example 28

Biological Assay 2

Delayed-Type Hypersensitivity Response (DTH)

This assay was performed essentially as disclosed in Kudlacz E. et al, see supra. Male C57BL/6J mice received i.v. injections of 1×10⁵ sheep red blood cells in a volume of 0.2 mL sterile phosphate buffered saline (PBS). Four days later, sensitized mice received an injection of 1×10⁸ sheep red blood cells in a volume of 30 μL sterile PBS into the left footpad. Twenty-four hours later, animals were sacrificed and their footpads removed and weighted. The DTH swelling response was calculated by subtracting the right footpad weight (baseline) from that of the left footpad (experimental). Test compounds or vehicle (0.2% carboxymethylcellulose and 1% Tween 80 in water) were administered p.o. once daily during both sensitization and challenge phases of the DTH response.Compounds of examples 1 cc, 1cr, 1ct, 5u, 10h and 10p were active in this assay when administered orally.

Claims

1. A compound of formula I:

2. (canceled)

3. The compound according to claim 1, wherein R1 is chosen from phenyl substituted with one or two R3.

4. The compound according to claim 3, wherein the groups R3 are placed at positions 3, 4 and/or 5 of the phenyl ring.

5. (canceled)

6. (canceled)

7. The compound according to claim 1, wherein: each R3 is independently chosen from C1-4alkyl, halogen, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, —OR6, Cy2aC1-4alkyl, —SO2NR6R6, —SO2NR7COR5, —NR6R6, —NR7COR6, and Cy1, wherein Cy1 is optionally substituted with one or more R9, and wherein Cy2 is optionally substituted with one or more R11;Cy1 is a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms chosen from N, S and O with the proviso that it contains at least one N atom, wherein said heterocycle is bonded to the rest of the molecule through a N atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO2 groups; andCy2 is a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms chosen from N, S and O, wherein said heterocycle is optionally bonded to the rest of the molecule through any available C or N atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO2 groups.

8. (canceled)

9. (canceled)

10. The compound according to claim 7, wherein R3 is chosen from —SO2NR6R6, —NR7COR6, and or Cy2C1-4alkyl, wherein Cy2 is optionally substituted with one or more R11.

11. The compound according to claim 1, wherein: R1 is a ring of formula R1d:

12. The compound according to claim 11, wherein R3 is chosen from hydroxyC1-4alkyl, Cy2C1-4alkyl, —NR6R6, —SO2NR6R6, and Cy1, wherein Cy1 is optionally substituted with one or more R9 and wherein Cy2 is optionally substituted with one or more R11; andCy2 is a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms chosen from N, S and O, wherein said heterocycle is optionally bonded to the rest of the molecule through any available C or N atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO2 groups.

13. The compound according to claim 12, wherein R3 is chosen from —SO2NR6R6 and Cy1, wherein Cy1 is optionally substituted with one or more R9.

14. The compound according to claim 13, wherein R3 is chosen from formulas (i)-(iii)

15. (canceled)

16. (canceled)

17. The compound according to claim 1 wherein R6 in R3 is chosen from hydrogen and R5, wherein R5 is C1-4alkyl optionally substituted with one or more R10.

18. (canceled)

19. The compound according to claim 1 wherein R2 is chosen from phenyl and a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, which is optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein R2 optionally contains from 1 to 4 heteroatoms chosen from N, O and S, wherein the adjacent atoms to the C atom at the position of attachment to the purine ring are C atoms, wherein one or more C or S atoms of the 5- or 6-membered fused ring are optionally oxidized forming CO, SO or SO2 groups, and wherein R2 is optionally substituted with one or more R4.

20. (canceled)

21. The compound according to claim 19, wherein R2 is a 5- or 6-membered aromatic heterocycle bonded to the purine ring through a C atom, which is optionally fused to a 5- or 6-membered saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring, wherein R2 contains from 1 to 4 heteroatoms chosen from N, O and S, wherein the adjacent atoms to the C atom at the position of attachment to the purine ring are C atoms, wherein one or more C or S atoms of the 5- or 6-membered fused ring are optionally oxidized forming CO, SO or SO2 groups, and wherein R2 is optionally substituted with one or more R4.

22. (canceled)

23. The compound according to claim 21, wherein R2 is 3-pyridyl optionally substituted with one or more R4.

24. The compound according to claim 23, wherein R2 is 3-pyridyl substituted with one or two R4.

25. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

30. The compound according to claim 1, wherein each R4 is independently chosen from C1-4alkyl, halogen, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, —CONR6R6, —SR6, —SOR5, —SO2R5, —NR6R6, NR7SO2R5, —NR7CONR6R6, and Cy1, wherein Cy1 is optionally substituted with one or more R9; andCy1 is a 5- or 6-membered saturated monocyclic heterocycle which contains 1 or 2 heteroatoms chosen from N, S and O with the proviso that it contains at least one N atom, wherein said heterocycle is bonded to the rest of the molecule through a N atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO2 groups.

31. (canceled)

32. The compound according to claim 1, wherein: R2 is a group of formula:

33. (canceled)

34. (canceled)

35. The compound according to claim 32, wherein R4 is —NR6R6.

36. The compound according to claim 1 wherein R6 is C1-4alkyl optionally substituted with one or more R10.

37. (canceled)

38. The compound according to claim 1 wherein each R25 is hydrogen.

39. (canceled)

40. (canceled)

41. (canceled)

42. (canceled)

43. (canceled)

44. A pharmaceutical composition comprising at least one compound chosen from compounds of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients

45. (canceled)

46. A method for the treatment or prevention of at least one disease chosen from transplant rejection; immune, autoimmune or inflammatory diseases; neurodegenerative diseases; and proliferative disorders, said method comprising administration of a compound of formula I:

47. (canceled)

48. A process for the preparation of a compound of formula I according to claim 1, which comprises: (a) reacting a compound of formula IV with a compound of formula V

49. The compound according to claim 1, wherein: R1 is a ring of formula R1d: