ES2369826T3 - PIRROLOPIRAZINE KINASE INHIBITORS. - Google Patents

Abstract

A compound of the formula I '' in which: R is R1, R2, R3 or R4; R1 is C1-C6 alkyl, C1-C6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a; R1a is R1b or R1c; R1b is halogen, oxo, hydroxy or -CN; R1c is -C (= O) O (R1f), -C (= O) (CH2) m (R1e), -O (CH2) m (R1e), -S (R1f), -S (O) 2 ( R1f) or -S (= O) (R1f), C1-C6 alkyl, C1-C6 alkoxy, amino, amido, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d ; R1d is H, halogen, hydroxy, C1-C6 alkyl, amino, C1-C6 alkoxy or C1-C6 haloalkyl; R1e is H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; R1f is H, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; m is the number 0, 1 or 2; R2 is N (R2a) 2; each R2a is independently H or R2b; each R2b is independently C1-C6 alkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkyl-alkylene, optionally substituted by one or more R2c; R2c is R2d or R2e; R2d is halogen, oxo or hydroxy; R2e is -N (R2g) 2, -C (= O) (R2g), -C (= O) O (R2g), -C (= O) N (R2g) 2, -N (R2g) C (= O) (R2g), -S (= O) 2 (R2g), -S (O) 2N (R2g) 2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f; each R2f is independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; each R2g is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or phenyl; R3 is -C (= O) R3a; R3a is C1-C6 alkyl, C1-C6 alkoxy, phenyl or N (R3b) 2; each R3b is independently H or C1-C6 alkyl; R4 is -O (R4a); R4a is H or R4b; R4b is C1-C6 alkyl, phenyl, benzyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, optionally substituted by one or more R4c; R4c is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy; Q4 is Q4a or Q4b; Q4a is halogen; Q4b is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, amino or C1-C6 haloalkyl optionally substituted by one or more Q4c; Q4c is Q4d or Q4e; each Q4d is independently halogen, hydroxy or cyano; each Q4e is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q4f; each Q4f is independently hydroxy, halogen, C1-C6 alkyl, C1-C6 alkenyl, oxo, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl or amino; with the proviso that when R is R4, R4 is -O (R4a), R4a is H and Q4 is Q4a, then Q4a is not H; or a pharmaceutically acceptable salt thereof.

Description

Pyrrolopyrazine Kinase Inhibitors

The present invention relates to the use of new pyrrolopyrazine derivatives, which are inhibitors of JAK and SYK that selectively inhibit JAK3 and are useful for the treatment of inflammatory and autoimmune diseases.

Protein kinases constitute one of the broadest groups of human enzymes that regulate many signaling processes, which consist of inserting phosphate moieties into proteins; in particular, tyrosine kinases phosphorylate proteins on the alcohol moiety of tyrosine. The tyrosine kinase group includes components that control cell growth, migration and differentiation. An abnormal kinase activity can cause a large number of human diseases, including cancer, autoimmune and inflammatory diseases. Since protein kinases are key regulators of cell signaling, they constitute a means to modulate cell function with small molecule inhibitors of kinase activity and, therefore, are taken as targets of pharmacological design. In addition, in the treatment of pathological processes mediated by kinases, selective and effective inhibitors of kinase activity are also useful for investigating cell signaling processes and for the identification of other cell targets of therapeutic interest.

US 2007/0049615 describes depirrolo [2,3b] pyridine derivatives for the treatment of Ret-mediated disease. US 2006/0148801 A1 describes fused bicyclic heteroaryl compounds for the treatment of cancer. JAK (Janus kinases) form a cytoplasmic protein-tyrosine kinase group that includes JAK1, JAK2, JAK3 and TYK2. Each of the JAKs is preferably associated with the intracyte plasma portion of discrete cytokine receptors (Annu. Rev. Immunol. 16, pp. 293–322, 1998). JAKs are activated after ligand binding and initiate signaling by phosphorylating cytokine receptors that, in themselves, are devoid of intrinsic kinase activity. This phosphorylation creates anchor sites in the receptors for other molecules known as STAT proteins (signal transducers and transcription activators) and phosphorylated JAKs bind to several STAT proteins. STAT proteins are DNA binding proteins activated by the phosphorylation of the tyrosine residues, which function not only as signaling molecules but also as transcription factors finally binding to specific DNA sequences that are present in the promoters of the response genes. of cytokines (Leonard et al., J. Allergy Clin. Immunol. 105, 877-888, 2000).

JAK / STAT signaling participates in the mediation of many abnormal immune responses, such as allergies, asthma, autoimmune diseases such as transplant rejection (foreign graft), rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in malignant tumors solid and hematological, for example in leukemia and lymphomas.

Therefore, JAK and STAT are components of multiple potentially interlaced signal transduction mechanisms (Oncogene 19, pp. 5662-5679, 2000), which indicates the difficulty of specifically focusing on an element of the JAK-STAT mechanism without interfering with other signal transduction mechanisms.

JAK kinases, including JAK3, are expressed in abundance in the primary leukemic cells of children suffering from acute lymphoblastic leukemia, the most common form of childhood cancer and studies have established a correlation between the activation of STATs in certain cells and the signals that regulate apoptosis (Demoulin et al., Mol. Cell. Biol. 16, 4710-6, 1996; Jurlander et al., Blood. 89, 4146-52, 1997; Kaneko et al., Clin. Exp Immun. 109, 185-193, 1997; and Nakamura et al., J. Biol. Chem. 271, 19483-8, 1996). It is also known that they are important for the differentiation, functioning and survival of lymphocytes. JAK3 especially plays an essential role in the functioning of lymphocytes, macrophages and mast cells. Given the importance of this JAK kinase, the compounds that modulate the JAK mechanism, including those that are selective of JAK3, can be useful for treating diseases and pathological conditions in which lymphocytes, macrophages or mast cells are involved (Kudlacz et al. ., Am. J. Transplant. 4, 51-57, 2004; Changelian, Science 302, 875-878, 2003). Pathological conditions, in which it may be therapeutically useful to target the JAK mechanism or the modulation of JAK kinases, in particular JAK3, include leukemia, lymphomas, transplant rejection (eg, transplant rejection of islet of pancreas, bone marrow transplant applications (eg graft versus host disease), autoimmune diseases (eg, diabetes) and inflammation (eg, asthma, reactions allergic) The pathological conditions that may benefit from the inhibition of JAK3 are described in more detail below.

However, unlike the relatively ubiquitous expression of JAK1, JAK2 and Tyk2, JAK3 has a more restricted and regulated expression. While some JAK (JAK1, JAK2, Tyk2) are used for a large number of cytokine receptors, JAK3 is used only for those cytokines that contain a γc in their receptor. JAK3 thus plays a role in cytokine signaling, whose receptor has shown that it uses the usual gamma chain; IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. JAK1 interacts, among others, with the cytokine receptors IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2 interacts among others with the receptors of IL-9 and TNF-alpha. After the binding of certain cytokines with their receptors (eg, IL-2, IL-4, IL7, IL-9, IL-15 and IL-21) the oligomerization of the receptor takes place, forming cytoplasmic kinase tails Associated JAKs that are carried in the vicinity and facilitate the transphosphorylation of the tyrosine residues of the JAK kinase. This trans-phosphorylation causes the activation of the JAK kinase.

Animal studies suggest that JAK3 not only plays a critical role in the maturation of B and T lymphocytes, but that the presence of JAK3 is also required to keep T cells functioning. Modulation of immune activity with this new mechanism may be useful for the treatment of T cell proliferation disorders, for example transplant rejection and autoimmune diseases.

In particular, JAK3 participates in a large number of biological processes. For example, it has been found that the proliferation and survival of murine mast cells induced by IL-4 and IL-9 depends on the signaling of JAK3 and the gamma chain (Suzuki et al., Blood 96, 2172-2180, 2000 ). JAK3 also plays a crucial role in after mast cell degranulation by the IgE receptor (Malaviya et al., Biochem. Biophys. Res. Commun. 257, 807-813, 1999) and it has been found that inhibition of JAK3 kinase prevents type I hypersensitivity reactions, including anaphylaxis (Malaviya et al., J. Biol. Chem. 274, 27028-27038, 1999). It has also been shown that inhibition of JAK3 results in immune suppression of foreign graft rejection (Kirken, Transpl. Proc. 33, 3268-3270, 2001). It has been found that JAK3 kinases participate in the mechanism involved in the early and late stages of rheumatoid arthritis (Muller-Ladner et al., J. Immunal. 164, 38943901, 2000); congenital amyotrophic lateral sclerosis (Trieu et al., Biochem. Biophys. Res. Commun. 267, 22-25, 2000); leukemia (Sudbeck et al., Clin. Cancer Res. 5, 1569-1582, 1999); fungoid mycoses, a form of T-cell lymphoma (Nielsen et al., Prac. Natl. Acad. Sci. USA 94, 6764-6769, 1997); and abnormal cell growth (Yu et al., J. Immunol. 159, 5206-5210, 1997; Catlett-Falcone et al., Immunity 10, 105-115, 1999).

JAK3 inhibitors are useful therapeutic agents such as immunosuppressive agents in organ transplants, foreign transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune disorders of Thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications where immunosuppression would be desirable.

Studies have also been published on the non-hematopoietic expression of JAK3, although its functional significance has not yet been clarified (J. Immunol. 168, pp. 2475–2482, 2002). Since bone marrow transplants for SCID are curative (Blood 103, pp. 2009–2018, 2004), it seems unlikely that JAK3 has essential non-redundant functions in other tissues or organs. Therefore, unlike other immunosuppressive drug targets, the restricted distribution of JAK is very striking. Agents acting on molecular targets with limited expression to the immune system could lead to an optimal relationship between efficacy and toxicity. Therefore, targeting JAK could theoretically offer immunosuppression where it is needed (that is, in cells that actively participate in immune responses), without causing effects outside these cell populations. Although defective immune responses have already been described in several STAT - / - strains (J. Investig. Med. 44, pp. 304-311, 1996; Curr. Opin. Cell. Biol. 9, pp. 233-239, 1997) , the ubiquitous distribution of STATs and the fact that these molecules lack enzymatic activity that could be taken as a target with small molecule inhibitors have contributed to discarding their selection as key targets of immunosuppression.

SYK kinase (tyrosine kinase of the spleen) is a receptor-free tyrosine kinase that is essential for the activation of B cells by BCR signaling. SYK is activated after binding to a phosphorylated BCR and, thus, initiates early signaling events after activation by the BCR. SYK-deficient mice show an early blockage of B cell development (Cheng et al., Nature 378, 303, 1995; Turner et al. Nature 378, 298, 1995). Therefore, the inhibition of the enzymatic activity of SYK has been proposed as a treatment for autoimmune disease, despite its effects on the production of autoantibodies.

In addition to the role of SYK in BCR signaling and B cell activation, it also plays a key role in FcεRI-mediated mast cell degranulation and in the activation of eosinophils. SYK is therefore involved in allergic disorders, including asthma (see review by Wong et al., Expert Opin. Investig. Drugs 13, 743, 2004). SYK binds to phosphorylated gamma chains of FcεRI through its SH2 domains and is essential for downstream signaling (Taylor et al., Mol. Cell. Biol. 15, 4149, 1995). SYK-deficient mast cells manifest defective degranulation, secretion of arachidonic acid and cytokines (Costello et al., Oncogene 13, 2595, 1996). This has also been revealed in pharmacological agents that inhibit the activity of SYK in mast cells (Yamamoto et al., J. Pharmacol. Exp. Ther. 306, 1174, 2003). Treatment with antisense oligonucleotides of the SYK inhibits antigen-induced infiltration of eosinophils and neutrophils in an animal model of asthma (Stenton et al., J. Immunol. 169, 1028, 2002). SYK-deficient eosinophils also have an unbalanced activation in response to stimulation of FcεR (Lach-Trifilieffe et al., Blood 96, 2506, 2000). Therefore, molecule inhibitors

Small SYK will be useful for the treatment of allergic-induced inflammatory diseases, including asthma.

In view of the number of pathological states contemplated as beneficiaries of the treatment that involves the modulation of the mechanisms of JAK and / or SYK, it is immediately apparent that the new compounds, which modulate the mechanisms of JAK and / or SYK , and the methods of using these compounds could provide substantial therapeutic benefits to a large number of patients. New pyrrolopyrazine derivatives are provided herein for use in the treatment of pathological conditions, in which the mechanisms of JAK and / or SYK are attacked or JAK or SYK kinases are inhibited, in particular JAK3, and which are Therapeutically useful for the treatment of inflammatory or autoimmune diseases.

The new pyrrolopyrazine derivatives provided herein selectively inhibit JAK3 and are useful for the treatment of inflammatory and autoimmune diseases. The compounds of the invention modulate the mechanisms of JAK and / or SYK are new derivatives of pyrrolopyrazine useful for the treatment of autoimmune and inflammatory diseases, the preferred compounds selectively inhibit JAK3. For example, the compounds of the invention can inhibit JAK3 and SYK, the preferred compounds are selective from JAK3 of JAK kinases and are new pyrrolopyrazine derivatives useful for the treatment of autoimmune and inflammatory diseases. On the other hand, the compounds of the invention can inhibit JAK3 and JAK2, said preferred compounds are selective from JAK3 of JAK kinases and are new derivatives of pyrrolopyrazine useful for the treatment of autoimmune and inflammatory diseases. Similarly, the compounds of the invention can inhibit JAK3 and JAK1, the preferred compounds are selective from JAK3 of JAK kinases and are novel pyrrolopyrazine derivatives useful for the treatment of autoimmune and inflammatory diseases.

This application provides a compound of the formula I '

in which:

123 4

ResR, R, RoR; R1 is C1-C6 alkyl, C1-C6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a;

1a 1b 1c

ResRoR; R1b is halogen, oxo, hydroxy or -CN;

1c 1f1e1e1f1f1f

Res -C (= O) O (R), –C (= O) (CH2) m (R), –O (CH2) m (R), -S (R), –S (O) 2 (R ) or -S (= O) (R), C1-C6 alkyl, C1-C6 alkoxy, amino, amido, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d;

R1d is H, halogen, hydroxy, C1-C6 alkyl, amino, C1-C6 alkoxy or C1-C6 haloalkyl; R1e is H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl;

R1f is H, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; m is the number 0, 1 or 2; R2 is N (R2a) 2;

2a 2b

each Res independently H or R; each R2b is independently C1-C6 alkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkyl-alkylene, optionally substituted by one or more R2c;

2c 2d 2e

ResRoR; R2d is halogen, oxo or hydroxy;

2e 2g2g2g2g2g2g2g2g

Res -N (R) 2, –C (= O) (R), –C (= O) O (R), –C (= O) N (R) 2, -N (R) C (= O ) (R), –S (= O) 2 (R), –S (O) 2N (R) 2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f;

each R2f is independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; each R2g is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or phenyl; R3 is –C (= O) R3a;

3a 3b

Res C1-C6 alkyl, C1-C6 alkoxy, phenyl or N (R) 2; each R3b is independently H or C1-C6 alkyl; R4 is –O (R4a);

4a 4b

ResHoR;

R4b is C1-C6 alkyl, phenyl, benzyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, optionally substituted by one or more R4c; R4c is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy;

4 4a 4b

QesQoQ; Q4a is halogen; Q4b is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, amino or C1-C6 haloalkyl,

optionally substituted by one or more Q4c;

4c 4d 4e

QesQoQ; each Q4d is independently halogen, hydroxy or cyano; each Q4e is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, cycloalkyl, phenyl,

heterocycloalkyl or heteroaryl, optionally substituted by one or more Q4f; each Q4f is independently hydroxy, halogen, C1-C6 alkyl, C1-C6 alkenyl, oxo, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl or amino;

44 4a4a 44a4a

With the condition of when ResR, Res – O (R), ResHyQesQ, then QnoseaH;

or a pharmaceutically acceptable salt thereof. In an embodiment of formula I, R is R1. In a variant of the above embodiment, R1 is C1-C6 alkyl. In a variant of the above embodiment of formula I, C1-C6 alkyl is tert-butyl. In another variant of the previous embodiment of formula I, R1 is -CHC (CH3) 3. In another variant of the above embodiment of formula I, R1 is iso-butyl. In another variant of the above embodiment of formula I, R1 is iso-propyl. In one embodiment of formula I, R1 is cycloalkyl. In one embodiment of formula I, R1 is heterocycloalkyl. In an embodiment of formula I, R1 is benzyl. In one embodiment of formula I, R1 is phenyl. In an embodiment of formula I, R is R2.

22 2nd

In an embodiment of formula I, R is Ry Res NH (R).

22 2a2a 2b

In a way of executing Formula I, ResR, ResNH (R) and Res.

22 2a2a 2b 2b

In one embodiment of formula I, R is R, Res NH (R) and Res Ry Res C1-C6 alkyl.

22 2a2a 2b 2b

In one embodiment of formula I, R is R, Res NH (R) and Res Ry Res iso-propyl.

22 2a2a 2b 2b

In one embodiment of formula I, R is R, Res NH (R) and Res Ry Res heterocycloalkyl.

22 2a2a 2b 2b

In one embodiment of the formula I, R is R, Res NH (R) and Res Ry Res cycloalkyl.

22 2a2a 2b 2b

In one embodiment of formula I, R is R, Res NH (R) and Res Ry Res heterocycloalkyl-alkylene.

22 2a2a 2b 2b

In one embodiment of formula I, R is R, Res NH (R) and Res Ry Res pyrrolidine.

22 2a2a 2b 2b

In one embodiment of formula I, R is R, Res NH (R) and Res Ry Res pyrrolidinylmethylene.

In certain embodiments of formula I, the compounds of interest conform more specifically to formula II:

II

wherein: R1 is C1-C6 alkyl, C1-C6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a;

1a 1b 1c

5 ResRoR; R1b is halogen, oxo, hydroxy or -CN;

1c 1f 1e1e1f1f1f

Res -C (= O) O (R), –C (= O) (CH2) m (R), –O (CH2) m (R), -S (R), –S (O) 2 (R ) or -S (= O) (R), C1-C6 alkyl, C1-C6 alkoxy, amino, amido, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d;

R1d is H, halogen, hydroxy, C1-C6 alkyl, amino, C1-C6 alkoxy or C1-C6 haloalkyl; R1e is H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; R1f is H, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; m is the number 0, 1 or 2; and 15 Q4 has the meaning defined here.

In certain embodiments of formula II, R1 is C1-C6 alkyl, preferably tert-butyl.

In certain embodiments of formula I ', the compounds of interest conform more specifically to formula III:

III

wherein: R2b is independently C1-C6 alkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkylalkylene, optionally substituted by one or more R2c;

2c 2d 2e

25 ResRoR; R2d is halogen, oxo or hydroxy;

2e 2g2g2g2g2g2g2g2g

Res -N (R) 2, –C (= O) (R), –C (= O) O (R), –C (= O) N (R) 2, -N (R) C (= O ) (R), –S (= O) 2 (R), –S (O) 2N (R) 2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f;

Each R2f is independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; each R2g is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or phenyl; Q4 has the meaning defined here.

2b 2c

In certain embodiments of the formula III, Res C1-C6 alkyl optionally substituted by one or more R, already defined.

In certain embodiments of formula III, R2b is C1-C6 alkyl.

In certain embodiments of the formulaws I, II or III, Q4 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 hydroxyalkyl, amino or C1-C6 haloalkyl optionally substituted by one or more Q4c, already defined.

In certain embodiments of one of the formulas I, II or III, Q4 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 hydroxyalkyl, amino or C1-C6 haloalkyl optionally substituted by one or plus C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, cycloalkyl, phenyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more

45 Q4f defined here.

In certain embodiments of one of the formulas I, II or III, Q4 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 hydroxyalkyl optionally substituted by a phenyl or heteroaryl, optionally substituted by an alkyl C1-C6.

In certain embodiments of one of the formulas I, II or III, Q4 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 hydroxyalkyl.

The application provides a compound of the formula I selected from the group consisting of: 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -3-methyl-butan-1-one; 2-Chloro-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide; 2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide; 2-Isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide; 1- (2-Chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclohexyl) -methanone; 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclopentyl) -methanone; 1- (2-ethynyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-ethyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-3-phenyl-propan-1-one; 1- [2- (1-Hydroxy-ethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1-Hydroxy-2-methyl-propyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-o-tolyl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-phenyl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-pyridin-4-yl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-pyridin-3-yl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - ((3aS, 6aS) -1-methyl-octahydro-pentalen-1-yl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - ((1S, 2S) -1,2-dimethyl-cyclopentyl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclohexyl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclopentyl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cycloheptyl) -methanone; adamantan-1-yl- (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone; (4-benzyloxy-1-methyl-cyclohexyl) - (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone; 1- (2-ethynyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; and 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -3-methyl-butan-1-one.

In one aspect, the application describes a method for treating an inflammatory and / or autoimmune disease, which consists in administering to a patient in need a therapeutically effective amount of the compound of the formula I.

In a variant of the above method, said prior method further consists in administering an additional therapeutic agent chosen from a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent to treat cardiovascular disease, an agent. to treat diabetes and an agent to treat immunodeficiency disorders.

In one aspect, the application describes a method for treating an inflammatory disease, which consists in administering to a patient in need a therapeutically effective amount of the compound of the formula I, in which R is R1.

In one aspect, the application describes a method for inhibiting a T cell proliferation disorder, which consists in administering to a patient in need thereof a therapeutically effective amount of the compound of the formula I.

In one aspect, the application describes a method for inhibiting a T cell proliferation disorder, which consists in administering to a patient in need thereof a therapeutically effective amount of the compound of the formula I, in which R is R2.

In a variant of the previous method, the proliferative disorder is cancer.

In one aspect, the application describes a method for treating a B-cell proliferation disorder, which consists in administering to a patient in need thereof a therapeutically effective amount of the compound of the formula I.

In one aspect, the application describes a method to treat an immune disorder, including: lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, organ transplant complications, foreign transplantation, diabetes, cancer, asthma, atopic dermatitis , autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease and leukemia, which consists in administering to a patient in need of a therapeutically effective amount of the compound of the formula I.

In one aspect, the application describes a method to prevent or treat all forms of organ rejection, including acute rejection of foreign graft (allograft) or xenograft and chronic rejection of foreign graft or xenograft, of vascularized or non-vascular transplants. vascularized, which consists in administering to a patient in need a therapeutically effective amount of the compound of the formula I.

In one aspect, the application describes a method to prevent or treat all forms of organ rejection, including acute rejection of foreign graft (allograft) or xenograft and chronic rejection of foreign graft or xenograft, of vascularized or non-vascular transplants. vascularized, which consists of administering to a patient in need the compound of the formula I.

In one aspect, the application describes a method to inhibit the activity of JAK3 which consists in administering the compound of formula I, said compound has an IC50 of 50 micromolar or less in an "in vitro" biochemical assay of JAK3 activity. .

In a variant of the above method, the compound exhibits an IC50 of 100 nanomolar or less in a "in vitro" biochemical assay of JAK3 activity.

In a variant of the above method, the compound has an IC50 of 10 nanomolar or less in a "in vitro" biochemical assay of JAK3 activity.

In one aspect, the application describes a method to inhibit the activity of the SYK activity which consists in administering the compound of the formula I, the compound exhibits an IC50 of 50 micromolar or less in an "in vitro" biochemical assay of activity of the SYK

In a variant of the above method, the compound exhibits an IC50 of 100 nanomolar or less in a "in vitro" biochemical assay of SYK activity.

In a variant of the above method, the compound exhibits an IC50 of 10 nanomolar or less in a "in vitro" biochemical assay of SYK activity.

In one aspect, the application describes a method of treating an inflammatory disease that consists of co-administering to a patient in need of an anti-inflammatory compound in combination with a therapeutically effective amount of the compound of the formula I.

In one aspect, the application describes a method of treating an inflammatory disease that consists of co-administering to a patient in need a therapeutically effective amount of an anti-inflammatory compound in combination with a compound of the formula I.

In one aspect, the application describes a method of treating an immune disorder that consists of co-administering to a patient in need of an immunosuppressive compound in combination with a therapeutically effective amount of the compound of the formula I.

In one aspect, the application describes a method of treating an immune disorder that consists of co-administering to a patient in need a therapeutically effective amount of an immunosuppressive compound in combination with a compound of the formula I.

The application provides a pharmaceutical composition containing the compound of formula I, mixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

In one variant, the above pharmaceutical composition further contains an additional therapeutic agent chosen from a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent to treat cardiovascular disease, an agent to treat diabetes. and an agent to treat immunodeficiency disorders.

In one aspect, the application provides the use of the compound of the formula I, I ’, II or III for the manufacture of a medicament for the treatment of an inflammatory disorder.

In one aspect, the application provides the use of the compound of the formula I for the manufacture of a medicament intended for the treatment of an inflammatory disorder.

In one aspect, the application provides the use of the compound of the formula I, I ’, II or III for the manufacture of a medicament for the treatment of an autoimmune disorder.

In one aspect, the application provides the use of the compound of the formula I for the manufacture of a medicament intended for the treatment of an autoimmune disorder.

In one aspect, the application provides the use of the compound of the formula I, I ’, II or III for the manufacture of a medicament for the treatment of an inflammatory disorder or an autoimmune disorder.

The articles "a" or "a" referred to an entity are used here to indicate one or more entities; for example, a compound indicates one or more compounds, but at least one compound. Therefore the terms "one" (or "one"), "one or more" and "at least one" can be used interchangeably.

The expression "has the meaning defined above" indicates the broadest definition of each group indicated in the summary of the invention or in the broader claim. In all the embodiments presented below, substituents that may be present and are not explicitly defined, retain the definition

15 broader indicated in the summary of the invention.

As used in this description, either in a transitory phrase, or in the body of the claim, the terms "understand (n)" and "understand" should be construed as having an open meaning. That is, the terms should be interpreted as synonyms for the phrases "have at least" or "include at least". When used in the context of a process, the term "understand" means that the process includes at least the mentioned steps, but may include additional steps. When used in the context of a compound or composition, the term "understand" means that the compound or composition includes at least the features or components mentioned, but may also include other features or additional components.

25 As used herein, unless explicitly stated otherwise, the conjunction "o" is used in the "inclusive" sense of "and / or" and not in the "exclusive" sense of "the one, or the other".

The term "independently" is used here to indicate that a variable is applied in any case, regardless of the presence or absence of another variable that has the same meaning or a different meaning within the same compound. Therefore, in a compound, in which R "appears twice and is defined as" independently carbon or nitrogen ", the two R" can be carbons, the two R "can be nitrogen, or an R" can be carbon and the other nitrogen.

If any variable (eg R, R 'or Q) appears more than once in any remainder or formula that represents and describes the compounds employed or claimed in the present invention, their definition at each occurrence is independent of their definition in the other appearances. In addition, combinations of substituents and / or variables are only permissible if such compounds give rise to stable compounds.

The symbols "*" at the end of a link or "-----" drawn through a link indicate in each case the point of attachment of a functional group or other chemical moiety to the rest of the molecule, from which It is part. For example:

or

MeC (= O) O

.

A link drawn into a cyclic system (unlike the one connected to a specific vertex) indicates that the link can be attached to any of the suitable atoms of said ring.

The terms "optionally" or "optionally" used herein indicate that the event or circumstance mentioned below may occur, but not necessarily and that the definition includes cases in which the event or circumstance occurs and cases in which It doesn't happen. For example "optionally substituted" indicates that the optionally substituted moiety may incorporate a hydrogen or a substituent.

The phrase "together form a bicyclic ring system" is used herein to indicate that they concur in the formation of a bicyclic ring, each ring may be formed by 4-7 carbon atoms or 4-7 carbon atoms and heteroatoms and may be saturated or unsaturated.

55 The term "approximately" used here indicates in the region of, roughly, or around. When the term “approximately” is used in combination with a numerical interval, then it modifies this interval by extending the upper and lower limits of the determined numerical interval. In general, the term "approximately" is used to modify a numerical value above and below the set value with a variation of 20%.

The definitions described herein can be completed to form chemically relevant combinations, for example "heteroalkylaryl", "haloalkylheteroaryl", "arylalkylheterocyclyl", "alkylcarbonyl", "alkoxyalkyl" and the like. When the term "alkyl" is used as a suffix after another term, for example in "phenylalkyl" or "hydroxyalkyl", this is done to indicate an alkyl moiety, already defined above, which is substituted by one or two substituents chosen from among the another group that is specifically named. Thus, "phenylalkyl" indicates an alkyl moiety having one or two phenyl substituents and therefore includes benzyl, phenylethyl and biphenyl. An "alkylaminoalkyl" is an alkyl moiety having one or two alkylamino substituents. "Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2- (hydroxymethyl), 3-hydroxypropyl, and the like. Therefore, as used herein, the term "hydroxyalkyl" defines a subgroup of heteroalkyl moieties defined below. The term - (ar) alkyl indicates an unsubstituted alkyl or an aralkyl moiety. The term (hetero) aryl or (het) aryl indicates an aryl moiety or a heteroaryl moiety.

Certain compounds of the formula I 'can have tautomería. Tautomeric compounds can exist in two

or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom from a first atom to a second. Normally tautomers are in equilibrium, attempts to isolate an individual tautomer generally produce a mixture, whose physical and chemical properties are consistent with a mixture of compounds. The equilibrium position depends on the chemical properties of the molecule. For example, in many aldehydes and aliphatic ketones, such as acetaldehyde, the keto form predominates, while in the phenols the enol form predominates. Typical prototropic tautomers include keto / enol tautomers (-C (= O) -CH-↔ -C (-OH) = CH-), amide / imidic acid (-C (= O) -NH-↔ -C (-OH) = N-) and amidine (-C (= NR) -NH-↔ -C (-NHR) = N-). The last two are especially frequent in the heteroaryl and heterocyclyl rings and the present invention encompasses all tautomeric forms of these compounds.

The technical and scientific terms used herein have the meanings that are normally attributed to them among experts in the field to which the present invention refers, unless otherwise defined. Reference is made here to the various methodologies and materials that the subject matter experts already know. Reference manuals that define the general principles of pharmacology include Goodman and Gilman: The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill Companies Inc., New York (2001). To carry out the present invention, suitable materials and / or methods, which are well known to the experts, can be used. However, preferred materials and methods are described. The materials, reagents and the like mentioned in the description that follows and in the examples can be purchased from commercial suppliers, unless otherwise indicated.

As used herein, the term "acyl" indicates a group of the formula -C (= O) R, wherein R is hydrogen or lower alkyl, defined herein. As used herein, the term "alkylcarbonyl" indicates a group of the formula C (= O) R, wherein R is alkyl defined herein. As used herein, the term C1-6 acyl indicates a -C (= O) R moiety, which has 6 carbon atoms. As used herein, the term "arylcarbonyl" indicates a group of the formula C (= O) R, wherein R is an aryl moiety; As used herein, the term "benzoyl" indicates an "arylcarbonyl" moiety, wherein R is phenyl.

As used herein, the term "alkyl" indicates a saturated, monovalent, straight or branched chain hydrocarbon moiety, containing from 1 to 10 carbon atoms. The term "lower alkyl" indicates a straight or branched chain hydrocarbon moiety, containing from 1 to 6 carbon atoms. As used herein, "C1-10 alkyl" indicates an alkyl moiety consisting of 1-10 carbons. Examples of alkyl moieties include, but are not limited to: methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

When the term "alkyl" is used as a suffix after another term, for example in "phenylalkyl" or "hydroxyalkyl", this indicates that an alkyl moiety, already defined above, is substituted by one or two substituents chosen from the other group that It is specifically mentioned. Thus, eg, "phenylalkyl" indicates an R'R moiety "-, in which R 'is a phenyl moiety and R" is an alkylene moiety, which is defined in this description, assuming that the point of union of the phenylalkyl moiety is found in the alkylene moiety. Examples of arylalkyl moieties include, but are not limited to: benzyl, phenylethyl, 3-phenylpropyl. The terms "arylalkyl" or "aralkyl" are interpreted similarly, except that R "is an aryl moiety. The terms "(het) arylalkyl" or "(het) aralkyl" are interpreted similarly, except that R 'is optionally an aryl or heteroaryl moiety.

As used herein, the term "haloalkyl" indicates a straight or branched chain alkyl moiety, as defined above, in which 1, 2, 3 or more hydrogen atoms have been replaced by a halogen. The term "lower haloalkyl" indicates a straight or branched chain alkyl moiety, having 1 to 6 carbon atoms, in which 1, 2, 3

or more hydrogen atoms have been replaced by a halogen. Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluorethyl, 1 chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluorethyl, 2-chloroethyl, 2 -bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3bromopropyl or 2,2,2-trifluoroethyl.

As used herein, the term "alkylene" indicates a linear divalent saturated hydrocarbon moiety, of 1 to 10 carbon atoms (eg, (CH2) n) or a branched divalent saturated hydrocarbon moiety, of 2 to 10 atoms. carbon (eg, -CHMe-or -CH2CH (i-Pr) CH2-), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene moiety will not be attached to the same atom. Examples of alkylene moieties include, but are not limited to: methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2-ethylbutylene.

As used herein, the term "alkoxy" indicates an -O-alkyl moiety, in which alkyl has the meaning defined above, for example methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy , t-butyloxy, pentyloxy, hexyloxy, including its isomers. As used herein, "lower alkoxy" indicates an -O-alkyl moiety, in which alkyl is "lower alkyl" already defined above. As used herein, "C1-10 alkoxy" indicates an -O-alkyl moiety, wherein alkyl is C1-10 alkyl.

The term "alkoxyalkyl" is used herein to indicate an R'R moiety "-, where R 'is an alkoxy moiety already defined before and R" is an alkylene moiety already defined before, assuming that the point of attachment of the alkoxyalkyl moiety is found in the alkylene moiety. C1-6 alkoxyalkyl indicates a moiety in which the alkyl portion contains 1-6 carbon atoms, not counting the carbon atoms of the alkoxy portion of the group. (C1-3 alkoxy) -C1-6 alkyl indicates a group in which the alkyl portion has 1-6 carbon atoms and the alkoxy portion has 1-3 carbons. Examples are: methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxymethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, t-butyloxybutyl, methoxypentyl, ethoxyphentyl, propyloxythostyle, propyloxyphenyl.

As used herein, the term "hydroxyalkyl" indicates an alkyl moiety, already defined above, in which one to three hydrogen atoms of different carbon atoms has / has been replaced by hydroxyl groups.

As used herein, the term "cycloalkyl" indicates a saturated carbocyclic ring having 3 to 8 carbon atoms, eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. As used herein, "C3-7 cycloalkyl" indicates a cycloalkyl consisting of 3-7 carbons in the carbocyclic ring.

The term "halogen" or "halo" is used herein to indicate fluorine, chlorine, bromine or iodine.

As used herein, the term "heteroaryl" or "heteroaromatic" indicates a monocyclic, bicyclic or tricyclic moiety of 5 to 18 ring atoms, which has at least one aromatic ring containing four to eight atoms, which incorporates one or more heteroatoms N, O or S, the other atoms of the ring are carbons, assuming that the point of attachment of the heteroaryl moiety is located in an aromatic ring. Those skilled in the art already know that heteroaryl rings have an aromatic character less pronounced than their counterparts formed exclusively by carbon atoms. Therefore, for the purposes of the invention, a heteroaryl group needs to have only a certain degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 or 6 ring atoms and 1 to 3 heteroatoms, which include, but are not limited to: pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolinyl, thiadiazolyl and oxadiaxolinyl, which may be optionally substituted by one or more, preferably one or two substituents, chosen from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to.

a: quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazolyl, bencisoxazolyl, benzothiazolyl and bencisothiazolyl.

The term "heteroaryloxy" is used herein to denote an -O- (heteroaryl) moiety, in which heteroaryl has the meaning already defined.

The term "(hetero) aryl" is used herein to denote an aryl or heteroaryl moiety, already defined.

As used herein, the term "heterocycloalkyl", "heterocyclyl" or "heterocycle" indicates a monovalent saturated cyclic moiety, consisting of one or more rings, preferably one or two rings, of three to eight atoms per ring, which incorporates one or more heteroatoms to the ring (chosen from N, O and S (O) 0-2), and which may be optionally substituted independently by one or more, preferably one or two substituents chosen from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, arylaminocarbonyla another thing. Examples of heterocyclic moieties include, but are not limited to azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl. The term "heterocycloalkyloxy" is used herein to denote a group -O- (heterocycloalkyl), in which heterocycloalkyl has the meaning already defined.

The phrase "organ rejection" includes rejection of foreign graft (allograft) and xenograft and chronic rejection of foreign graft (allograft) and xenograft when vascularized and / or non-vascularized transplants (eg bone marrow, are assimilated, of islet cells of the pancreas).

5 The most commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmospheres (atm), 9borabicyclo [3.3.1] nonane (9-BBN or BBN), tert-butoxycarbonyl (Boc), pyrocarbonate di-tert-butyl or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts (CASRN) registration number, benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4- diazabicyclo [2.2.2] octane (DABCO), diethylaminoazufre trifluoride (DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo [4.3.0] non-5-eno (DBN), 1,8-diazabicyclo [5.4. 0] undec-7-eno (DBU), N, N '

10 dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-isopropyl azodicarboxylate (DIAD), di-isobutyl aluminum hydride (DIBAL or DIBAL-H) , di-iso-propylethylamine (DIPEA), N, N-dimethyl-acetamide (DMA), 4-N, N-dimethylaminopyridine (DMAP), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1, 1'-bis- (diphenylphosphino) ethane (dppe), 1,1'-bis- (diphenylphosphino) ferrocene (dppf), 1 (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H

Ethyl quinoline-1-carboxylate (EEDQ), diethyl ether (Et2O), O- (7-azabenzotriazol-1-yl) hexafluorphosphate N, N, N'N'-tetramethyluronium (HATU), acetic acid (HOAc ), 1-N-hydroxybenzotriazole (HOBt), high-efficiency liquid chromatography (HPLC), iso-propanol (IPA), lithium hexamethyl-disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2 - (mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (MS), methyl and t-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxyanhydride (NCA), N

Chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i- Pr), pounds per square inch (psi), pyridine (pyr), room temperature (RT or t.amb.), Tert-butyldimethylsilyl or t-BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6 , 6-tetramethylpiperidine-1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1,1'-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluorborate (TBTU),

25 thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or tosyl (Ts), N-urethane-N- carboxyanhydride (UNCA). The conventional nomenclature, which includes the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo has its usual meanings when applied to an alkyl moiety (Rigaudy and Klesney, Nomenclature in Organic Chemistry, IUPAC, 1979, Pergamon Press, Oxford).

Examples of representative compounds contemplated by the present invention and encompassed by the scope of the invention are set forth in the following table. These examples and the following embodiments are provided to allow experts a better understanding and implementation of the present invention. They should not be considered as a limitation of the scope of the invention, but as merely illustrative and representative thereof.

35 In general, this application uses the nomenclature based on the AUTONOM ™ v.4.0 program, a computerized system of the Beilstein Institute for the generation of the systematic nomenclature of the IUPAC. If a discrepancy arises between the structure represented and the name attributed to it, then priority must be given to the structure represented. In addition, if the stereochemistry of a structure or portion of a structure is not indicated,

40 eg with solid or broken lines, then the structure or portion of the structure should be interpreted to cover all stereoisomers thereof.

Table I shows examples of compounds of the formula I.

45 Table 1

compound

systematic name structure m.p.

I-1

1- (2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) -3-methyl-butan1-one N N N Br O 183-187.5

I-3

2-Chloro-5H-pyrrolo [2,3b] pyrazine-7-carboxylic acid isopropylamide N N N N O Cl 278-279

I-4

2isopropenyl-5H-pyrrolo [2,3b] pyrazine-7-carboxylic acid isopropylamide NN N N O

compound

systematic name structure m.p.

I-5

2isopropyl-5H-pyrrolo [2,3b] pyrazine-7-carboxylic acid isopropylamide NN N N O

I-6

1- (2-Chloro-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethylpropan-1-one N N Cl N O 209-210

I-7

(2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) - (1-methylcyclohexyl) -methanone N N N Br O

I-8

1- (2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethylpropan-1-one N N N Br O 213.0-214.0

I-9

1- (2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one N N N O

I-10

(2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) - (1-methylcyclopentyl) -methanone N N N O Br 206.9-207.9

I-11

1- (2-ethynyl-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethylpropan-1-one N N N O 229.0-231.0

I-12

1- (2-ethyl-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethylpropan-1-one N N N O 215.0-216.0

I-13

1- (2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethyl-3-phenyl-propan-1-one Br HN N N O

I-14

1- [2- (1-Hydroxy-ethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one N N HN O OH

compound

systematic name structure m.p.

HN O

1- [2- (1-hydroxy-2-methyl-

N

I-15

propyl) -5H-pyrrolo [2,3- N

b] pyrazin-7-yl] -2,2-dimethyl

propan-1-one

OH

HN O

1- [2- (hydroxy-o-tolyl-methyl) -5H-

N N

I-16

pirrolo [2,3-b] pirazin-7-il] -2,2

dimethyl-propan-1-one

OH

N HN O

1- [2- (hydroxy-phenyl-methyl) -5H-

N

I-17

pirrolo [2,3-b] pirazin-7-il] -2,2

dimethyl-propan-1-one

OH

HN O

1- [2- (hydroxy-pyridin-4-yl-

N

I-18

methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl- N

propan-1-one

OH N

HN O

1- [2- (hydroxy-pyridin-3-yl-

N

I-19

methyl) -5H-pyrrolo [2,3-b] - N

pyrazin-7-yl] -2,2-dimethyl

propan-1-one

OH N

I-20

(2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) - ((3aS, 6aS) -1-methyl-octahydro-pentalen-1il) -methanone Br N N HN O H H

I-21

(2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) - ((1S, 2S) -1,2-dimethyl-cyclopentyl) -methanone N N HN O Br

compound

systematic name structure m.p.

I-22

(2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) - (1-methylcyclohexyl) -methanone HN N N Br O

I-23

(2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) - (1-methylcyclopentyl) -methanone HN N N O Br

I-24

(2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) - (1-methylcycloheptyl) -methanone N N HN O Br

I-25

adamantan-1-yl- (2-bromo5H-pyrrolo [2,3-b] pyrazin-7-yl) methanone N N HN Br O

I-26

(4-benzyloxy-1-methyl-cyclohexyl) - (2-bromo-5Hpyrrolo [2,3-b] pyrazin-7-yl) methanone N N HN O Br O

I-27

(4-benzyloxy-1-methyl-cyclohexyl) - (5H-pyrrolo [2,3b] pyrazin-7-yl) -methanone N N HN O O

I-28

1- (2-ethynyl-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethylpropan-1-one N N HN O

I-29

1- (2-ethyl-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethylpropan-1-one N N HN O

compound

systematic name structure m.p.

I-30

1- (2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one N HN NO

I-31

1- (2-Chloro-5H-pyrrolo [2,3b] pyrazin-7-yl) -2,2-dimethylpropan-1-one N HN N Cl O

I-32

1- (2-Bromo-5H-pyrrolo [2,3b] pyrazin-7-yl) -3-methyl-butan1-one N Br N N H O

The compounds of the present invention can be formulated in a wide variety of oral dosage forms and excipients. Oral administration can be carried out in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention are effective when administered by other routes, including continuous (intravenous drip), topical, parenteral,

5 intramuscular, intravenous, subcutaneous, transdermal (including a penetration enhancing agent), buccal, nasal, administration by inhalation and by suppository, among other routes of administration. The preferred mode of administration is generally oral, using a convenient daily dose regimen, which can be adjusted according to the severity of the disease and the patient's response to the active ingredient.

A compound or compounds of the present invention, as well as their pharmaceutically usable salts, together with one or more conventional excipients, carriers or diluents, can be integrated into a form of pharmaceutical compositions and unit doses. The pharmaceutical compositions and unit dosage forms may contain the conventional ingredients in conventional proportions, with or without additional compounds or active ingredients and the unit dosage forms may contain any suitable effective amount of the

15 active ingredient, proportionate to the daily dose range that is intended to be administered. The pharmaceutical compositions can be used in the form of solids, for example filled tablets or capsules, semi-solids, powders, extended-release formulations or liquids, for example solutions, suspensions, emulsions, elixirs or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. A typical preparation contains 5% to 95% of

20 compound or active compounds (w / w). The term "preparation" or "dosage form" may include both solid and liquid formulations of the active compound and the person skilled in the art will appreciate that an active ingredient can be part of different preparations depending on the organ or tissue that are the object of the treatment. , of the desired dose and pharmacokinetic parameters.

The term "excipient" used in this description means a compound that is useful for manufacturing the pharmaceutical composition, is generally safe, non-toxic and not bothersome in the biological sense or in any other sense and includes both the excipients acceptable for veterinary use and those of human pharmaceutical use. The compounds of this invention may be administered alone, but in general they will be administered in admixture with one or more pharmaceutically acceptable excipients, diluents or carriers, which will be chosen taking into account the route of administration.

30 intended and standard pharmaceutical practice.

"Pharmaceutically acceptable" it means that which is useful in the preparation of a pharmaceutical composition, which is generally safe, non-toxic and undesirable biologically or otherwise and includes what is acceptable for veterinary as well as human pharmaceutical use.

A "pharmaceutically acceptable salt" form of an active ingredient may also initially confer a desirable pharmacokinetic property on the active ingredient, which is absent in the non-salt form and may positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body.

A "pharmaceutically acceptable salt" form of an active ingredient may also initially confer a desirable pharmacokinetic property of the active ingredient, which is absent in the non-salt form and may even positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the organism. The phrase "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the original compound. Such salts include: (1) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or those formed with organic acids, for example acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, acid citric, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, acid 2-Naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor sulfulfic acid, 4-methylbicyclo acid [2.2.2] -oct-2-eno-1 carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton, present in the original compound, is replaced by a metal ion, eg, an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

Solid preparations include powders, tablets, pills, capsules, seals (hollow wafers), suppositories and dispersible granules. A solid excipient may also contain one or more substances that also act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material. In powders, the excipient is generally a finely divided solid, mixed with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with the excipient that has a sufficient binder capacity in suitable proportions and is compacted to acquire the desired shape and size. Suitable excipients include but are not limited to: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. . In addition to the active substance, solid preparations may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like.

Liquid formulations are also suitable for oral administration and include preparations in liquid form, including emulsions, syrups, elixirs, aqueous solutions and aqueous suspensions. Also included are solid form preparations that are intended to become liquid form preparations immediately before use. The emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or they may contain emulsifying agents, for example lecithin, sorbitol monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding the appropriate dyes, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with a viscous material, for example natural gums

or synthetics, resins, methyl cellulose, sodium carboxymethyl cellulose and other known suspending agents.

The compounds of the present invention can be formulated for parenteral administration (eg by injection, for example bolus injection or continuous infusion) and can be presented in unit dosage forms in ampoules, pre-packaged syringes, small infusion containers volume or multi-dose containers, which also contain a preservative. The compositions may also take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous excipients, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil) and injectable organic esters (eg ethyl oleate) and may contain agents. of formulation, for example preservatives, humectants, emulsifiers or suspensions, stabilizers and / or dispersants. Alternatively, the active ingredient can be presented in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution for reconstitution before use in an ideal vehicle, eg sterile, pyrogen-free water. The compounds of the present invention can also be formulated for topical administration on the epidermis in the form of ointments, creams or lotions or in the form of transdermal plaster (patch). Ointments and creams can be formulated for example with an aqueous or oily base by adding suitable thickening and / or gelling agents. Lotions can be formulated on an aqueous or oily base and will generally carry one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents. Formulations suitable for topical administration in the mouth include diamond-shaped tablets containing an active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pills containing the active ingredient in an inert base, for example gelatin and glycerin or sucrose and acacia; and the oral lotions that the active substance contains in an ideal liquid excipient.

The compounds of the present invention can be formulated for administration in the form of suppositories. First, a low melting wax is melted, for example a mixture of fatty acid glycerides or cocoa butter and then the active ingredient is dispersed homogeneously there, for example by stirring. The molten homogeneous mixture is then poured into molds of the appropriate volume, allowed to cool and solidify.

The compounds of the present invention can be formulated for vaginal administration. Pessaries, buffers, creams, gels, pastes, foams or sprayers which, in addition to the active ingredient, contain excipients known in the art are known as suitable.

The compounds of the present invention can be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, eg with a dropper, a pipette or a nebulizer. The formulations can be supplied as a single dose or multidose. In the latter case of an eyedropper or pipette, the use can be made by the same patient who is administered a suitable predetermined volume of the solution or suspension. In the case of the nebulizer, the use can be carried out, for example, by means of a spray pump that atomizes a fixed, calibrated quantity.

The compounds of the present invention can be formulated for aerosol administration, especially for the respiratory tract, including intranasal administration. In general, the compound should have a small particle size, eg of the order of five (5) microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. The active substance is supplied in a pressurized container containing a suitable propellant, for example a chlorofluorinated hydrocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. Conveniently, the aerosol may further contain a surfactant, for example lecithin. The drug dose can be controlled by a calibrated valve. Alternatively, the active ingredients can be supplied in the form of dry powder, eg a powdery mixture containing the compound in a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP). The powdered excipient will form a gel in the nasal cavity. The powder composition may be presented as a unit dose, eg in capsules or cartridges, eg gelatin or in blister packs, from which the powder will be administered by an inhaler.

If desired, the formulations can be manufactured with enteric coating, adapted to an administration with persistent or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient tolerance is crucial to the treatment regimen. Compounds of transdermal delivery systems are often housed in a solid support adhered to the skin. The compound of interest can also be combined with a penetration enhancer, eg azone (1-dodecylaza-cycloheptan-2-one). Delivery systems with persistent release are subcutaneously inserted into the subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a lipid soluble membrane, eg silicone rubber or a biodegradable polymer, eg polylactic acid.

Suitable formulations together with pharmaceutical vehicles, diluents and excipients are described in the Remington: The Science and Practice of Pharmacy, 1995, coordinated by E.W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. A scientist skilled in formulations may modify the formulations within the teaching of the specification to obtain numerous formulations intended for a specific route of administration without thereby destabilizing the compositions of the present invention or compromising their therapeutic activity.

The modification of the present compounds to make them more soluble in water or in another vehicle, for example, can easily be carried out by minor modifications (salt formation, esterification, etc.), which are well known to those skilled in the art. . Those skilled in the art also know how to modify the route of administration and the dosage regimen of a particular compound in order to better manage the pharmacokinetics of the present compounds so that they have the maximum beneficial effect on patients. The term "therapeutically effective amount" used in the description means the amount required to reduce the symptoms of the disease in an individual. The dose should be adjusted to the individual factors of each particular case. Such a dose can vary within wide limits, depending on numerous factors, such as the severity of the disease to be treated, the age and the general state of health of the patient, other medications that the patient is taking, the route and the form of administration and the preferences and experience of the doctor who attends to the patient. A daily dose of 0.01 to 1000 mg / kg of body weight per day in monotherapy and / or combination therapy regime may be appropriate for oral administration. A preferred daily dose is between 0.1 and 500 mg / kg of body weight, especially between 0.1 and 100 mg / kg of body weight and very especially preferred between 1.0 and 10 mg / kg of body weight per day. . Therefore, for administration to a 70 kg person, the dose could be between 7 mg and 0.7 g per day. The daily dosage can be administered in a single dose or taken or divided into several sub-doses, for example between 1 and 5 sub-doses per day. In general, treatment begins with small doses, lower than the optimal dose of the compound. The dose is then increased until the optimum effect is achieved for the individual patient. Experts in treating diseases of the type described here will be able, without

5 carry out unnecessary experiments and based on their personal knowledge and experience and considering the teachings of this application, to evaluate the therapeutically effective amount of the compounds of the present invention for a specific disease and patient.

Pharmaceutical preparations are preferably presented in unit dosage form. In that way, the

The preparation is subdivided into unit doses containing the appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package contains discrete amounts of the preparation, for example tablets, packaged capsules and powders in vials. The unit dosage form may also be a capsule, a tablet, a seal or even a pill, or it may be the appropriate number of any one of these in packaged form.

The following examples illustrate the obtaining and biological evaluation of the compounds within the scope of the invention. These following examples and embodiments are provided to allow the experts in organic synthesis a better understanding and practice of the present invention. They should not be considered as a limitation of the scope of the invention, but as merely illustrative and representative thereof.

Examples

Example 1

Ethyl 2-bromo-6-methyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylate

20 ml of anhydrous N-methylpyrrolidine are deposited in a flask and the 60% NaH NaH (840 mg, 21 mmol) is introduced at 0 ° C. After stirring for 15 min, ethyl acetoacetate (2.73 g, 10.8 mmol) is slowly added. After stirring for an additional 20 min, 3,5-dibromo-pyrazin-2-ylamine (5.04 g, 20 mmol) is added. The

30 ice bath reactor and heated at 140oC for 3 days. The dark mixture is cooled to t.amb. and diluted with diethyl ether and water. The mixture is filtered and distributed. The organic phase is washed with water and then with brine, dried with Na2SO4, filtered and concentrated, obtaining a dark red oil. This is purified by chromatography through silica gel (4: 1 hexanes: EtOAc), obtaining 290 mg of ethyl 2-bromo-6-methyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylate.

35 Example 2

2-isopropenyl-5H-pyrrolo [2,3-b] pyrazine

40 2-Bromo-5H-pyrrolo [2,3-b] pyrazine (400 mg, 2 mmol), prop-1-en-2-ylboronic acid (190 mg, 2.2 mmol), potassium carbonate are mixed (838 mg, 6 mmol) and 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride (249 mg, 0.3 mmol) in dioxane (40 ml) and water (10 ml) and heated to 105 ° C for 1 hour. The reaction mixture was poured onto ethyl acetate and extracted with ethyl acetate. The extracts are combined, washed with brine, dried (Na2SO4), filtered and purified through silica gel, obtaining 134 mg of the compound.

45 epigraph.

2- [3- (3,3-Dimethyl-pyrrolidin-1-yl) -phenyl] -5H-pyrrolo [2,3-b] pyrazine is obtained from 2-bromo-2H-pyrrolo [2, 3b] pyrazine according to the general procedures described in these examples.

Example 3

7-iodo-2-isopropenyl-5H-pyrrolo [2,3-b] pyrazine

The 2-isopropenyl-5H-pyrrolo [2,3b] pyrazine (89 mg, 0.56 mmol) is dissolved in DMF (5 ml) and potassium hydroxide (200 mg) is added, then the iodine is added dropwise (199 mg, 0.78 mmol) dissolved in DMF (1.5 ml). It shakes

10 the reaction mixture for 3 h, is poured into water and extracted with ethyl acetate. The extracts are combined, washed with water and then with brine, dried (Na2SO4), filtered and volatile components removed under reduced pressure. The crude reaction mixture is purified through silica gel, obtaining 92 mg of the epigraph compound.

15 2- [3- (3,3-Dimethyl-pyrrolidin-1-yl) -phenyl] -5H-pyrrolo [2,3-b] pyrazine is obtained according to the general procedures described in these examples and protected with TIPS according to the general procedures described in these examples.

Example 4

2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide

Mix 7-iodo-2-isopropenyl-5H-pyrrolo [2,3b] pyrazine (154 mg, 0.54 mmol), palladium acetate (6 mg, 0.03 mmol) and xanthphos (17 mg, 0, 03 mmol) in DMF / toluene (1: 3, 5 ml). The flask is purged twice with argon and

25 carbon monoxide is bubbled through the mixture in for 1 min. Isopropylamine (128 mg, 2.16 mmol) is added and stirred at 100 ° C for 1 h. After 45 min the volatile components are removed under reduced pressure, the residue is partitioned between ethyl acetate and water, extracted twice, dried (Na2SO4), filtered and purified through silica gel, obtaining 76 mg. of 2-isopropenyl-5H-pyrrolo [2,3b] pyrazine-7-carboxylic acid isopropylamide.

Example 5

2-Isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide

The 2-isopropenyl-5H-pyrrolo [2,3b] pyrazine-7-carboxylic acid isopropylamide (60 mg, 0.25 mmol) in ethanol (10 ml) and palladium on carbon (8 mg) is added. The reaction mixture is stirred for 2 h in a Parr hydrogenator with a hydrogen pressure of 55 psi, then filtered through Celite. Volatile components are removed under reduced pressure, obtaining 60 mg of the 2-isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide.

Example 6

A solution of the 2-chloro-5H-pyrrolo [2,3-b] pyrazine (0.62 g, 4 mmol) in 20 ° C is treated at 0 ° C

10 ml of dimethylformamide with potassium hydroxide (0.47 g, 8.4 mmol, crushed) and iodine is added portionwise (1.03 g, 4 mmol). The mixture is heated to room temperature and stirred at this temperature for 10 m. The mixture is diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bisulfite. The aqueous phase is washed with ethyl acetate four times, the organic phases are combined, dried with magnesium sulfate, filtered and concentrated, used to obtain the following example.

15 Example 7

2-Chloro-7-iodo-5-triisopropylsilanyl-5H-pyrrolo [2,3-b] pyrazine

A solution of the 2-chloro-7-iodo-5H-pyrrolo [2,3-b] pyrazine from the previous step in 30 ml of tetrahydrofuran with lithium hexamethyldisilylamide (6 ml, is treated under argon and stirring at 0 ° C. 1 M in hexanes, 6 mmol) and then with triisopropylsilyl chloride (1.1 ml, 5.2 mmol). After 30 min at 0 ° C the solution is heated to room temperature, diluted with 20% ethyl acetate in hexanes, washed twice with water and once with brine. The organic phase is dried with magnesium sulfate, filtered, the solvent is removed and the resulting residue is subjected to

25 flash chromatography with 2.5% ethyl acetate in hexanes, obtaining 2-chloro-7-iodo-5-triisopropylsilanyl-5Hpyrrolo [2,3-b] pyrazine (1.68 g, 95% as a whole) the two steps).

Example 8

30 1- (2-Chloro-5-triisopropylsilanyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-ol

The 2-chloro-7-iodo-5-triisopropylsilanyl-5H-pyrrolo [2,3-b] pyrazine (0.56 g, 1.28 mmol) is dissolved in 10 ml of dry tetrahydrofuran and stirred under argon while cooling to -78 ° C. A solution of isopropyl magnesium chloride with lithium chloride (3 ml, 1M, 3 mmol) is added with a syringe. After 10 min it is added in

One portion of the pivaldehyde as is (0.325 ml, 3 mmol, distilled). After 1 h at -78 ° C, the reaction mixture is treated with a saturated aqueous solution of ammonium chloride, diluted with ethyl acetate and allowed to warm to room temperature. The organic phase is washed successively with a saturated aqueous solution of sodium bicarbonate and brine. The solution is dried with magnesium sulfate, filtered and the solvent is removed, using the residue directly for the next step.

40 Example 9

1- (2-Chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one

5 The residue from the previous example is dissolved in 30 ml of methylene chloride and treated with Dess-Martin's Periodylene (0.76 g). After 10 min, the reaction mixture is diluted with ethyl acetate and washed successively with a saturated aqueous solution of sodium bisulfite, a saturated aqueous solution of sodium bicarbonate and brine. After drying with magnesium sulfate, filtering and removing the solvent, the residue is taken up in 30 ml of tetrahydrofuran and treated with 10 drops of 1 M sodium hydroxide and 10 drops of a saturated aqueous solution of

10 sodium bicarbonate. The mixture is stirred for 2 h, diluted with ethyl acetate and washed twice with a saturated aqueous solution of sodium bicarbonate and once with brine. The organic phase is dried with magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography using 20% ethyl acetate in hexanes as eluent gives 1- (2-chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1 -one desired (0.18 g, 59% for the set of steps). This material is a solid, from m.p. = 209-210 ° C.

15 Example 10

1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one

To a suspension of 5-bromo-4,7-diazaindole (1.97 g, 9.95 mmol) in 40 ml of dichloromethane, diethyl aluminum chloride (1.0 M in hexane) is added at 0-5 ° C , 30 ml, 30 mmol). The reaction mixture is stirred at 0-5 ° C for 30 min and then pivaloyl chloride (12 ml, 97 mmol) is added. The mixture is heated to reflux and stirred for 15 h, then cooled to 0-5 ° C. A saturated aqueous solution of NaHCO3 (40 ml) is carefully added and the mixture is partitioned between 300 ml of a saturated aqueous solution of NaCl and 300 ml of ethyl acetate. Is filtered

25 the mixture through a Celite cartridge and the phases are separated. The aqueous phase is extracted with 300 ml of ethyl acetate. The organic phases are combined, dried with MgSO4, filtered and concentrated, forming a residue. Chromatography through silica gel (20 to 60% EtOAc in hexanes) gives 2.50 g (89%) of 1- (2-bromine-5H-pyrrolo [2,3-b] pyrazin-7-yl ) -2,2-dimethyl-propan-1-one in the form of a matt white solid.

30 Example 11

1- [2-Bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one

The sodium hydride (60% in mineral oil, 0.019 g, 0.48 mmol) is added at 0-5 ° C to a stirred solution of 1- (2

Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one (0.094 g, 0.33 mmol) in 1.5 ml of N, N ' dimethylformamide The yellow bubbling mixture is stirred at 0-5 ° C for 15 min, then 2- (trimethylsilyl) ethoxymethyl chloride (0.075 ml, 0.42 mmol) is added. The resulting cloudy yellow mixture is stirred at t.amb. for 3 h and partition between 10 ml of water and 10 ml of ethyl acetate. The organic phase is washed successively with two 10 ml portions of water and 10 ml of a saturated aqueous solution of NaCl, dried with MgSO4, filtered and concentrated, leaving an orange oil. Chromatography through silica gel (10% EtOAc in hexanes) gives 0.129 g (93%) of 1- [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3 -b] pyrazin-7-yl] -2,2-dimethylpropan-1-one slightly impure, in the form of yellow oil, which is used without further purification.

Example 12

2-Bromo-7-iodo-5-triisopropylsilanyl-5H-pyrrolo [2,3-b] pyrazine

10 2.4 g of 2-bromo-7-iodo-5H-pyrrolo [2,3-b] pyrazine (7.4 mmol, 1 eq.) Are dissolved in 74 ml of tetrahydrofuran. The flask is cooled in an ice bath and 8 ml of lithium bis (trimethylsilyl) amide (1M solution in hexanes, 8 mmol, 1.08 eq.) Is added dropwise. The reaction solution is stirred at room temperature for 20 min. It is cooled in an ice bath and 1.7 ml of triisopropylsilyl chloride (7.94 mmol, 1.07 eq.) Is slowly added. After 1 h at room temperature, more lithium bis (trimethylsilyl) amide (0.4 ml, 0.4 mmol, 0.05 eq.) And chloride are added

Triisopropylsilyl (0.2 ml, 0.9 mmol, 0.12 eq.). After 1 h more, the reaction is over. The flask is cooled in an ice bath and ethyl acetate, water and a sodium bicarbonate solution are added. The phases are separated and the aqueous phase is extracted once more with ethyl acetate. The ethyl acetate phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude residue is purified by chromatography through silica gel (ethyl acetate / hexanes), obtaining 2.3 g (64%) of product and 0.84 g of

20 starting material (35%).

Example 13

1- (2-Bromo-5-triisopropylsilanyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-ol

2.05 g of 2-bromo-7-iodo-5-triisopropylsilanyl-5H-pyrrolo [2,3-b] pyrazine (4.28 mmol, 1 eq.) Are dissolved in 60 ml of dry tetrahydrofuran. The solution is cooled in an acetone / dry ice bath under argon. 1.91 ml of butyllithium (2.13 M solution in hexanes, 4.07 mmol, 0.95 eq.) Are added. After 30 s, 1.16 ml of trimethylacetaldehyde (distillate, 10.71 mmol, 2.5 eq.) Are added quickly. The mixture is stirred at -78 ° C for 30 min, it is

30 treated by adding an ammonium chloride solution and stirring at room temperature. Ethyl acetate and water are added to the reaction mixture and the phases are separated. The aqueous phase is extracted once more with ethyl acetate, the ethyl acetate phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude residue is purified by chromatography through silica gel (ethyl acetate / hexanes), obtaining 0.39 g (20%) of product and 0.64 g of acetal product (27%). Both compounds are

35 employ for the next reaction.

Example 14 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one

0.4 g of 1- (2-bromo-5-triisopropylsilanyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-ol (0.9)

5 mmol, 1 eq.) In 9 ml of tetrahydrofuran. 1.8 ml of tetrabutylammonium fluoride (1M solution in THF, 1.8 mmol, 2 eq.) Is added and the reaction mixture is stirred at room temperature. After hours, the reaction is over and water, a solution of sodium bicarbonate and ethyl acetate are added. The phases are separated and the aqueous phase is extracted twice more with ethyl acetate. The ethyl acetate phases are washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated, forming a residue.

10 The 2.2 mmole deprotection residue of the starting compound is dissolved in 22 ml of dichloromethane. 1.02 g of Dess-Martin periodine is added (2.4 mmol, 1.1 eq.) And the mixture is stirred at room temperature. After one hour the reaction mixture is processed by the addition of water, a solution of sodium bicarbonate and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate a

15 more times. The ethyl acetate phases are washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude residue is purified by chromatography through silica gel (ethyl acetate / hexanes), yielding 0.53 g (85%) of product.

Example 15

(2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclohexyl) -methanone

Under a N2 atmosphere a suspension of 2-bromo-5H-pyrrolo [2,3-b] pyrazine (104 mg, 0.53 mmol) is cooled to 0 ° C

25 in anhydrous dichloromethane (3 ml). The diethyl aluminum chloride (1M in hexanes, 1.57 ml, 1.57 mmol) is rapidly added and the reaction mixture is stirred for 30 minutes. The 1-methylcyclohexanecarbonyl chloride (844 mg, 5.3 mmol) is added dropwise and the reaction mixture is refluxed overnight. The reaction mixture is cooled to 0 ° C and treated with a saturated aqueous solution of NaHCO3. The biphasic solution is concentrated and the remaining aqueous solution is extracted with ethyl acetate (3x). The organic phases are collected,

30 are dried with MgSO4, filtered and concentrated, obtaining a greenish oil. The residue is purified by chromatography through silica gel using as eluent EtOAc from 20 to 50% in hexanes, obtaining 144 mg (85%) of the (2-bromo-5H-pyrrolo [2,3-b] pyrazine) 7-yl) - (1-methyl-cyclohexyl) -methanone as a slightly yellow solid, mp = 198-199oC, M + H = 322.

35 Example 16

Potassium tert-butoxide (1.0 M in tetrahydrofuran, 45.6 ml, 45.6 mmol) is added dropwise to a solution of 3,5-bis-trimethylsilanylethynyl-pyrazine-2-ylamine (4.36 g, 15.2 mmol) in 60 ml of tetrahydrofuran. The reaction mixture is heated to reflux, stirred for 15 h, allowed to cool to t.amb. and it is treated with 100 ml of water. The resulting mixture is diluted with 250 ml of ethyl acetate and filtered through a Celite cartridge, rinsing with 200 ml of ethyl acetate and 100 ml of water. The phases of the filtered liquid are separated, the organic phase is washed successively with two portions of 200 ml of water and 200 ml of a saturated aqueous solution of NaCl, dried with MgSO4, filtered and concentrated, yielding 0.911 g (42% ) of 2-ethynyl-5H-pyrrolo [2,3-b] pyrazine in the form of an impure brown solid, which is used without further purification.

Example 17

1- (2-ethynyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one

Diethyl aluminum chloride (1.0 M in hexanes, 19.1 ml, 19.1 mmol) is added at 0-5 ° C to a suspension of impure 2-ethynyl-5H-pyrrolo [2,3-b] pyrazine ( 0.911 g, 6.36 mmol) in 25 ml of dichloromethane. The mixture is stirred at 0-5 ° C for 30 min and the pivaloyl chloride (7.8 ml, 63.6 mmol) is added slowly. The mixture is heated to reflux and stirred for 6 h, then cooled to 0-5 ° C. A saturated aqueous solution of NaHCO3 (50 ml) is carefully added, the resulting mixture is diluted with 100 ml of ethyl acetate and filtered through a Celite cartridge, rinsing with ethyl acetate and water. The phases of the filtered liquid are separated and the aqueous phase is extracted with 250 ml of ethyl acetate. The organic phases are combined, dried with MgSO4, filtered and concentrated, leaving a residue. By chromatography through silica gel (20 to 60% EtOAc in hexanes), 0.188 g (12%) of 1- (2-ethynyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) are obtained ) -2,2-dimethyl-propan-1-one in the form of a brown solid.

Example 19

1- [2- (1-Hydroxy-ethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one

Step 1 Partially dissolve 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one (1.5 g, 5.3 mmoles) in 18 ml of toluene and ethylene glycol (0.9 ml, 15.9 mmol) and then hydrated p-toluenesulfonic acid are added and the mixture is boiled under reflux in a Dean-Stark trap for 24 h The reaction mixture is cooled to room temperature and a solution of ammonium chloride, water and ethyl acetate is added, the phases are separated and the aqueous phase is extracted twice with ethyl acetate, the ethyl acetate phases are combined. , washed with a saturated sodium chloride solution and dried with sodium sulfate After filtering and concentrating the residue is purified by chromatography through silica gel (ethyl acetate / hexanes), obtaining 1.44 g (83% ) of 2-bromo-7- (2-tert-butyl- [1,3] dioxolan-2-yl) -5H-pyrrolo [2,3-b] pyrazine.

Step 2 Dissolve the 2-bromo-7- (2-tert-butyl- [1,3] dioxolan-2-yl) -5H-pyrrolo [2,3-b] pyrazine (0.2 g, 0.61 mmol) in 6 ml of tetrahydrofuran. Sodium hydride (49 mg, 1.22 mmol, 60% dispersion in mineral oil) is added and the mixture is stirred for 15 min. The mixture is cooled in an acetone / dry ice bath and butyl lithium (0.37 ml, 0.92 mmol, 2.5 M solution in hexanes) is added slowly. After 5 min acetaldehyde (85 µl, 1.52 mmol) is added. After 1 h more, a solution of ammonium chloride is added, then water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phases are combined, washed with a saturated sodium chloride solution and dried with sodium sulfate. After filtering and concentrating, the residue is purified by chromatography through silica gel (methanol / dichloromethane), yielding 109 mg (61%) of 1- [7- (2-tert-butyl- [1,3] dioxolan-2- il) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -ethanol. (M + H) + = 292.

Step 3 Dissolve 1- [7- (2-tert-butyl- [1,3] dioxolan-2-yl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -ethanol (105 mg , 0.36 mmol) in 4 ml of 1,4-dioxane. 3M hydrochloric acid (1.2 ml) is added and the mixture is stirred for 18 h. The reaction mixture is neutralized by the addition of a solution of sodium bicarbonate, then ethyl acetate and water are added. The phases are separated and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phases are combined, washed with a saturated sodium chloride solution and dried with sodium sulfate. After filtering and concentrating, the residue is purified by chromatography through silica gel (methanol / dichloromethane) and recrystallized from ethyl acetate / hexanes, yielding 65 mg (73%) of product, m.p. = 152-155 ° C, (M + H) + = 248.

Applying the general procedures described in these examples, the following compounds are obtained: 1- [2- (1-hydroxy-2-methyl-propyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2, 2-dimethyl-propan-1-one. The isobutyraldehyde is replaced by acetaldehyde in step 2; from p.f. = 148-150 ° C, (M + H) + = 276. 7- (2,2-Dimethylpropionyl) -5H-pyrrolo [2,3-b] pyrazine-2-carboxylic acid isopropylamide. Carbon dioxide is replaced by acetaldehyde in step 2. After the general procedures described in these examples are applied, isopropylamine is used and step 3 is continued; from p.f. = 206-208 ° C, (M + H) + = 289. 1- (2-acetyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethylpropan-1-one. The product of step 3 is treated with the Dess-Martin periodical according to the general procedures described in these examples; from p.f. = 221-223 ° C, (M + H) + = 246.

1- (2-Isobutyryl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one. 1- [2- (1-Hydroxy-2-methyl-propyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one is treated with the periodiene of Dess-Martin, according to the general procedures described in these examples; from p.f. = 233-235 ° C, (M + H) + = 274.

1- [2- (hydroxy-o-tolyl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one. The o-tolualdehyde is used instead of the acetaldehyde in step 2; from p.f. = 181-183 ° C, (M + H) + = 324.

1- [2- (hydroxy-phenyl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one. Benzaldehyde is used instead of acetaldehyde in step 2; from p.f. = 168-170 ° C, (M + H) + = 310.

2,2-dimethyl-1- [2- (2-methyl-benzoyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one. 1- [2- (1-Hydroxy-o-tolyl-methyl) 5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one is treated with the periodioan from Dess-Martin, in accordance with the general procedures described in these examples; from p.f. = 152-154 ° C, (M + H) + = 322.

1- (2-Benzoyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one. 1- [2- (1-Hydroxy-phenyl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one is treated with Dess- Martin, according to the general procedures described in these examples; from p.f. = 190-192 ° C, (M + H) + = 308.

1- [2- (hydroxy-pyridin-4-yl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one. 4-Pyridinecarboxaldehyde is used instead of acetaldehyde in step 2; from p.f. = 189.1-194.9 ° C, (M + H) + = 311.

1- [2- (hydroxy-pyridin-3-yl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one. 3-Pyridinecarboxaldehyde is used instead of acetaldehyde in step 2; from p.f. = 192-194 ° C, (M + H) + = 311.

2,2-dimethyl-1- [2- (pyridine-4-carbonyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one. 1- [2- (1-Hydroxy-pyridin-4-ylmethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one is treated with the Dess-Martin periodical, according to the general procedures described in these examples; from p.f. = 218-220 ° C, (M + H) + = 309.

2,2-dimethyl-1- [2- (pyridine-3-carbonyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one. 1- [2- (1-Hydroxy-pyridin-3-ylmethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one is treated with the Dess-Martin periodical, according to the general procedures described in these examples; from p.f. = 218-220 ° C, (M + H) + = 309.

Example 20 (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cycloheptyl) -methanone

Under a N2 atmosphere, a suspension of 2-bromo-5H-pyrrolo [2,3-b] pyrazine (100 mg, 0.505 mmol) in anhydrous dichloromethane (10 ml) is cooled to 0 ° C. The diethyl aluminum chloride (1M in hexanes, 1.50 ml, 1.50 mmol) is rapidly added and the reaction mixture is stirred for 30 minutes. The 1-methylcycloheptanecarbonyl chloride (882 mg, 5.05 mmol) is added dropwise and the reaction mixture is boiled under reflux overnight. The reaction mixture is cooled to 0 ° C and treated with a saturated aqueous solution of NaHCO3. The biphasic solution is concentrated and the remaining aqueous solution is extracted with ethyl acetate. The organic phases are combined, dried with MgSO4, filtered and concentrated, obtaining a pale brown solid. The residue is purified by chromatography through silica gel using as eluent EtOAc from 19 to 74% in hexane, yielding 55 mg (32%) of the (2-bromo-5H-pyrrolo [2,3-b] pyrazine- 7-yl) - (1-methyl-cycloheptyl) -methanone as a white solid, mp 197.7-198.2 ° C, (M + H) + = 336.

Example 21

2-benzyloxy-1-methyl-cyclohexanecarbonyl chloride

A solution of 4-benzyloxy-1-methyl-cyclohexanecarboxylic acid (1.71 g, 6.89 mmol) in thionyl chloride (10 ml) is heated at reflux for 2 hours. The reaction mixture is concentrated under high vacuum, obtaining 1.84 g of the 2-benzyloxy-1-methyl-cyclohexanecarbonyl chloride as a yellow oil.

Example 22

(4-benzyloxy-1-methyl-cyclohexyl) - (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone

A solution of 2-bromo-5H-pyrrolo [2,3-b] pyrazine (531 mg, 2.68 mmol) and 4-benzyloxy-1-methyl-cyclohexanecarboxyl chloride (2.15 g) is treated dropwise. , 8.05 mmol) in anhydrous toluene (16 ml) with Et2AlCl (1M in hexanes, 5.36 ml, 5.36 mmol). The reaction mixture is stirred at 90 ° C for 16 hours. The reaction mixture is cooled to room temperature, treated with a saturated solution of NaHCO3 and extracted with ethyl acetate (3x). The organic phases are collected, dried with MgSO4, filtered and concentrated, obtaining a dark brown oil.

By chromatography through silica gel using 0 to 50% Et2O eluent in DCM, 205 mg (18%) of the (4-benzyloxy-1-methyl-cyclohexyl) - (2-bromo-5H-pyrrolo) are obtained [2,3-b] pyrazin-7-yl) -methanone as a pale yellow solid. M-H = 426.

Example 23

(4-benzyloxy-1-methyl-cyclohexyl) - (5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone

With a pressure of H2 of 1 atm, a solution of the (4-benzyloxy-1-methyl-cyclohexyl) - (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone solution is hydrogenated for 2 days (13 mg, 0.03 mmol), KOH (1 mg, 0.02 mmol) and 10% Pd on C

25 (10 mg) in EtOH (8 ml). The reaction mixture is filtered through a Celite cartridge using THF and DCM. The filtered liquid is concentrated, leaving a white solid, which is purified by chromatography through silica gel using 0 to 70% Et2O eluent in DCM, obtaining 9 mg (882%) of the (4-benzyloxy-1- methylcyclohexyl) - (5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone as a white solid; M + H = 350.

30 Information on the JAK test Determination of Janus kinase inhibition IC50 (JAK) The enzymes and peptide substrate used are described below: JAK1: Invitrogen recombinant human kinase domain (cat. No. PV4774) JAK3 : Millipore recombinant human kinase domain (cat. No. 14-629)

JAK2: Millipore recombinant human kinase domain (cat. No. 14-640) substrate: biotinylated 14-mer peptide at the N-terminus, derived from the JAK1 activation loop with peptide substrate sequence: biotin-KAIETDKEYYTVKD

The test conditions applied are described below:

40 assay buffer: JAK kinase buffer: 50mM Hepes [pH 7.2], 10mM MgCl2, 1mM DTT, 1 mg / ml BSA. The test is carried out in this buffer. Assay format: The activity of the three JAK kinases is measured in an end-point radioactive assay and with trace amounts of ATP-P33. The tests are performed on 96-hole polypropylene plates.

Experimental method All concentrations are final in the reaction mixture and all incubations are performed at room temperature. The test steps are described below: The compounds are diluted in series with 100% DMSO for example 10x of the initial concentration of 1mM. The final concentration of DMSO in the reaction is 10%.

The compounds are pre-incubated with the enzyme (0.5 nM JAK3, 1 nM JAK2, 5 nM JAK1) for 10 minutes. The reactions are initiated by the addition of a cocktail of two substrates (ATP and peptide premixed in the JAK kinase buffer). In the JAK2 / JAK3 assays, ATP and the peptide are used in concentrations of 1.5 µM and 50 µM, respectively. The JAK1 assay is carried out with an ATP concentration of 10 µM and a peptide concentration of 50 µM.

The test duration of JAK2 and JAK3 is 20 minutes. The JAK1 trial lasts 40 minutes. In the three enzymes, the reactions are terminated by the addition of 0.5M EDTA at a final concentration of 100 mM.

25 µl of the terminated reactions are poured onto 150 µl of a 7.5% (v / v) suspension of streptavidin-coated Sepharose spheres in 1x phosphate buffered saline without MgCl2 and without CaCl2 containing 50mM EDTA on MultiScreen filter plates -BV 1.2 µm of 96 holes.

After a 30 minute incubation, the spheres are washed under vacuum with the following buffers: 3 to 4 washes with 200 µl of 2M NaCl. 3 to 4 washes with 200 µl of 2M NaCl plus 1% (v / v) phosphoric acid. 1 wash with water.

15 Wash plates are dried in an oven at 60 ° C for 1-2 hours.

70 µl of Microscint 20 scintillation liquid is added to each hole of the filter plates and after a 30 minute incubation the radioactive beads are measured in a Perkin Elmer microplate scintillation counter. 20 Representative IC50 results are shown in the following table II.

Table II

Compound

IC50 h-jak2-sf21-c IC50 h-jak3-sf21-c

I-3

3,5358 3.8826

I-21

2.7526 1,493155

I-25

1,0478 0.2855

25 Information on the SYK Assay IC50 Determination of Spleen Tyrosine Kinase Inhibition (SYK, Spleen Tyrosine Kinase) The SYK kinase assay is a standard assay adapted to the 96-hole plate format. This test is performed in a 96-hole format for the determination of IC50 with 8 samples representing 10 semilog dilutions and a reaction volume of 40 µl. This assay measures the incorporation of radiolabelled γATP-P33 into a

30 biotinylated peptide substrate at the N-terminus, derived from the naturally occurring phosphoaceptor consensus sequence (biotin-11aa DY * E). Phosphorylated products are detected after terminating the EDTA reactions and adding the streptavidin coated spheres. Representative results are shown in the previous table II.

Test plates: 0.65 µm 96-hole MultiScreen filter plates (Millipore, Cat. No. MADVNOB10)

35 Streptavidin coated spheres: Streptavidin SepharoseTM, 5.0 ml suspension, in 50 mM EDTA / diluted with PBS (1: 100), (Amersham, cat. No. 17-5113-01)

Compounds: 10 mM in 100% dimethyl sulfoxide (DMSO), conc. compound final: 0.003-100 µM in 10% DMSO 40

Enzyme: SYK purified by RPA, truncated tyrosine kinase construct of spleen aa 360-635, standard solution 1 mg / ml, MW: 31.2 KDa, conc. final = 0.0005 µM.

45 Peptide 1: biotinylated peptide derived from a naturally occurring phosphorus acceptor consensus sequence (biotin-EPEGDYEEVLE), QCB special product number, 20mM standard solution, conc. final = 5.0 µM.

ATP: 20 mM adenosine-5’-triphosphate, (ROCHE, cat. No. 93202720), final concentration = 20µM

50 Buffer: HEPES: 2-hydroxyethyl-piperazine-2-ethanesulfonic acid (Sigma, cat. No. H-3375), final concentration = 50 mM HEPES, pH 7.5

BSA: bovine serum albumin, fraction V, without fatty acids (Roche Diagnostics GmbH, Cat. No. 9100221) diluted to a final concentration of 0.1%

EDTA: 500 mM EDTA standard solution, (GIBCO, cat. No. 15575-038), final concentration = 0.1 mM DTT: 1,4-dithiothreitol (Roche Diagnostics GmbH, cat. No. 197777), conc. final = 1 mM MgCl2 x 6H2O: MERCK, cat. 105833.1000, final concentration = 10 mM Test dilution buffer (ADB): 50 mM HEPES, 0.1 mM EGTA, 0.1 mM vanadate Na, 0.1 mM β-glycerophosphate, 10 mM MgCl2, 1 mM DTT, 0 , 1% BSA, pH 7.5

Wash buffer of the splinters: 10 g / l PBS (phosphate buffered saline) with 2M NaCl + 1% phosphoric acid.

Experimental method In a volume of 40 µl 26 µl of recombinant, purified human SYK360-635 are mixed, diluted with ADB [0.5 nM], with 4 µl of 10X concentrations of the compounds to be tested, [usually between 100 µM and 0.003 µM] in [10%] DMSO and the mixture is incubated at t.amb. for 10 min.

The kinase reaction is initiated by the addition of 10 µl of 4x substrate cocktail containing the DYE peptide substrate [0 or 5 µM], ATP [20 µM] and γATP-P33 [2 µCi / rxn]. After incubation at 30 ° C for 15 min, the reaction is terminated by transferring 25 µl of the reaction mixture to a 0.65 µm MADVNOB Millipore plate / membrane of 96 holes containing 200 µl of 5mM EDTA and coated with 20% streptavidin in PBS. Unbound radionuclotides are removed by vacuum washing with 3 x 250 µl of 2M NaCl; 2 x 250 µl of 2M NaCl + 1% phosphoric acid; 1 x 250 µl of H2O. After the last wash the plates / membrane are transferred to an adapter plate, dried by heat at 60 ° C for 15 min, 50 µl of a scintillation cocktail is added to each hole and after 4 h the amount of radioactivity is measured in a counter of the type "top counter".

The percentage of inhibition is calculated based on the proportion of uninhibited enzyme:% inhibition = 100 / (1 + (IC50 / conc. Inhibitor) n)

The IC50 is calculated using a non-linear curve adjustment with the XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK).

The present invention has been described in some detail by way of illustration and example, to facilitate clarity and understanding. It is obvious to those skilled in the art that changes and modifications can be made within the scope of the appended claims. Therefore, it is assumed that the above description has an illustrative and non-restrictive purpose. The scope of the invention will therefore not be determined with reference to the above description, but will be determined with reference to the following appended claims.

Claims (9)

1. A compound of the formula I ' 5 in which: 123 4 ResR, R, RoR; R1 is C1-C6 alkyl, C1-C6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a; 1a 1b 1c ResRoR; R1b is halogen, oxo, hydroxy or -CN; 1c 1f1e1e1f1f1f Res -C (= O) O (R), –C (= O) (CH2) m (R), –O (CH2) m (R), -S (R), –S (O) 2 (R ) or -S (= O) (R), C1-C6 alkyl, C1-C6 alkoxy, amino, amido, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d; R1d is H, halogen, hydroxy, C1-C6 alkyl, amino, C1-C6 alkoxy or C1-C6 haloalkyl; R1e is H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; R1f is H, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; m is the number 0, 1 or 2; R2 is N (R2a) 2; 2a 2b 20 each Res independently H or R; each R2b is independently C1-C6 alkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkyl-alkylene, optionally substituted by one or more R2c; 2c 2d 2e ResRoR; R2d is halogen, oxo or hydroxy; 2e 2g2g2g2g2g2g2g2g 25 Res -N (R) 2, –C (= O) (R), –C (= O) O (R), –C (= O) N (R) 2, -N (R) C (= O) (R), –S (= O) 2 (R), –S (O) 2N (R) 2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f; each R2f is independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; each R2g is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or phenyl; R3 is -C (= O) R3a; 3a 3b Res C1-C6 alkyl, C1-C6 alkoxy, phenyl or N (R) 2; each R3b is independently H or C1-C6 alkyl; R4 is –O (R4a); 4a 4b ResHoR; R4b is C1-C6 alkyl, phenyl, benzyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, optionally substituted by one or more R4c; R4c is halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy; 4 4a 4b QesQoQ; Q4a is halogen; Q4b is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, amino or C1-C6 haloalkyl, optionally substituted by one or more Q4c; 4c 4d 4e QesQoQ; each Q4d is independently halogen, hydroxy or cyano; each Q4e is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, amino, cycloalkyl, phenyl, Heterocycloalkyl or heteroaryl, optionally substituted by one or more Q4f; each Q4f is independently hydroxy, halogen, C1-C6 alkyl, C1-C6 alkenyl, oxo, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl or amino; 44 4a4a 44a4a With the condition of when ResR, Res – O (R), ResHyQesQ, then QnoseaH;

or a pharmaceutically acceptable salt thereof. fifty

2.

The compound of claim 1, wherein R is R1.

3.

The compound of claim 2, wherein R1 is C1-C6 alkyl, preferably tert-butyl.

4. The compound of claim 2, wherein R1 is cycloalkyl.

2 2 2a2a 2b 2b

5.

The compound of claim 1, wherein R is Ry Res NH (R) and Res R, Res preferably C1-C6 alkyl.

6.

A compound chosen from the group consisting of: 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -3-methyl-butan-1-one; 2-Chloro-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide; 2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide; 2-Isopropyl-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid isopropylamide; 1- (2-Chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclohexyl) -methanone; 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclopentyl) -methanone; 1- (2-ethynyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-ethyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-3-phenyl-propan-1-one; 1- [2- (1-Hydroxy-ethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1-Hydroxy-2-methyl-propyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-o-tolyl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-phenyl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-pyridin-4-yl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (hydroxy-pyridin-3-yl-methyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - ((3aS, 6aS) -1-methyl-octahydro-pentalen-1-yl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - ((1S, 2S) -1,2-dimethyl-cyclopentyl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclohexyl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclopentyl) -methanone; (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cycloheptyl) -methanone; adamantan-1-yl- (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone; (4-benzyloxy-1-methyl-cyclohexyl) - (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -methanone; 1- (2-ethynyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Isopropenyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; 1- (2-Chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one; Y 1- (2-Bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -3-methyl-butan-1-one.

7.

A compound of the formula II

in which: R1 is C1-C6 alkyl, C1-C6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a; 1a 1b 1c ResRoR; R1b is halogen, oxo, hydroxy or -CN; 1c 1f1e1e1f1f1f Res -C (= O) O (R), –C (= O) (CH2) m (R), –O (CH2) m (R), -S (R), –S (O) 2 (R ) or –S (= O) (R), C1-C6 alkyl, C1-C6 alkoxy, amino, amido, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d; R1d is H, halogen, hydroxy, C1-C6 alkyl, amino, C1-C6 alkoxy or C1-C6 haloalkyl; R1e is H, C1-C6 alkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; R1f is H, C1-C6 alkyl, C1-C6 haloalkyl, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; The number 0,1ó2 and Q4 is as defined according to claim 1. 8. A compound according to claim 1 of formula III: III wherein: R2b is independently C1-C6 alkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkylalkylene, optionally substituted by one or more R2c; 2c 2d 2e 5 ResRoR; R2d is halogen, oxo or hydroxy; 2e 2g2g2g2g2g2g2g2g Res -N (R) 2, –C (= O) (R), –C (= O) O (R), –C (= O) N (R) 2, -N (R) C (= O ) (R), –S (= O) 2 (R), –S (O) 2N (R) 2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f; 10 each R2f is independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; each R2g is independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or phenyl and Q4 has the meaning defined in claim 1. 9. Use of the compound of any one of claims 1-8 for the manufacture of a medicament for the treatment of an inflammatory disorder or an autoimmune disorder. 10. Compound of any one of claims 1-8 for use in the treatment of an inflammatory disorder or an autoimmune disorder.