ES2367342T3 - PYRROLOPYRAZINES AS KINASE INHIBITORS. - Google Patents

Abstract

A compound of formula I ** Formula ** wherein: 1 2 3 4 R is R, R, R or R; R1 is C1-6 alkyl, C1-6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a; 1a 1b 1c 10 R is R or R; R1b is halogen, oxo, hydroxy, or -CN; 1c 1f 1e 1f 1f 1f R is -C (= O) O (R), -C (= O) CH2 (R), -S (R), -S (O) 2 (R) or -S (= O) - (R), C1-6 alkyl, C1-6 alkoxy, amino, amido, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d; R1d is H, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy or C1-6 haloalkyl; R1e is H, C1-6 alkyl, C1-6 alkoxy, -CN, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R1f is H, C1-6 alkyl, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R2 is N (R2a) 2; 2a 2b each R is independently H or R; Each R2b is independently C1-6 alkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl or heterocycloalkyl-alkylene, optionally substituted by one or more R2c; 2c 2d 2e R is R or R; R2d is halogen, oxo, or hydroxy; 2e 2g 2g 2g 2g 2g 2g 2g 2g R is -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, C1-6 alkyl, C1-6 alkoxy, C1 haloalkyl -6, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f; each R2f is independently H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl; each R2g is independently H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or phenyl; R3 is -C (= O) R3a; 3a 3b R is C1-6 alkyl, C1-6 alkoxy, phenyl or N (R) 2; each R3b is independently H or C1-6 alkyl; R4 is -O (R4a); 4a 4b R is H or R; R4b is C1-6 alkyl, phenyl, benzyl, C1-6 haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, optionally substituted by one or more R4c; R4c is halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy; Q1 is phenyl substituted by two Q1a, which together form a heterocyclic or heteroaryl ring system, optionally 1b 1c substituted by one or more Q or Q; Q1b is halogen, hydroxy, oxo, or -CN; 1c 1d 1e 40 Q is Q or Q; 1d 1e 1e 1e 1e 1e 1e 1e Q is -O (Q), -S (Q), -S (= O) (Q), -S (= O) 2 (Q), -C (= O) N (Q) 2, - N (Q1e) S (= O) 2 (Q), -C (= O) (Q), 1e 1e 1e 1e 1e 1e 1e 1e C (= O) O (Q), -N (Q) 2; -N (Q) C (= O) (Q), -N (Q) C (= O) O (Q) or -N (Q) C (= O) N (Q) 2; 1e 1e each Q is independently H or Q; each Q1 is independently C1-6 alkyl, lower alkenyl, phenyl, benzyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1f; 1f 1g 1h Q is Q or Q; 1g 1h 1h 1h Q is halogen, hydroxy, oxo, -C (= O) (Q) or -N (Q) C (= O) (Q); each Q1h is independently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, amino, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1i; Each Q1i is independently halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy; or a pharmaceutically acceptable salt thereof, wherein "phenyl substituted by two Q1a that together form a heterocyclic or heteroaryl ring system" is used herein to indicate that two Q1a moieties of the phenyl ring are joined together to form a system of saturated, partially saturated or unsaturated ring, containing four to eight atoms and incorporating one or more N, O or S heteroatoms, the other ring atoms are carbons, resulting in a bicyclic ring system.

Description

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

Protein kinases constitute one of the broadest groups of human enzymes that regulate many signaling processes, which consist of inserting phosphate residues into proteins; in particular, tyrosine kinases phosphorylate proteins on the alcohol moiety of tyrosine. The group of tyrosine kinases includes components that control cell growth, migration, and differentiation. 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 provide a means of modulating cell function with small molecule inhibitors of kinase activity and are therefore targeted in drug design. In addition to the treatment of kinase-mediated disease processes, selective and effective inhibitors of kinase activity are also useful for investigating cell signaling processes and for identifying other cellular targets of therapeutic interest.

Azoindoles and their use for the treatment of pathological conditions susceptible to be modulated by inhibition of protein kinases have been described in document WO 03/000688 A1.

JAKs (Janus kinases) form a group of cytoplasmic protein tyrosine kinases that includes JAK1, JAK2, JAK3 and TYK2. Each of the JAKs is preferentially associated with the intracytoplasmic 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, which are themselves devoid of intrinsic kinase activity. This phosphorylation creates docking sites in receptors for other molecules known as STAT proteins (signal transducers and activators of transcription), and the phosphorylated JAKs bind to various STAT proteins. The STAT or STATs proteins are DNA-binding proteins activated by the phosphorylation of 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 cytokine response genes (Leonard et al., J. Allergy Clin. Immunol. 105, 877-888, 2000).

JAK / STAT signaling is involved in mediating 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 malignant tumors. solid and hematological, for example in leukemia and lymphomas.

Thus, JAKs and STATs are components of multiple potentially intertwined signal transduction mechanisms (Oncogene 19, pp. 5662–5679, 2000), indicating the difficulty of specifically targeting one element of the JAK-STAT mechanism without interfering with other signal transduction mechanisms.

JAK kinases, including JAK3, are abundantly expressed in the primary leukemic cells of children with acute lymphoblastic leukemia, the most common form of childhood cancer, and studies have established a correlation between STAT activation in certain cells and 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). They are also known to be important for lymphocyte differentiation, function and survival. JAK3 in particular plays an essential role in the functioning of lymphocytes, macrophages, and mast cells. Given the importance of this JAK kinase, compounds that modulate the JAK mechanism, including those that are selective for JAK3, may be useful for treating diseases and conditions involving lymphocytes, macrophages, or mast cells (Kudlacz et al. ., Am. J. Transplant. 4, 51-57, 2004; Changelian, Science 302, 875-878, 2003). Disease states, in which it may be therapeutically useful to target the JAK mechanism or modulation of JAK kinases, particularly JAK3, include leukemia, lymphomas, transplant rejection (eg, transplant rejection islet pancreas, bone marrow transplant applications (eg graft-versus-host disease), autoimmune diseases (eg, diabetes), and inflammation (eg, asthma, reactions The disease states that may benefit from JAK3 inhibition 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 JAKs (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, the receptor of which has been shown to use the usual gamma chain; IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK1 interacts, among others, with the receptors of the cytokines IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2 interacts with the receptors of IL-9 and the TNF-alpha. Following the binding of certain cytokines to their receptors (eg, IL-2, IL-4, IL7, IL-9, IL-15, and IL-21), oligomerization of the receptor occurs, forming cytoplasmic kinase tails. Associated JAKs that are brought into proximity 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 B and T lymphocyte maturation, but the presence of JAK3 is also constitutively 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, IL-4 and IL-9 induced proliferation and survival of murine mast cells has been shown to depend on JAK3 and gamma chain signaling (Suzuki et al., Blood 96, 2172-2180, 2000 ). JAK3 also plays a crucial role in IgE receptor-mediated post degranulation of mast cells (Malaviya et al., Biochem. Biophys. Res. Commun. 257, 807-813, 1999) and inhibition of JAK3 kinase prevents type I hypersensitivity reactions, including anaphylaxis (Malaviya et al., J. Biol. Chem. 274, 27028-27038, 1999). Inhibition of JAK3 has also been shown to result in immune suppression of foreign graft rejection (Kirken, Transpl. Proc. 33, 3268-3270, 2001). JAK3 kinases have been shown to 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); mycosis fungoides, a form of T-cell lymphoma (Nielsen et al., Prac. Natl. Acad. Sci. EMPLEA 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 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 on the non-hematopoietic expression of JAK3 have also been published, 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 striking. Agents that act 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 deliver immunosuppression where it is needed (ie, in cells actively participating in immune responses), without causing effects outside of 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 targeted with small molecule inhibitors have contributed to their selection as key immunosuppression targets.

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

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 eosinophil activation. SYK is thus involved in allergic disorders, including asthma (see the review by Wong et al., Expert Opin. Investig. Drugs 13, 743, 2004). SYK binds to the 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, arachidonic acid secretion, and cytokines (Costello et al., Oncogene 13, 2595, 1996). This has also been shown in pharmacological agents that inhibit SYK activity in mast cells (Yamamoto et al., J. Pharmacol. Exp. Ther. 306, 1174, 2003). Treatment with SYK antisense oligonucleotides 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 exhibit unbalanced activation in response to FcεR stimulation (Lach-Trifilieffe et al., Blood 96, 2506, 2000). Therefore, small molecule inhibitors of SYK will be useful for the treatment of allergy-induced inflammatory diseases, including asthma.

In view of the number of disease states considered as beneficiaries of treatment that involves modulation of JAK and / or SYK mechanisms, it is immediately evident that the new compounds, which modulate JAK and / or SYK mechanisms and the methods of using these compounds could

5 provide substantial therapeutic benefits to large numbers of patients. New derivatives of pyrrolopyrazine are provided herein for use in the treatment of disease states, in which the JAK and / or SYK mechanisms are attacked or JAK or SYK kinases, in particular JAK3, are inhibited and which are therapeutically useful for the treatment of inflammatory or autoimmune diseases.

The novel 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, compounds of the invention can inhibit JAK3 and SYK, preferred compounds are selective for

15 JAK3 of the JAK kinases and are new derivatives of pyrrolopyrazine 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 for JAK3 of JAK kinases and are new pyrrolopyrazine derivatives useful for the treatment of autoimmune and inflammatory diseases. Similarly, compounds of the invention can inhibit JAK3 and JAK1, preferred compounds are selective for JAK3 of JAK kinases.

20 and are new pyrrolopyrazine derivatives useful for the treatment of autoimmune and inflammatory diseases.

This application provides a compound of formula I

image 1

25 in which:

123 4

ResR, R, RoR; R1 is C1-6 alkyl, C1-6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a;

1a 1b 1c

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

1c 1f1e1f1f1f

Res -C (= O) O (R), -C (= O) CH2 (R), -S (R), -S (O) 2 (R) or -S (= O) - (R), C1-6 alkyl, C1-6 alkoxy, amino, amido, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d;

R1d is H, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy or C1-6 haloalkyl; R1e is H, C1-6 alkyl, C1-6 alkoxy, -CN, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R1f is H, C1-6 alkyl, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl;

R2 is N (R2a) 2;

2a 2b

each Res independently H or R; Each R2b is independently C1-6 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,

C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f; each R2f is independently H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl; each R2g is independently H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or phenyl;

R3 is -C (= O) R3a;

3a 3b

Res C 1-6 alkyl, C 1-6 alkoxy, phenyl or N (R) 2; each R3b is independently H or C1-6 alkyl; R4 is -O (R4a);

4a 4b

ResHoR;

R4b is C1-6 alkyl, phenyl, benzyl, C1-6 haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, optionally substituted by one or more R4c; R4c is halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy;

Q1 is phenyl substituted by two Q1a, which together form a heterocyclic or heteroaryl ring system, optionally

1b 1c

replaced by one or more Qo Q; Q1b is halogen, hydroxy, oxo, or -CN;

1c 1d 1e

QesQoQ;

1d 1e1e1e1e1e1e1e

Qes -O (Q), -S (Q), -S (= O) (Q), -S (= O) 2 (Q), -C (= O) N (Q) 2, -N (Q1e ) S (= O) 2 (Q), -C (= O) (Q),

1e1e1e1e1e1e1e1e

C (= O) O (Q), -N (Q) 2; -N (Q) C (= O) (Q), -N (Q) C (= O) O (Q) or -N (Q) C (= O) N (Q) 2;

1e 1e

each Q is independently H or Q; each Q1 is independently C1-6 alkyl, lower alkenyl, phenyl, benzyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1f;

1f 1g 1h

QesQoQ;

1g 1h1h1h

Q is halogen, hydroxy, oxo, -C (= O) (Q) or -N (Q) C (= O) (Q); each Q1h is independently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, amino, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1i; each Q1i is independently halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy;

or a pharmaceutically acceptable salt thereof, where "phenyl substituted by two Q1a that together form a heterocyclic or heteroaryl ring system" is used here to indicate that two Q1a moieties of the phenyl ring are joined together to form a saturated ring system,

partially saturated or unsaturated, containing four to eight atoms and incorporating one or more heteroatoms N, O or S, the other ring atoms are carbons, resulting in a bicyclic ring system. In a variant of the previous embodiment, R is R1. In a variant of the above embodiment, R1 is C1-6 alkyl. In a variant of the above embodiment, R1 is tert-butyl.

1 1a 1c1c 1e1e 1e1e

In another variant of the previous embodiment, Res tert-butyl, Qes Q, Qes Q, Qes Q 'and Q' is pyrrolidine. In another variant of the above embodiment, R1 is -CHC (CH3) 3. In another variant of the previous embodiment, R1 is isobutyl. In another variant of the previous embodiment, R1 is isopropyl. In one embodiment of the compound of formula I, R1 is cycloalkyl. In one embodiment of the compound of formula I, R1 is heterocycloalkyl. In one embodiment of the compound of formula I, R1 is benzyl. In one embodiment of the compound of formula I, R1 is phenyl. In one embodiment of the compound of formula I, R is R2.

22 2a

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

2a 2b

In a variant of the previous form of execution, Res R. In a variant of the previous embodiment, R2b is lower alkyl. In a variant of the previous embodiment, R2b is isopropyl. In one embodiment of the compound of formula I, R2b is heterocycloalkyl. In one embodiment of the compound of formula I, R2b is cycloalkyl. In one embodiment of the compound of formula I, R2b is heterocycloalkyl-alkylene. In a variant of the above embodiment, R2b is pyrrolidine.

In a variant of the previous embodiment, R2b is pyrrolidinyl methylene.

1a 1c

In a variant of the previous embodiment, Qes Q.

1a 1c1c 1e1e 1e1e

In another variant of the previous embodiment, Qes Q, Qes Q, Qes Q 'and Q' is heterocycloalkyl.

11a 1c1c 1e1e 1e1e

In yet another variant of the above embodiment, Q is Q, Qes Q, Qes Q, Qes Q ', Q' is pyrrolidine.

11a 1c1c 1d1d 1e1e

In yet another variant of the above embodiment, Q is Q, Qes Q, Qes Q, Qes -O (Q), Qes Q1e 'and Q1e' is lower alkyl.

11a 1c1c 1d1d 1e1e

In yet another variant of the above embodiment, Q is Q, Qes Q, Qes Q, Qes -O (Q), Qes Q1e ', Q1e' is methyl.

1a 1b

In one embodiment of the compound of formula I, Qes Q. In a variant of the above embodiment, Q1b is halogen. In another variant of the previous embodiment, Q1b is hydroxy.

1a 1c

In one embodiment of the compound of formula I, Qes Q.

1c 1d1d 1e1e 1e1e

In a variant of the above embodiment, Qes Q, Qes -O (Q), Qes Q 'and Q' is lower alkyl, optionally substituted by one or more Q1f.

In a variant of the above embodiment, Q1e 'is methyl optionally substituted by one or more Q1f.

1f 1h 1h

In another variant of the above embodiment, Qes Q and Q is heterocycloalkyl. In a variant of the above embodiment, Q1h is morpholine.

1a 1c1c 1e1e 1e1e

In a form of execution of the compound of the formula I, QesQ, QesQ, QesQ'andQ'es heterocycloalkyl, optionally substituted by one or more Q1f. In a variant of the above embodiment, Q1e 'is pyrrolidine, optionally substituted by one or more Q1f.

In another variant of the above embodiment, Q1e 'is piperazine, optionally substituted by one or more Q1f. In yet another variant of the above embodiment, Q1e 'is piperidine, optionally substituted by one or more Q1f.

In yet another variant of the above embodiment, Q1e 'is morpholine, optionally substituted by one or

more Q1f. In yet another variant of the above embodiment, Q1e 'is pyrrolidinone, optionally substituted by one or more Q1f.

1a 1c1c 1d1d 1e1e 1e

In one embodiment of the compound of formula I, Qes Q, Qes Q, Qes -C (= O) (Q), Qes Q 'and Q1e' is heterocycloalkyl, optionally substituted by one or more Q1f. In certain embodiments of formula I, the compounds in question conform more specifically to the

formula II: wherein R1 is C1-6 alkyl, C1-6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a;

image 1

1a 1b 1c

ResRoR;

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

1c 1f1e1f1f1f

Res -C (= O) O (R), -C (= O) CH2 (R), -S (R), -S (O) 2 (R) or -S (= O) (R), alkyl C1-6, C1-6 alkoxy, amino, amido, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d;

R1d is H, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy or C1-6 haloalkyl;

R1e is H, C1-6 alkyl, C1-6 alkoxy, -CN, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl;

R1f is H, C1-6 alkyl, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; and

Q1 has the meaning defined here.

In certain embodiments of formula II, R1 is C1-6 alkyl, preferably tert-butyl.

In certain embodiments of formula I or II, Q1 is dihydrobenzodioxynyl, benzodioxolyl, dihydrobenzoxazinyl, indolyl, dihydrobenzothiazinyl, quinolinyl or indazolyl, optionally substituted by one or more

1b 1c

Q or Q which have the meanings defined here.

Preferably Q1 is indolyl, dihydrobenzoxazinyl or benzoxazinone, optionally substituted by one or more Q1b

or Q1c which have the meanings defined here.

In one aspect, the application provides a compound of formula I selected from the group consisting of:

1- [2- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -3-methyl-butane-1- ona; 1- (2-benzo [1,3] dioxol-5-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -3-methyl-butan-1-one; 2,2-dimethyl-1- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -5H-pyrrolo [2,3-b] pyrazin-7 -yl] -propan-1-one; 1- [2- (1H-indol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin-3- ona; 2,2-dimethyl-1- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7 -yl] -propan-1-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] oxazin-3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4-methyl-4H-benzo [1,4] oxazin-3-one; 2,2-dimethyl-1- [2- (1-pyridin-3-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2,4-trimethyl-4H-benzo [1,4] oxazin- 3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4-ethyl-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; 4-benzyl-6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; 1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-6-yl] -5H-pyrrolo [2,3-b] pyrazin-7-yl} -2,2- dimethylpropan-1-one; 2,2-dimethyl-1- {2- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1H-indol-6-yl] -5H-pyrrolo [2 , 3-b] pyrazin-7-yl} -propan-1-one; 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide; 2,2-dimethyl-1- [2- (1-piperidin-4-yl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-6- [7- (1-methyl-cyclohexanecarbonyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] oxazin-3-one; 7- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] thiazin-3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4-pyridin-2-ylmethyl-4H-benzo [ 1,4] oxazin-3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4- (2-morpholin-4-yl-ethyl ) -4H-benzo [1,4] oxazin-3-one;

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4- (3-hydroxy-2-hydroxymethyl-propyl) -2,2- dimethyl-4Hbenzo [1,4] oxazin-3-one; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -methanesulfonamide; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide; 1- [2- (4-benzenesulfonyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2, 2-dimethyl-propan-1-one; N- (4- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-ylsulfamoyl} -phenyl) -acetamide; N- (4- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,3-dihydro-benzo [1,4] oxazine-4-sulfonyl} -phenyl) acetamide; 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-yl } -benzenesulfonamide; 1- {2- [4- (4-amino-benzenesulfonyl) -3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] -5H-pyrrolo [2,3-b] pyrazin-7 -yl} -2,2-dimethylpropan-1-one; 4-chloro-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -4-fluorobenzenesulfonamide; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -4-methoxybenzenesulfonamide; 6-Chloro-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide -3-sulfonic; Pyridine-3-sulfonic acid {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide ; 6-amino-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide -3-sulfonic; (1-methyl-cyclohexyl) - [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -5H-pyrrolo [2,3-b] pyrazin-7 -yl] -methanone; 2,2-dimethyl-1- (2-quinolin-5-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one; 1- [2- (1H-indazol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1H-indazol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 2,2-dimethyl-1- (2-quinolin-6-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one; 2,2-dimethyl-1- [2- (1-methyl-1H-indazol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one; 2,2-dimethyl-1- [2- (3-methyl-1H-indazol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one; 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-5-yl] -5H-pyrrolo [2,3-b] pyrazin-7-yl} -2,2- dimethylpropan-1-one; 2,2-dimethyl-1- [2- (1-pyridin-3-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- {2- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1H-indol-5-yl] -5H-pyrrolo [2 , 3-b] pyrazin-7-yl} -propan-1-one; 2,2-dimethyl-1- [2- (3-piperidin-4-yl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; [2- (1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] - (1-methyl-cyclohexyl) -methanone; 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-yl } -N-methyl-benzenesulfonamide; and 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -N- methylbenzenesulfonamide.

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

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

In one aspect, the application provides a method of treating an inflammatory disease state, consisting of administering to a patient in need of it a therapeutically effective amount of the compound of formula I, in the that R is R1.

In one aspect, the application provides a method for inhibiting a T-cell proliferative disorder, consisting of in administering to a patient in need thereof a therapeutically effective amount of the compound of formula I.

In one aspect, the application provides a method for inhibiting a T-cell proliferative disorder, consisting of in administering to a patient in need thereof a therapeutically effective amount of the compound of formula I, in where R is R2.

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

In one aspect, the application provides a method of treating a B cell proliferative disorder, consisting of in administering to a patient in need thereof a therapeutically effective amount of the compound of formula I.

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

In one aspect, the application provides a method for preventing or treating all forms of organ rejection, including acute rejection of one's own or foreign graft, vascularized or non-vascularized transplants, which consists of administering to a patient in need of it an amount therapeutically effective compound of formula I.

In one aspect, the application provides a method for preventing or treating all forms of organ rejection, including acute rejection of one's own or foreign graft, vascularized or non-vascularized transplants, which consists in administering the compound to a patient in need thereof. of formula I.

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

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

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

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

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

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

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

In one aspect, the application provides a method of treating an inflammatory disorder consisting of co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound in combination with the compound of formula I.

In one aspect, the application provides a method of treating an immune disease state consisting of co-administering to a patient in need thereof an immunosuppressive compound in combination with a therapeutically effective amount of the compound of formula I.

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

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

The application provides the above composition, which further contains a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

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

The application refers to a compound of formula III

image 1

in which:

123 4

ResR, R, RoR; R1 is lower alkyl, lower 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 1f1e1f1f1f

Res -C (= O) O (R), -C (= O) CH2 (R), -S (R), -S (O) 2 (R) or -S (= O) (R), alkyl lower, lower alkoxy, amino, amido, lower haloalkoxy, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, or heterocycloalkyloxy optionally substituted by one or more R1d; R1d is H, halogen, hydroxy, lower alkyl, lower alkoxy, or lower haloalkoxy; R1e is H, lower alkyl, lower alkoxy, -CN, lower haloalkoxy, phenyl, heteroaryl, cycloalkyl or heterocycloalkyl; R1f is H, lower alkyl, lower haloalkoxy, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl;

R2 is N (R2a) 2;

2a 2b

each Res independently H or R; each R2b is independently lower 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, lower alkyl, lower alkoxy, lower haloalkoxy, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f; each R2f is independently H, halogen, lower alkyl, lower alkoxy, lower haloalkoxy; each R2g is independently H, lower alkyl, lower alkoxy, lower haloalkoxy or phenyl;

R3 is -C (= O) R3a;

3a 3b

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

4a 4b

ResHoR; R4b is lower alkyl, phenyl, benzyl, lower haloalkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, optionally substituted by one or more R4c; R4c is halogen, hydroxy, lower alkyl, lower haloalkoxy, or lower alkoxy;

123 4

QesQ, Q, QoQ; Q1 is phenyl, optionally substituted by one or more Q1a;

1a 1b 1c

QesQoQ;

1b 1e1e1e

Q is halogen, hydroxy, -CN, -S (Q), -S (O) 2 (Q) or -S (= O) (Q);

1c 1d 1e

QesQoQ;

1a 1b 1c

or two Q together form a bicyclic ring system, optionally substituted by one or more Qo Q;

1d 1e1e1e1e1e1e1e1e

Qes -O (Q), -S (= O) 2 (Q), -C (= O) N (Q) 2, -S (= O) 2 (Q), -C (= O) (Q) , -C (= O) O (Q), -N (Q) 2; -N (Q)

1e1e1e1e1e

C (= O) (Q), -N (Q) C (= O) O (Q) or -N (Q) C (= O) N (Q) 2;

1e 1e

each Q is independently H or Q '; each Q1e 'is independently lower alkyl, phenyl, benzyl, lower haloalkoxy, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1f;

1f 1g 1h

QesQoQ;

1g 1h

Q is halogen, hydroxy, oxo or -C (= O) (Q); Q1h is lower alkyl, lower haloalkoxy, lower alkoxy, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1i; Q1i is halogen, hydroxy, lower alkyl, lower haloalkoxy, or lower alkoxy;

Q2 is cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, optionally substituted by one or more Q2a;

2a 2b 2c

QesQoQ;

5

fifteen

25

35

Four. Five

55

Q2b is halogen, oxo, hydroxy, -CN, -SCH3, -S (O) 2CH3 or -S (= O) CH3;

2c 2d 2e

QesQoQ;

2a 2b 2c

or two Q together form a bicyclic ring system, optionally substituted by one or more Qo Q;

2d 2e2e2e2e2e2e2e2e

Qes -O (Q), -S (= O) 2 (Q), -C (= O) N (Q) 2, -S (O) 2 (Q), -C (= O) (Q), -C (= O) O (Q), -N (Q) 2; -N (Q) C (= O)

2e2e2e2e2e

(Q), -N (Q) C (= O) O (Q) or -N (Q) C (= C) N (Q) 2;

2e 2e

each Q is independently H or Q; each Q2e is independently lower alkyl, phenyl, benzyl, lower haloalkoxy, cycloalkyl, heterocycloalkyl

or heteroaryl, optionally substituted by one or more Q2f;

2f 2g 2h

QesQoQ;

2g 2h

Q is halogen, hydroxy, oxo or -C (= O) (Q); Q2h is lower alkyl, lower haloalkoxy, lower alkoxy, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q2i; Q2i is halogen, hydroxy, lower alkyl, lower haloalkoxy, or lower alkoxy;

3 3a3a3a3a3a3a3a3a

Qes -OQ, -SQ, -C (= O) (Q), -S (= O) (Q), -S (-O) 2 (Q), -N (Q) 2, -NHC (= O ) (Q), -C (= O) N (Q) 2 or -NHC (= O) N (Q3a) 2;

3a 3b 3c

each Qes independently Qo Q; Q3b is H; Q3c is lower alkyl, lower haloalkoxy, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl, optionally replaced by one or more Q3d; Q3d is halogen, hydroxy, lower alkyl, lower alkoxy, or lower haloalkoxy;

4 4a 4b

QesQoQ;

Q4a is H or halogen; and

Q4b is lower alkyl, lower alkenyl, lower alkynyl, or lower haloalkoxy;

44 4a4a 44a4

with the condition that ifResR, Res-O (R), ResHyQesQ, thenQnoseaH;

or a pharmaceutically acceptable salt thereof.

The articles "a" or "an" referring 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 phrase "has the meaning defined above" indicates the broader definition of each group that is indicated in the summary of the invention or in the broader claim. In all other embodiments presented below, the substituents, which may be present and are not explicitly defined, retain the broader definition 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 "comprise" and "comprise" should be construed as having an open meaning. That is, the terms should be interpreted as synonymous with 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 steps mentioned, but may include additional steps. When used in the context of a compound or composition, the term "comprise" means that the compound or composition includes at least the characteristics or components mentioned, but may also include other additional characteristics or components.

As used herein, unless explicitly stated otherwise, the conjunction "or" 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 applies in any case, regardless of the presence or absence of another variable having the same or different meaning within the same compound. Therefore, in a compound, where R "appears twice and is defined as" independently carbon or nitrogen ", the two R" can be carbons, the two R "can be nitrogens, or one 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 used or claimed in the present invention, its definition at each occurrence is independent of its definition. in the other appearances. Furthermore, combinations of substituents and / or variables are only permissible if such compounds give rise to stable compounds.

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

image2

or

image1 image1 MeC (= O) O

image 1 .

A bond drawn into a ring system (as opposed to one connected to a particular vertex) indicates that the bond can join any of the appropriate atoms on that ring.

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

The phrase "phenyl substituted by two Q1a that together form a heterocyclic or heteroaryl ring system" is used herein to indicate that the two Q1a moieties of the phenyl ring are joined to form a saturated, partially saturated or unsaturated ring system containing four to eight atoms and incorporating one or more N, O, or S heteroatoms, the other ring atoms are carbons, resulting in a bicyclic ring system.

The term "approximately" used here indicates in the region of, roughly, or around. When the term "about" is used in combination with a numerical range, then it modifies this range by extending the upper and lower limits of the given numerical range. 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", "cycloalkylalkyl" 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 radical, already defined above, which is substituted by one or two substituents chosen from the another group that is specifically named. Thus eg "phenylalkyl" denotes an alkyl moiety having one or two phenyl substituents and thus 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 so on. Accordingly, as used herein, the term "hydroxyalkyl" defines a subset 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.

Compounds of formula I can exhibit tautomerism. 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, the physical and chemical properties of which are consistent with a mixture of compounds. The equilibrium position depends on the chemical properties of the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while the enol form predominates in phenols. Common 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 latter two are especially prevalent in 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 normally attributed to them among those of ordinary skill in the field to which the present invention relates, unless otherwise defined. Reference is made here to the various methodologies and materials, which are already familiar to those skilled in the art. Reference manuals defining general principles of pharmacology include Goodman and Gilman: The Pharmacological Basis of Therapeutics, 10th ed., McGraw Hill Companies Inc., New York (2001). Suitable materials and / or methods can be used to carry out the present invention, which are already known to those skilled in the art. However, preferred materials and methods are described. Materials, reagents and the like mentioned in the description that follow and in the examples are available from commercial suppliers, unless otherwise indicated.

As used herein, the term "acyl" indicates a group of the formula -C (= O) R, where R is hydrogen or lower alkyl, defined herein. As used herein, the term "alkylcarbonyl" indicates a group of the formula C (= O) R, where R is alkyl as defined herein. As used herein, the term C 1-6 acyl denotes a -C (= O) R moiety, having 6 carbon atoms. As used herein, the term "arylcarbonyl" indicates a group of the formula C (= O) R, where R is an aryl moiety; As used herein, the term "benzoyl" indicates an "arylcarbonyl" moiety, where R is phenyl.

As used herein, the term "alkyl" indicates a straight or branched chain monovalent saturated 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 radical, already defined above, is substituted by one or two substituents chosen from the other group that is specifically mentioned. Thus, eg, "phenylalkyl" indicates a residue R'R "-, where R 'is a phenyl residue and R" is an alkylene residue, which is defined in this description, assuming that the point of linkage 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 "hetarylalkyl" or "hetaralkyl" are interpreted similarly, except that R 'is optionally an aryl or a heteroaryl moiety.

As used herein, the term "haloalkyl" indicates a straight or branched chain alkyl moiety, already 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-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2 -bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl.

As used herein, the term "alkylene" denotes a linear divalent saturated hydrocarbon residue of 1 to 10 carbon atoms (eg, (CH2) n) or a branched divalent saturated hydrocarbon residue 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, where alkyl has the meaning defined above, for example methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy , t-butyloxy, pentyloxy, hexyloxy, including their isomers. As used herein, "lower alkoxy" denotes an -O-alkyl moiety, where alkyl is "lower alkyl" as defined above. As used herein, "C1-10 alkoxy" denotes an -O-alkyl moiety, where alkyl is C1-10 alkyl.

As used herein, the term "hydroxyalkyl" indicates an alkyl moiety, already defined above, in which one to three hydrogen atoms of different carbon atoms have / have 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, "C 3-7 cycloalkyl" indicates a cycloalkyl formed by 3-7 carbons on 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, having at least one aromatic ring containing four to eight atoms, incorporating one or more N, O or S heteroatoms, the other ring atoms are carbons, assuming that the point of attachment of the heteroaryl moiety is located on an aromatic ring. Those skilled in organic chemistry already know that heteroaryl rings have a less pronounced aromatic character than their counterparts made up exclusively of carbon atoms. Therefore, for the purposes of the invention, a heteroaryl group need only have 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, including, but not limited to: pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolinyl, thiadiazolyl and oxadiazolinyl, which may be optionally substituted by one or more, preferably one or two substituents, chosen from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halogen, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic residues include, but are not limited to

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

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, alkylaminocarbonylamino, alkylaminocarbonylamino, arylsulfonylamino, alkylaminocarbonylamino, alkylaminocarbonylamino, arylaminocarbonylamino, alkylaminocarbonylamino otherwise indicated. Examples of heterocyclic moieties include, but are not limited to: azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxethanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, thiomoridinyl, tetrahydrofuranyl, eethalinidanyl, thiomoridinyl.

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

5 Commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmospheres (atm), 9-borabicyclo [3.3.1] nonane (9-BBN or BBN), tert-butoxy-carbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts registration number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl-diimidazole (CDI), 1, 4-diazabicyclo [2.2.2] octane (DABCO), diethylamino sulfur trifluoride (DAST), dibenz

10 leadenoacetone (dba), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N'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 hydrochloride

15 (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), ethyl 2-ethoxy-2Hquinoline-1-carboxylate (EEDQ), diethyl ether ( Et2O), O- (7-azabenzotriazol-1-yl) hexafluorophosphate N, N, N'N'-tetramethyluronium (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high liquid chromatography efficacy (HPLC), isopropanol (IPA), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (mesyl or Ms), methyl (Me), acetonitrile (MeCN), acid m-chloroperbenzoic (MCPBA), spectrum of

20 masses (MS), methyl 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), isopropyl (i-Pr), pounds per square inch (psi), pyridine (pir), 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-tetramethyl

25 heptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU), 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). 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,

30 IUPAC, 1979, Pergamon Press, Oxford).

Compounds and obtaining

Examples of representative compounds contemplated by the present invention are listed in the following table and

35 for the scope of the invention. These examples and the preparations that follow are provided to enable those skilled in the art to better understand and practice the present invention. They should not be construed as a limitation of the scope of the invention, but as merely illustrative and representative thereof.

In general, this application uses the nomenclature based on the AUTONOM ™ v.4.0 program, a system

40 computerized by the Beilstein Institute for the generation of the IUPAC systematic nomenclature. If a discrepancy arises between the depicted structure and the name attributed to it, then the depicted structure should be given priority. Furthermore, if the stereochemistry of a structure or portion of a structure is not indicated, eg, by solid or broken lines, then the structure or portion of the structure should be interpreted as encompassing all stereoisomers thereof.

Table I lists examples of compounds of formula I.

Table I

no.

systematic name structure m.p.

I-1

1- [2- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -5H-pyrrolo [2,3b] pyrazin-7-yl] -3-methyl-butan-1-one

no.

systematic name structure m.p.

I-2

1- (2-benzo [1,3] dioxol-5-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -3-methyl-butan-1-one

I-3

2,2-dimethyl-1- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl ] -propan-1-one 233.0234.0

I-4

1- [2- (1H-indol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethylpropan-1-one

I-5

1- [2- (1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethylpropan-1-one

I-6

1- [2- (1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethylpropan-1-one

I-7

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one

I-8

2,2-dimethyl-1- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl ] -propan-1-one

no.

systematic name structure m.p.

I-9

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4Hbenzo [1,4] oxazin-3-one

I-10

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4methyl-4H-benzo [1,4] oxazin-3-one

I-11

2,2-dimethyl-1- [2- (1-pyridin-3-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

I-12

2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

I-13

2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

I-14

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] 2,2,4-trimethyl-4H-benzo [1,4] oxazin-3 -ona

no.

systematic name structure m.p.

I-15

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4-ethyl-2,2-dimethyl-4H-benzo [1,4] oxazin- 3-one

I-16

4-benzyl-6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin- 3-one

I-17

1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-6-yl] -5H-pyrrolo [2,3b] pyrazin-7-yl} -2,2-dimethylpropan- 1-one

I-18

2,2-dimethyl-1- {2- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) 1H-indol-6-yl] -5H-pyrrolo [2, 3-b] pyrazin-7-yl} -propan-1-one

I-19

4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide

I-20

2,2-dimethyl-1- [2- (1-piperidin-4-yl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

no.

systematic name structure m.p.

I-21

2,2-dimethyl-6- [7- (1-methylcyclohexanecarbonyl) -5Hpyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo 1,4] oxazin-3-one

I-22

7- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4Hbenzo [1,4] thiazin-3-one

I-23

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4-pyridin-2-ylmethyl-4H-benzo [1, 4] oxazin-3-one

I-24

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4- (2-morpholin-4-ylethyl) -4H- benzo [1,4] oxazin-3-one

I-25

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4 (3-hydroxy-2-hydroxymethylpropyl) -2,2-dimethyl-4Hbenzo [1,4] oxazin-3-one

I-26

N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] 1H-indol-4-yl} -methanesulfonamide

no.

systematic name structure m.p.

I-27

N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] 1H-indol-4-yl} -benzenesulfonamide

I-28

1- [2- (4-benzenesulfonyl-3,4-dihydro-2H-benzo [1,4] oxazin-6yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2- dimethyl-propan-1-one

I-29

N- (4- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-ylsulfamoyl} -phenyl ) -acetamide

I-30

N- (4- {6- [7- (2,2-dimethyl-propionyl) -5 H-pyrrolo [2,3-b] pyrazin-2-yl] -2,3-dihydro-benzo [1,4] oxazine -4-sulfonyl} -phenyl) acetamide

I-31

4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3b] pyrazin-2-yl] -1-methyl-1H-indol-4-yl} - benzenesulfonamide

I-32

1- {2- [4- (4-amino-benzenesulfonyl) -3,4-dihydro-2Hbenzo [1,4] oxazin-6-yl] -5H-pyrrolo [2,3-b] pyrazin-7-yl } -2,2-dimethyl-propan-1-one

I-33

4-chloro-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide

no.

systematic name structure m.p.

I-34

N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] 1H-indol-4-yl} -4-fluorobenzenesulfonamide

I-35

N- {6- [7- (2,2-dimethyl) -propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] 1H-indol-4-yl} -4-methoxybenzenesulfonamide

I-36

6-Chloro-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] 1H-indol-4-yl} -amide 3-sulfonic

I-37

Pyridine-3-sulfonic acid {6- [7- (2,2-dimethylpropionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1Hindol-4-yl} -amide

I-38

6-amino-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] 1H-indol-4-yl} -amide 3-sulfonic

I-39

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

no.

systematic name structure m.p.

I-40

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

I-41

1- [2- (1H-indazol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one

I-42

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

I-43

2,2-dimethyl-1- (2-quinolin-6-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) propan-1-one

I-44

2,2-dimethyl-1- [2- (1-methyl-1H-indazol-4-yl) -5H-pyrrolo [2,3b] pyrazin-7-yl] -propan-1-one

I-45

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

no.

systematic name structure m.p.

I-46

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

I-47

1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-5-yl] -5H-pyrrolo [2,3b] pyrazin-7-yl} -2,2-dimethylpropan- 1-one

I-48

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

I-49

2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

I-50

2,2-dimethyl-1- {2- [3- (1-methyl-, 2,3,6-tetrahydro-pyridin-4-yl) -1Hindol-5-yl] -5H-pyrrolo [2,3- b] pyrazin-7-yl} -propan-1-one

no.

systematic name structure m.p.

I-51

2,2-dimethyl-1- [2- (3-piperidin-4-yl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

I-52

[2- (1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] - (1-methylcyclohexyl) -methanone

I-53

4-amino-N- {6- [7- (2,2-dimethyl) -propionyl) -5H-pyrrolo [2,3b] pyrazin-2-yl] -1-methyl-1H-indol-4-yl} -N-methylbenzenesulfonamide

I-54

4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3b] pyrazin-2-yl] -1H-indol-4-yl} -N-methyl- benzenesulfonamide

Dosage and administration

The compounds of the present invention can be formulated in a wide variety of oral and oral dosage forms.

5 excipients. Oral administration can be in the form of tablets, coated tablets, dragees, 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, 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. Pharmaceutical compositions and unit dosage forms can contain conventional ingredients in conventional proportions, with or without additional compounds or active ingredients, and unit dosage forms can contain any suitable effective amount of the active ingredient, proportionate to the range of daily doses to be used. intends to manage. The pharmaceutical compositions can be used in the form of solids, for example filled tablets or capsules, semisolids, powders, prolonged 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% active compound (s) (w / w). The term "preparation" or "dosage form" can include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that a

The active ingredient can be part of different preparations depending on the organ or tissue being treated, the desired dose and the pharmacokinetic parameters.

The term "excipient" used in this description means a compound that is useful in making the pharmaceutical composition, is generally safe, non-toxic, and biologically and otherwise non-nuisance, and includes both veterinary-acceptable excipients and excipients. for human pharmaceutical use. The compounds of this invention may be administered alone, but will generally be administered in admixture with one or more pharmaceutically acceptable excipients, diluents, or carriers, which will be chosen with the intended route of administration and standard pharmaceutical practice in mind.

"Pharmaceutically acceptable" means that it is useful for the manufacture of a pharmaceutical composition that is generally safe, non-toxic, not bothersome in a biological sense or in any other sense, and that includes that it is acceptable for veterinary use and also for the use human pharmacist.

A "pharmaceutically acceptable salt" form of an active ingredient can also initially confer a desirable pharmacokinetic property on the active ingredient, which is absent from the non-salt form and can positively affect the pharmacodynamics of the active ingredient with respect to its therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) the 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, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, 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 parent compound, is replaced by a metal ion, eg, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid excipient may further contain one or more substances that further act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, disintegrating agents for tablets or an encapsulating material. In powders, the excipient is generally a finely divided solid, mixed with the finely divided active principle. In tablets, the active ingredient is generally mixed with the excipient having a sufficient binding capacity in suitable proportions and compacted to 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, methyl cellulose, sodium carboxymethyl cellulose, a low melting point wax, cocoa butter and the like. . In addition to the active principle, the solid preparations can 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 be converted into liquid form preparations immediately prior to use. The emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or they can contain emulsifying agents, for example lecithin, sorbitol monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, 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, methylcellulose, sodium carboxymethylcellulose and other known suspending agents.

The compounds of the present invention may be formulated for parenteral administration (eg by injection, eg bolus injection or continuous infusion) and may be presented in unit dosage forms in ampoules, prepackaged syringes, small infusion containers. volume or multidose 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 nonaqueous excipients, diluents, solvents, or carriers include propylene glycol, polyethylene glycol, vegetable oils (eg, olive oil), and injectable organic esters (eg, ethyl oleate) and may contain agents formulation, for example preserving, wetting, emulsifying or suspending agents, 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 a suitable vehicle, eg sterile, pyrogen-free water.

The compounds of the present invention may also be formulated for topical administration to the epidermis in the form of ointments, creams or lotions or in the form of a 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 may 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 lozenge-shaped lozenges containing an active ingredient in a flavored base, usually sucrose and acacia or tragacanth; lozenges containing the active ingredient in an inert base, for example gelatin and glycerin or sucrose and acacia; and oral lotions containing the active ingredient in a suitable liquid carrier.

The compounds of the present invention can be formulated for administration in the form of suppositories. First, a low-melting wax, for example a mixture of fatty acid glycerides or cocoa butter, is melted, and then the active ingredient is homogeneously dispersed therein, 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, tampons, creams, gels, pastes, foams or sprays that, in addition to the active principle, contain excipients that are known in the art as suitable are known to be suitable in the art.

The compounds of the present invention can be formulated for nasal administration. Solutions or suspensions are applied directly to the nasal cavity by conventional means, eg with a dropper, pipette, or nebulizer. The formulations can be delivered in single or multi-dose form. In the latter case of a dropper or pipette, the use can be effected 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 eg by means of a spray pump that atomises a fixed, calibrated quantity.

The compounds of the present invention can be formulated for aerosol administration, especially to the respiratory tract, including intranasal administration. In general, the compound should have a small particle size, eg, on 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 ingredient is supplied in a pressurized container containing a suitable propellant, for example a chlorofluorohydrocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other appropriate 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 dry powder form, eg a powdery mixture containing the compound in a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powdery carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, eg in capsules or cartridges eg gelatin or in blister packs, from which the powder will be administered by inhaler.

If desired, the formulations can be made enteric coated, adapted to a sustained or controlled release administration 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. Transdermal delivery system compounds are often housed on a solid support adhered to the skin. The compound of interest can be further combined with a penetration enhancer, eg azone (1-dodecylaza-cycloheptan-2-one). Persistent release delivery systems are inserted subcutaneously 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 carriers, diluents, and excipients are described in Remington: The Science and Practice of Pharmacy, 1995, edited by E.W. Martin, Mack Publishing Company, 19th Edition, Easton, Pennsylvania. A scientist skilled in formulations will be able to modify the formulations within the teachings of the specification to obtain numerous formulations intended for a particular route of administration without thereby destabilizing the compositions of the present invention or compromising their therapeutic activity.

Modification of the present compounds to make them more soluble in water or in another vehicle, for example, can be easily 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 in 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 dose can vary within wide limits, depending on numerous factors, such as the severity of the disease to be treated, the age and general state of health of the patient, other medications that the

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patient is taking, the route and form of administration and the preferences and experience of the physician who attends the patient. For oral administration, a daily dose of 0.01 to 1000 mg / kg of body weight per day as monotherapy and / or combination therapy may be appropriate. 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, less than the optimal dose of the compound. The dose is then increased until the optimal effect for the individual patient is reached. Those skilled in treating diseases of the type described herein will be able, without unnecessary experimentation 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 disease and specific patient.

The pharmaceutical preparations are preferably presented in unit dosage form. In such form, 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 can also be a capsule, a tablet, a cachet or even a lozenge, or it can be the appropriate number of any one of these in packaged form.

The following examples illustrate the production and biological evaluation of the compounds within the scope of the invention. These examples and the preparations that follow are provided to allow those skilled in the art a clearer understanding and better practice of the present invention. They should not be considered as limiting the scope of the invention, but as merely illustrative and representative thereof.

Examples

Example 1

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin-3- ona

image 1

6-Bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one (61 mg, 0.24 mmol, Bioorg. Med. Chem. 15, 5912, 2007) and bispinacholate are dissolved -diboron (73 mg, 0.29 mmol)) in 2.5 ml of 1,4-dioxane. The solution and flask are purged with argon. Potassium acetate (59 mg, 0.6 mmol) and palladium-bis (diphenylphosphino) ferrocene dichloride (10 mg, 0.012 mmol) were added, the flask was sealed and the reaction mixture was stirred at 100 ° C for 3 h. The reaction mixture was cooled to room temperature and 1- (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethylpropan-1-one (0.1 g, 0.35 mmol). The reaction mixture was diluted with 1 ml of 1,4-dioxane and 0.6 ml of water. Palladium-bis (diphenylphosphino) ferrocene dichloride (15 mg, 0.019 mmol) and potassium carbonate (98 mg, 0.71 mmol) are added. The sealed vial is placed in a microwave reactor and heated at 150 ° C for 30 min. More palladium catalyst (7 mg, 0.0095 mmol) is added and the reaction is repeated at 140 ° C for 30 min. The reaction mixture was poured into ethyl acetate and sodium bicarbonate solution. The phases are separated and the aqueous phase is extracted once more with ethyl acetate. The ethyl acetate phases are combined, washed with a saturated sodium chloride solution and dried over sodium sulfate. It is filtered and concentrated, the residue is purified by chromatography through silica gel (methanol / dichloromethane), obtaining 31 mg (35%) of the product; m.p. => 300 ° C, MS (M + H) + = 379.

The following are obtained in the same way: 2,2-dimethyl-1- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) -5H-pyrrolo [2,3 -b] pyrazin-7-yl] -propan-1-one. Using 6-bromo-4-methyl-3,4-dihydro-2H-benzo [1,4] oxazine instead of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3 -one;

m.p. = 255-265 ° C, (M + H) + = 351.

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] oxazin-3-one. Using 6-bromo-4Hbenzo [1,4] oxazin-3-one in place of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; m.p. => 350 ° C, (M + H) + = 351.

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4-methyl-4H-benzo [1,4] oxazin-3-one. Using 6-bromo-4-methyl-4H-benzo [1,4] oxazin-3-one in place of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; m.p. = 277-278 ° C, (M + H) + = 365.

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2,4-trimethyl-4H-benzo [1,4] oxazin- 3-one. Using 1- [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one instead of 1 - (2-bromo5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one and alkylating the final product with sodium hydride and iodomethane in N, N-dimethylformamide, with according to the general deprotection procedures described in these examples;

m.p. = 265-266 ° C, (M + H) + = 393.

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4-ethyl-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one. Using 1 [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one instead of 1- (2bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one and alkylating the final product with sodium hydride and iodomethane in N, N-dimethylformamide, according to the general deprotection procedures described in these examples; m.p. = 224-226 ° C, (M + H) + = 407.

4-benzyl-6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one. Using 1- [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one instead of 1- (2bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one and alkylating the final product with sodium hydride and benzyl bromide at N, N -dimethylformamide, according to the general deprotection procedures described in these examples; m.p. = 248-249 ° C, (M + H) + = 469.

4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide. Using 4-amino-N- (6-bromo-1H-indol-4-yl) -benzenesulfonamide in place of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3one; m.p. = 285-292 ° C, (M + H) + = 489.

2,2-dimethyl-6- [7- (1-methyl-cyclohexanecarbonyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] oxazin-3-one. Using (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methylcyclohexyl) -methanone in place of 1- (2-bromo-5H-pyrrolo [2,3- b] pyrazin7-yl) -2,2-dimethyl-propan-1-one; m.p. => 300 ° C, (M + H) + = 419.

7- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] thiazin-3-one. Using 7-bromo-4H-benzo [1,4] thiazin-3-one in place of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; m.p. => 300 ° C, (M + H) + = 367.

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4-pyridin-2-ylmethyl-4H-benzo [ 1,4] oxazin-3-one. Using 1- [2-bromo-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethylpropan-1-one in place of 1- ( 2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one and alkylating the final product with sodium hydride and 2-picolyl chloride, HCl salt, in N, N-dimethylformamide, according to the general deprotection procedures described in these examples; m.p. = 245-247 ° C, (M + H) + = 470.

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4- (2-morpholin-4-yl-ethyl ) -4H-benzo [1,4] oxazin-3-one. Using 1- [2-bromo-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one instead of 1 - (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one and alkylating the final product with sodium hydride and 2- (4- morpholino) -ethyl in N, N-dimethylformamide, according to the general deprotection procedures described in these examples; m.p. = 271-273 ° C, (M + H) + = 492.

6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4- (3-hydroxy-2-hydroxymethylpropyl) -2,2-dimethyl- 4H-benzo [1,4] oxazin-3-one. Using 1- [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan1-one instead of 1 - (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethylpropan-1-one, alkylating the final product with sodium hydride and the methanesulfonate of 2-phenyl- [1 , 3] dioxan-5-ylmethyl in N, N-dimethylformamide and then deprotecting with aqueous HCl in addition to the deprotection methods generally described in these examples; m.p. = 271-273 ° C, (M + H) + = 492.

N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -methanesulfonamide. Using N- (6-bromo-1H-indol-4-yl) -methanesulfonamide (obtained by treating 6-bromo-1H-indol-4-ylamine with methanesulfonyl chloride in pyridine) instead of 6-bromo-2 , 2-dimethyl-4H-benzo [1,4] oxazin-3-one; m.p. => 300 ° C, (M + H) + =

412.

N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide. Using N- (6-bromo-1H-indol-4-yl) -benzenesulfonamide (obtained by treating 6-bromo-1H-indol-4-ylamine with benzenesulfonyl chloride in pyridine) instead of 6-bromo-2 , 2-dimethyl-4H-benzo [1,4] oxazin-3-one; m.p. = 275-285 ° C, (M + H) + = 474.

Ethyl 2- {2-benzenesulfonylamino-4- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -phenoxy} -2-methylpropionate. Using 1- [2-bromo-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one instead of 1 - (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one and alkylating the final product with potassium tert-butoxide and benzenesulfonyl chloride in N , N-dimethylformamide, according to the general deprotection procedures described in these examples; m.p. = 93-95 ° C, (M + H) + = 565.

1- [2- (4-benzenesulfonyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2, 2-dimethylpropan-1-one. Using 4-benzenesulfonyl-6-bromo-3,4-dihydro-2H-benzo [1,4] oxazine (obtained by treatment of 6-bromo3,4-dihydro-2H-benzo [1,4] oxazine (Bioorg Med. Chem. 15, 5912, 2007) with benzenesulfonyl chloride in pyridine) instead of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; m.p. = 217-219 ° C, (M + H) + = 477.

N- (4- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-ylsulfamoyl} -phenyl) -acetamide. Using N- [4- (6-bromo-1-methyl-1H-indol-4-ylsulfamoyl) -phenyl] -acetamide (obtained by treating 6-bromo1H-indol-4-ylamine first with sodium hexamethyldisilazide and iodomethane in N, N-dimethylformamide, and then with 4-acetylamino-benzenesulfonyl chloride in pyridine) instead of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3one; m.p. = 275-276 ° C, (M + H) + = 545.

N- (4- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,3-dihydrobenzo [1,4] oxazine- 4-sulfonyl} -phenyl) acetamide. Using N- [4- (6-bromo-2,3-dihydro-benzo [1,4] oxazine-4-sulfonyl) -phenyl] -acetamide (obtained by treatment of 6-bromo-3,4-dihydro -2H-benzo [1,4] oxazine (Bioorg. Med. Chem. 15, 5912, 2007) with 4-acetylaminobenzenesulfonyl chloride in pyridine) instead of 6-bromo-2,2-dimethyl-4H-benzo [1, 4] oxazin-3-one; m.p. = 273274 ° C, (M + H) + = 534.

4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -l-methyl-1H-indol-4-yl } -benzenesulfonamide. Using N- [4- (6-bromo-1-methyl-1H-indol-4-ylsulfamoyl) -phenyl] -acetamide (obtained by treating 6-bromo1H-indol-4-ylamine first with hexamethyldisilazide sodium and iodomethane in N, N-dimethylformamide and then with 4-acetylaminobenzenesulfonyl chloride in pyridine) instead of 6-bromo-2,2-dimethyl-4Hbenzo [1,4] oxazin-3-one. Subsequently it is treated with an aqueous solution of sodium hydroxide; m.p. = 243-245 ° C, (M + H) + = 503.

1- {2- [4- (4-amino-benzenesulfonyl) -3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] -5H-pyrrolo [2,3-b] pyrazin-7 -yl} -2,2-dimethylpropan-1-one. Using N- [4- (6-bromo-2,3-dihydrobenzo [1,4] oxazine-4-sulfonyl) -phenyl] -acetamide (obtained by treatment of 6-bromo-3,4-dihydro-2H -benzo [1,4] oxazine (Bioorg. Med. Chem. 15, 5912, 2007) with 4-acetylaminobenzenesulfonyl chloride in pyridine) instead of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one. Subsequently it is treated with an aqueous solution of sodium hydroxide; m.p. = 174-176 ° C, (M + H) + = 492.

4-chloro-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide. Using N- (6-bromo-1H-indol-4-yl) -4-chloro-benzenesulfonamide (obtained by treating 6-bromo-1H-indol-4-ylamine with 4-chloro-benzenesulfonyl chloride in pyridine ) instead of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one;

m.p. = 264-266 ° C, (M + H) + = 508.

N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -4-fluorobenzenesulfonamide. Using N (6-bromo-1 H-indol-4-yl) -4-fluoro-benzenesulfonamide (obtained by treating 6-bromo-1H-indol-4-ylamine with 4-fluoro-benzenesulfonyl chloride in pyridine ) instead of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; m.p. = 295-297 ° C, (M + H) + = 492.

N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -4-methoxybenzenesulfonamide. Using N- (6-bromo-1H-indol-4-yl) -4-methoxy-benzenesulfonamide (obtained by treating 6-bromo-1H-indol-4-ylamine with 4-methoxy-benzenesulfonyl chloride in pyridine ) instead of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one;

m.p. = 231-233 ° C, (M + H) + = 504.

6-Chloro-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide -3-sulfonic. Using tert-butyl (6-bromo-1H-indol-4-yl) -carbamate in place of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one, deprotecting with trifluoroacetic acid in dichloromethane and then treating with 6-chloropyridine-3-sulfonyl chloride in pyridine; m.p. = 267-269 ° C, (M + H) + = 509.

Pyridine-3-sulfonic acid {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide . Using pyridine-3-sulfonic acid (6-bromo-1H-indol-4-yl) -amide (obtained by treating 6-bromo-1H-indole-4ylamine with 3-pyridinesulfonyl chloride, to HCl, in pyridine) instead of 6-bromo-2,2-dimethyl-4Hbenzo [1,4] oxazin-3-one; m.p. = 305-307 ° C, (M + H) + = 475.

6-amino-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide -3-sulfonic. Using tert-butyl (6-bromo-1H-indol-4-yl) -carbamate in place of 6-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one, deprotecting with trifluoroacetic acid in dichloromethane and then treating with 6-chloropyridine-3-sulfonyl chloride in pyridine. The methods described in J. Org. Chem. 72, 6797, 2007, to introduce the amine; m.p. = 213-217 ° C, (M + H) + = 490.

Example 2

image 1

2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] propan-1-one .

10 To a solution of 1- [2- (1H-indol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2, 2-dimethyl-propan1-one (50 mg, 0.11 mmol; obtained as described in Example 45, but using the Sem-protected starting material) in DMF (1 ml) NaHMDS (0.25 ml, 1M in THF) and stir at rt. for 20 min. 2-Chloromethylpyridine hydrochloride (21.6 mg, 0.13 mmol) is added in one portion. Stir at ambient temperature.

15 for 1 h, TLC analysis (25% EtOAc in hexanes) indicates the presence of a new, more polar product. The reaction mixture was poured into 25 ml of saturated sodium bicarbonate solution and extracted with EtOAc (2 x 15 ml). The organic phases are combined, washed with brine, dried over MgSO4 and concentrated to form a yellow oil. Chromatography (SiO2; 0% -13% -25% EtOAc in hexanes) gives 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one as

20 transparent oil. Applying the general deprotection procedures described in these examples, the SEM group is eliminated, obtaining 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] propan-1-one (47%; MS = 410 [M + H]; mp = 194-196 ° C).

It is obtained by a similar method:

2,2-dimethyl-1- [2- (1-pyridin-3-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1 -ona. Using 1- [2- (1Hindol-6-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan- 1-one in place of 1- [2- (1Hindol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2.2 -dimethyl-propan-1-one and 3-picolyl chloride, HCl salt, in place of 2-chloromethylpyridine hydrochloride; m.p. = 225-227 ° C, (M + H) + = 410.

2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1 -ona. Using 1- [2- (1Hindol-6-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan- 1-one in place of 1- [2- (1Hindol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2.2 -dimethyl-propan-1-one and 2-picolyl chloride, HCl salt, in place of 2-chloromethylpyridine hydrochloride; m.p. = 256-260 ° C, (M + H) + = 410.

35 2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1 -ona. Using 1- [2- (1Hindol-6-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan- 1-one in place of 1- [2- (1Hindol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2.2 -dimethyl-propan-1-one and 4-bromomethylpyridine, HCl salt, in place of 2-chloromethylpyridine hydrochloride; m.p. = 267-272 ° C, (M + H) + = 410.

40 1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-6-yl] -5H-pyrrolo [2,3-b] pyrazin-7-yl} -2.2 -dimethylpropan-1-one. Using 1- [2 (1H-indol-6-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan -1-one instead of 1- [2 (1H-indol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2 , 2-dimethyl-propan-1-one and 1-benzyl-pyrrolidin-3-yl methanesulfonate in place of 2-chloromethylpyridine hydrochloride; m.p. = 126-133 ° C, (M + H) + = 478.

2,2-dimethyl-1- {2- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1H-indol-6-yl] -5H-pyrrolo [ 2,3-b] pyrazin-7-yl} -propan-1-one. Using 1- [2- (1H-indol-6-yl) -5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan- 1-one in place of 1- [2- (1H-indol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2 , 2-dimethyl-propan-1-one and 1-methyl-4-piperidone instead of 2-chloromethylpyridine hydrochloride and sodium methoxide instead of

50 sodium hexamethyldisilazide; m.p. = 247-254 ° C, (M + H) + = 414.

2,2-dimethyl-1- [2- (1-piperidin-4-yl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona. Using 1- [2- (1H-indol6-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan- 1-one in place of 1- [2- (1H-indol5-yl) -5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl -propan-1-one and tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate in place of 2-chloromethylpyridine hydrochloride; m.p. = 201-207 ° C, (M + H) + =

402. Example 3

image 1

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

10 A mixture of 1- (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one (1 g , 3.5 mmol), hexabutyldistanne (2 ml, 4.1 mmol) and Pd (PPh3) 4 (200 mg, 0.17 mmol) in dioxane (16 ml). The resulting mixture is treated with more Pd (PPh3) 4 (135 mg, 0.12 mmol), stirred at 150 ° C in a microwave for 30 min and concentrated. The crude product is purified by flash chromatography using 90 g of silica gel and EtOAc in hexanes as eluent, obtaining 425 mg (25%) of 2,2-dimethyl-1- (2

Tributylstannyl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one as a brown oil. M + H 494.

Example 4

2,2-dimethyl-1- [2- (6-pyrrolidin-1-yl-pyridin-2-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

20 A mixture of 2,2-dimethyl-1- (2-tributylstananyl-5H-pyrrolo [2,3b] pyrazin-7-yl) -propan-1-one (115 mg, 0.23 mmol), 2-bromo-6-pyrrolidin-1-yl-pyridine (53 mg, 0.23 mmol) and Pd (PPh3) 4 (27 mg, 0.023 mmol) in dioxane (1 ml). The resulting mixture is treated with more Pd (PPh3) 4 (27 mg, 0.023 mmol), stirred at 150 ° C in the microwave for 30 min and concentrated. The crude product is purified by

25 Flash chromatography using 4 g of silica gel and EtOAc in hexanes as eluent, 3 consecutive purifications are carried out by preparative thin layer chromatography using as eluent a 2: 1 mixture of hexanes: EtOAc and recrystallization from CH2Cl2 and ethyl ether, obtaining 1.5 mg of 2,2-dimethyl-1- [2- (6-pyrrolidin-1-yl-pyridin-2-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan -1-one in the form of a yellow powder. M + H 350.

30 Example 5

image 1

2,2-dimethyl-1- [2- (4-pyrrolidin-1-yl-pyridin-2-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7 -il] -propan-1-one

35 A solution of t-BuLi (0.78 ml, 1.3M solution in pentane, 1 mmol) is poured dropwise into THF (1 ml) at -78 ° C. To the resulting yellow solution, a brown solution of 2-bromo-4-pyrrolidin-1-yl-pyridine (110 mg, 0.5 mmol) in THF (2.5 ml) is added dropwise. The resulting brown solution is stirred for 1 h, a solution of ZnCl2 (163 mg, 1.2 mmol) in THF (2.4 ml) is added dropwise, it is stirred at room temperature for 2.5 h, it is treated

40 with a solution of 1- [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1- one (164 mg, 0.4 mmol) and Pd (PPh3) 4 (9 mg, 0.008 mmol) in THF (2 ml) and stir overnight. The brown solution is treated with a saturated aqueous solution of ethylenediaminetetraacetic acid (2.4 ml), stirred for 15 min, slowly treated with a saturated solution of Na2CO3 and extracted with CH2Cl2. The organic phases are combined, dried with Na2SO4 and concentrated, obtaining 300 mg of a residue. The product is purified in

45 crude by flash chromatography using 12 g of silica gel and as eluent EtOAc from 0 to 50% in hexanes, obtaining 100 mg (61%) of 1- [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) - Starting 5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethylpropan-1-one as a yellow oil and 50 mg (26%) of 2,2-dimethyl-1- [2- (4-pyrrolidin-1-yl-pyridin-2-yl) 5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one . M + H 480.

Example 6 5 2,2-dimethyl-1- [2- (4-pyrrolidin-1-yl-pyridin-2-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one

A yellow solution of 2,2-dimethyl-1- [2- (4-pyrrolidin-1-yl-pyridin-2-yl) 5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo is stirred at room temperature for 3 h [2,3-b] pyrazin-7-yl] -propan-1-one (25 mg, 0.05 mmol) in CH2Cl2 (1 ml) and trifluoroacetic acid (0.5 ml), concentrate and subject twice azeotropic distillation with toluene. A suspension of the residue and NaOAc · 3H2O (70 mg, 0.5 mmol) in EtOH (0.5 ml) is stirred at room temperature overnight, diluted with EtOAc and concentrated. The resulting residue is partitioned between H2O and CH2Cl2, the organic phases are combined, dried with Na2SO4 and concentrated, obtaining 40 mg of a yellow foam. The crude product is purified by preparative thin-layer chromatography using a 90: 9.5: 0.5 mixture of

CH2Cl2: MeOH: conc. NH4OH, yielding 16 mg (88%) of 2,2-dimethyl-1- [2- (4-pyrrolidin-1-yl-pyridin-2-yl) -5Hpyrrolo [2,3 -b] pyrazin-7-yl] -propan-1-one as a yellow solid; m.p. = 260-263 ° C, M + H 350.

Example 7

image3

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

A solution of t-BuLi (1.1 ml, 1.3 M solution in pentane, 1.2

25 mmol). To the resulting yellow solution, a solution of 2-bromopyridine (60 µl, 0.6 mmol) in THF (2.5 ml) is added dropwise. The reaction mixture was stirred for 1 hr, treated dropwise with a solution of ZnCl2 (204 mg, 1.5 mmol) in THF (2.8 ml), stirred at room temperature for 2.5 h, treated with a solution of 1- [2-bromo-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one (206 mg, 0.5 mmol) and Pd (PPh3) 4 (30 mg, 0.026 mmol) in THF (2 ml) and stir overnight. The reaction mixture is treated with

In a saturated aqueous solution of ethylenediaminetetraacetic acid (2.5 ml), stir for 15 min, slowly treat with a saturated solution of Na2CO3, (~ 4 ml) until pH ~ 9 and partition between H2O and EtOAc. The organic phases are combined, dried with Na2SO4 and concentrated, obtaining 300 mg of a brown oil. The crude product is purified by flash chromatography using 12 g of silica gel and EtOAc from 5 to 40% in hexanes as eluent, yielding 87 mg (42%) of 2,2-dimethyl-1- [2-pyridine- 2-yl-5- (2-trimethylsilanylethoxymethyl) -5H-pyrrolo [2,3

B] pyrazin-7-yl] -propan-1-one as a brown oil. M + H 411.

Example 8

image 1

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

A yellow solution of 2,2-dimethyl-1- [2-pyridin-2-yl-5- (2-trimethylsilanyl

ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one (87 mg, 0.2 mmol) in CH2Cl2 (1 mL) and trifluoroacetic acid

(0.5 ml), concentrated and azeotroped with toluene twice. Stir at temperature

5 room overnight a suspension of the residue and NaOAc · 3H2O (290 mg, 2 mmol) in EtOH (1.5 ml),

Dilute with EtOAc and concentrate. The resulting residue is partitioned between H2O and CH2Cl2, the phases are combined

organic substances, dried with Na2SO4 and concentrated, yielding 85 mg of a yellow solid. The product is purified

crude by preparative thin layer chromatography using as eluent a 90: 9.5: 0.5 mixture of

CH2Cl2: MeOH: conc. NH4OH, yielding 55 mg of a yellow solid. The yellow solid is washed with MeOH, 10 CH2Cl2 and Et2O, obtaining 28 mg (47%) of 2,2-dimethyl-1- (2-pyridin-2-yl-5H-pyrrolo [2,3-b] pyrazin -7-yl) -propan-1-one

as a brown solid; m.p. = 276-278 ° C, M + H 281.

Example 9

image 1

15 1- [2- (3-ethyl-phenyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one

In a microwave tube, 1- (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethylpropan-1-one (152 mg, 0.54 mmol) are introduced , 3-ethylphenylboronic acid (89 mg, 0.59 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloro-palladium (II) (35 mg, 0.042 mmol) and K2CO3 (186 mg, 1, 34 mmol). Dioxane (4 ml) and water (1 ml) are added and the tube is heated in the microwave at 150 ° C for 45 min. The reaction mixture was filtered through a Celite cartridge. Collect the filtrate and partition between EtOAc and water. The organic phases are combined, dried over MgSO4, filtered and concentrated, forming a dark brown solid. The crude product is purified by chromatography through silica gel using EtOAc from 20 to 50% in hexanes as eluent, yielding 82 mg (50%) of 1- [2- (3-ethyl-phenyl) -5H- pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethylpropan-1-one as a yellow solid; m.p.

25 = 199-200.1 ° C, M + H = 308.

Example 10

(1-methyl-cyclohexyl) - [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -5H-pyrrolo [2,3-b] pyrazin-7 -il] -methanone.

30 (1-methyl-cyclohexyl) - [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -5H-pyrrolo [2,3-b ] pyrazin-7-yl] methanone from (2-bromo-5H-pyrrolo [2,3-b] pyrazin-7-yl) - (1-methyl-cyclohexyl) -methanone and 4-methyl-7 - (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -3,4-dihydro-2H-benzo [1,4] oxazine according to the general procedures described in these examples; m.p. = 243-244 ° C, M + H = 391.

35 Example 11

image 1

40 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] propan-1- ona 5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

55

To a solution of 1- [2- (1H-indol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2- dimethyl-propan-1one (50 mg, 0.11 mmol; obtained as described in Ex. 45, but using only Sem protected starting material) in DMF (1 ml) NaHMDS (0.25 ml , 1M in THF) and stirred at rt. for 20 min. 2-Chloromethylpyridine hydrochloride (21.6 mg, 0.13 mmol) is added in a single portion. After shaking at t.amb. over 1 hr, TLC analysis (25% EtOAc in hexanes) indicates that a new, more polar product has formed. The reaction mixture was poured into 25 ml of saturated sodium bicarbonate solution and extracted with EtOAc (2 x 15 ml). The organic phases are combined, washed with brine, dried over MgSO4 and concentrated to give a yellow oil. Chromatography (SiO2; 0% -13% -25% EtOAc in hexanes) gives 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one as a clear oil. According to the general procedures described in these examples, the SEM group is eliminated, obtaining 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] propan-1one (47%; MS = 410 [M + H]; mp = 194-196 ° C).

Compounds obtained by the SEM alkylation and elimination method described here:

1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-5-yl] -5H-pyrrolo [2,3-b] pyrazin-7-yl} -2,2- dimethylpropan-1-one: (M + H) + = 478; 1H-NMR (DMSO): δ = 8.97 (s), 8.48 (s), 3.73 (d), 3.65 (d) ppm;

2,2-dimethyl-1- [2- (1-pyridin-3-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- one: (M + H) + = 410; m.p. = 170171 ° C;

2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- one: (M + H) + = 410; m.p. = 241243 ° C;

2,2-dimethyl-1- {2- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1H-indol-5-yl] -5H-pyrrolo [2 , 3-b] pyrazin-7-yl} -propan-1-one: (M + H) + = 414; m.p. = 263-265 ° C; using only the N-methylpiperidin-4-one and sodium methoxide in refluxing methanol in the first step;

2,2-dimethyl-1- [2- (3-piperidin-4-yl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- one: (M + H) + = 402; 1H-NMR (DMSO): δ = 8.98 (s), 8.47 (s), 3.1 (d, broad), 2.95 (m), 2.73 (t, broad), 1, 54 (s) ppm; using only NBoc-piperidin-4-one and sodium methoxide in refluxing methanol in the first step, and subsequent transfer hydrogenation using ammonium formate and Pd / C in refluxing methanol before removing the protecting groups; Sodium methoxide in methanol is used in place of sodium acetate in ethanol in the deprotection step.

Example 12

image 1

4-amino-N-methyl-N- [1-methyl-6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-indol-5-yl] -benzenesulfonamide and 4-amino-N-methyl-N- [6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-indol-5-yl] -benzenesulfonamide

To a solution of 4-amino-N- (6-bromo-1H-indol-5-yl) -benzenesulfonamide (750 mg, 2.05 mmol) in DMF (6 ml) is added NaHMDS (2.77 ml, 1M in THF) and stir at rt. for 20 min. Methyl iodide (0.153 ml, 2.46 mmol) is added in one portion. After shaking at t.amb. for 2.5 h, TLC analysis (10% MeOH in dichloromethane) indicates the presence of two new less polar products. The reaction mixture was poured into 75 ml of saturated sodium bicarbonate solution and extracted with EtOAc (2 x 50 ml). The organic phases are combined, washed with brine, dried over MgSO4 and concentrated to form a yellow oil. Chromatography (SiO2; 0% to 5% MeOH in dichloromethane) gives 4-amino-N- (6-bromo-1-methyl1H-indol-5-yl) -N-methyl-benzenesulfonamide as less polar product ( MS = 394, 396 [M + H]) and 4-amino-N- (6-bromo-1H-indol-5-yl) -N-methyl-benzenesulfonamide (purity only 85%) as a more polar product ( MS = 380, 382 [M + H]). The corresponding boronates are obtained separately according to the general procedures described in these examples: 4-amino-N-methyl-N- [1-methyl-6- (4,4,5,5-tetramethyl- [1,3 , 2] dioxaborolan-2-yl) -1Hindol-5-yl] -benzenesulfonamide: (MS = 442 [M + H]); 4-amino-N-methyl-N- [6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) 1H-indol-5-yl] -benzenesulfonamide, after chromatography (SiO2; 1% to 5% MeOH in dichloromethane): (MS = 428 [M + H]).

Example 13

image 1

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

5 A solution of 1- [2-cyclopentyloxy-5- (2-trimethylsilanyl-ethoxymethyl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] 2,2-dimethyl-propan is stirred for 5 h -1-one (0.017 g, 0.041 mmol) in 1 ml of dichloromethane and 1 ml of trifluoroacetic acid and then concentrated to form a yellow oil. Chromatography through silica gel (0-> 40% EtOAc in hexanes) gives 0.012 g of a white solid. 1H-NMR spectroscopy indicates that this intermediate compound

10 is a formaldehyde adduct of the desired product. The solid is dissolved in 1 ml of ethanol and the sodium acetate trihydrate solution (0.064 g, 0.47 mmol) is treated. The colorless mixture is stirred for 5 h and concentrated. The residue is partitioned between 5 ml of ethyl acetate and 5 ml of water. The organic phase is washed successively with 5 ml of water and 5 ml of a saturated aqueous NaCl solution, dried with MgSO4, filtered and concentrated to 0.007 g (57%) of 1- (2-cyclopentyloxy-5H -pyrrolo [2,3-b] pyrazin-7-yl) -2,2-dimethyl-propan-1-one as a white solid

15 slightly contaminated.

Example 14

image 1

20 1- [3- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -pyrrolidin-2-one

To a flask containing 1- (3-bromo-phenyl) -pyrrolidin-2-one (713 mg), bis (pinacholate) diboron (1.51 g), a complex of [1,1'-bis ( diphenylphosphino) ferrocene] dichloropalladium (II) (121 mg) and potassium acetate (874 mg) are added 10

25 ml of DMSO and the resulting mixture is stirred at 90 ° C for 16 h. The reaction mixture was cooled and filtered through Celite. The mixture is partitioned between water and dichloromethane, the organic phase is dried over Na2SO4, filtered and concentrated. Purification by chromatography through silica gel (0 to 100% ethyl acetate in hexanes) yields 286 mg of 1- [3- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -pyrrolidin-2-one. Subsequent steps consist of a standard Suzuki condensation, iodination, and aminocarbonylation.

30 JAK Trial Information

Determination of IC50 of Janus kinase (JAK) inhibition

35 The enzymes and peptide substrate used are described below:

JAK1: Invitrogen Recombinant Human Kinase Domain (Cat. # PV4774)

JAK3: Millipore recombinant human kinase domain (cat # 14-629) or prepared.

40 JAK2: Millipore Recombinant Human Kinase Domain (Cat # 14-640) Substrate: N-terminal biotinylated 14-mer peptide derived from JAK1 activation loop with peptide substrate sequence: Biotin-KAIETDKEYYTVKD

The test conditions applied are described below:

5 Assay buffer: JAK kinase buffer: 50mM Hepes [pH 7.2], 10mM MgCl2, 1mM DTT, 1mg / ml BSA. The assay is carried out in this buffer.

Assay format: the activity of the three JAK kinases is measured in a radioactive end-point assay and with 10 trace amounts of ATP-P33. Assays are performed in 96-well polypropylene plates.

Experimental method

All concentrations are final in the reaction mixture and all incubations are carried out at room temperature. The test steps are described below:

Compounds are serially diluted with 100% DMSO for example 10x the initial concentration of 1mM. The final concentration of DMSO in the reaction is 10%.

Compounds are pre-incubated with the enzyme (0.5 nM JAK3 (commercial product), 0.2 nM JAK3 (prepared), 1 nM JAK2, 5 nM JAK1) for 10 minutes.

Reactions are initiated by adding a cocktail of two substrates (ATP and peptide premixed in JAK kinase buffer). The JAK2 / JAK3 assays use ATP and peptide 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 duration of the test of the JAK2 and JAK3 is 20 minutes. The JAK1 test lasts 40 minutes. In all three enzymes the reactions are terminated by the addition of 0.5M EDTA to a final concentration of 100 mM.

30 25 µl of the completed reactions are poured onto 150 µl of a 7.5% (v / v) suspension of Sepharose-coated streptavidin spheres in 1x phosphate buffered saline without MgCl2 and without CaCl2 containing 50mM EDTA on filter plates MultiScreen-BV 1.2 µm 96-hole.

35 After a 30 minute incubation, the beads are washed in vacuo 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) of phosphoric acid. 1 wash with water.

The plates of the washings are dried in an oven at 60oC for 1-2 hours.

70 µl of Microscint 20 scintillation liquid is added to each well of the filter plates and after a 30 minute incubation the radioactive counts are measured in a Perkin Elmer microplate scintillation counter. Representative IC50 results are listed in Table II below.

Table II

Compound

IC50 h-jak3-sf21-c

I-49

0.1522

I-50

0.1548

I-52

0.03242

I-54

0.1579

Information about the SYK trial Determination of IC50 of spleen tyrosine kinase inhibition (SYK, Spleen Tyrosine Kinase)

The SYK kinase assay is a standard assay adapted to the 96-well plate format. This assay is performed in a 96-well format for IC50 determination with 8 samples representing 10 semilog dilutions. and a reaction volume of 40 µl.

This assay measures the incorporation of radiolabeled γATP-P33 into a biotinylated peptide substrate at the N-terminus, derived from the naturally-occurring phosphoaceptor consensus sequence (biotin-11aa DY * E). Phosphorylated products are detected after finishing the reactions with EDTA and adding the streptavidin-coated beads. Representative results are listed in Table II above.

Assay plates: 96-well MultiScreen 0.65 µm filter plates (Millipore, cat. no. MADVNOB10)

Streptavidin-coated beads: Streptavidin SepharoseTM, 5.0 mL suspension, in 50 mM EDTA / diluted with PBS (1: 100), (Amersham, Cat # 17-5113-01)

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

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

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

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

Buffer: HEPES: 2-Hydroxyethyl-piperazine-2-ethanesulfonic acid (Sigma, cat # H-3375), final concentration = 50 mM HEPES, pH 7.5

BSA: Bovine Serum Albumin, Fraction V, Fatty Acid Free (Roche Diagnostics GmbH, Cat. No. 9100221) diluted to a final concentration of 0.1%

EDTA: 500 mM EDTA standard solution, (GIBCO, cat. # 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

Assay dilution buffer (ADB): 50 mM HEPES, 0.1 mM EGTA, 0.1 mM Na vanadate, 0.1 mM β-glycerophosphate, 10 mM MgCl2, 1 mM DTT, 0.1% BSA, pH 7 ,5

Bead wash buffer: 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 human SYK360-635, purified, diluted with ADB [0.5 nM], is mixed with 4 µl of 10X concentrations of the test compounds, [usually between 100 µM and 0.003 µM] in [10%] DMSO and the mixture is incubated at rt. for 10 min.

The kinase reaction is started by adding 10 µl of 4x substrate cocktail containing the peptide substrate DYE [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 96-well 0.65 µm Millipore MADVNOB membrane / plate containing 200 µl of 5mM EDTA and beads coated with 20% streptavidin in PBS.

Unbound radionucleotides are removed by vacuum washing with 3 x 250 µl 2M NaCl; 2 x 250 µl of 2M NaCl + 1% phosphoric acid; 1 x 250 µl H2O. After the last wash the plates / membrane are transferred to an adapter plate, heat dried at 60 ° C for 15 min, 50 µl of a scintillation cocktail is added to each well and after 4 h the amount of radioactivity is measured in a counter. of the "top counter" type.

The percentage of inhibition is calculated based on the proportion of uninhibited enzyme:

% inhibition = 100 / (1 + (IC50 / conc. inhibitor) n)

IC50 is calculated using non-linear curve fit with 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 is for illustrative and not restrictive purposes. The scope of the invention will therefore not be determined with reference to the foregoing description, but will be determined with reference to the following appended claims.

Claims (14)

1. A compound of formula I image 1 5 in which: 123 4 ResR, R, RoR; R1 is C1-6 alkyl, C1-6 alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, optionally substituted by one or more R1a; 1a 1b 1c 10 ResRoR; R1b is halogen, oxo, hydroxy, or -CN; 1c 1f1e1f1f1f Res -C (= O) O (R), -C (= O) CH2 (R), -S (R), -S (O) 2 (R) or -S (= O) - (R), C1-6 alkyl, C1-6 alkoxy, amino, amido, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy optionally substituted by one or more R1d; R1d is H, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy or C1-6 haloalkyl; R1e is H, C1-6 alkyl, C1-6 alkoxy, -CN, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R1f is H, C1-6 alkyl, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R2 is N (R2a) 2; 2a 2b each Res independently H or R; Each R2b is independently C1-6 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, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, phenyl, heteroaryl, heteroaryloxy, cycloalkyl or heterocycloalkyl, optionally substituted by one or more R2f; each R2f is independently H, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl; each R2g is independently H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl or phenyl; R3 is -C (= O) R3a; 3a 3b Res C 1-6 alkyl, C 1-6 alkoxy, phenyl or N (R) 2; each R3b is independently H or C1-6 alkyl; R4 is -O (R4a); 4a 4b ResHoR; R4b is C1-6 alkyl, phenyl, benzyl, C1-6 haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, optionally substituted by one or more R4c; R4c is halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy; Q1 is phenyl substituted by two Q1a, which together form a heterocyclic or heteroaryl ring system, optionally 1b 1c replaced by one or more Qo Q; Q1b is halogen, hydroxy, oxo, or -CN; 1c 1d 1e 40 QesQoQ; 1d 1e1e1e1e1e 1e1e Qes -O (Q), -S (Q), -S (= O) (Q), -S (= O) 2 (Q), -C (= O) N (Q) 2, -N (Q1e ) S (= O) 2 (Q), -C (= O) (Q), 1e1e1e1e1e1e1e1e C (= O) O (Q), -N (Q) 2; -N (Q) C (= O) (Q), -N (Q) C (= O) O (Q) or -N (Q) C (= O) N (Q) 2; 1e 1e each Q is independently H or Q; each Q1 is independently C1-6 alkyl, lower alkenyl, phenyl, benzyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1f; 1f 1g 1h QesQoQ; 1g 1h1h1h Q is halogen, hydroxy, oxo, -C (= O) (Q) or -N (Q) C (= O) (Q); each Q1h is independently H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, amino, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted by one or more Q1i; Each Q1i is independently halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy; or a pharmaceutically acceptable salt thereof, where "phenyl substituted by two Q1a that together form a heterocyclic or heteroaryl ring system" is used 55 here to indicate that two Q1a moieties of the phenyl ring are joined together to form a saturated, partially saturated or unsaturated ring system, containing four to eight atoms and incorporating one or more N, O or S heteroatoms, the others Ring atoms are carbons, resulting in a bicyclic ring system. 5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55

2.

The compound of claim 1, wherein R is R1.

3.

The compound of claim 2, wherein R1 is C1-6 alkyl, preferably tert-butyl.

22 2a2a 2b 4. The compound of claim 1, wherein R is Ry Res NH (R), preferably wherein Res is R defined in claim 1. 1a 1b1b 7. The compound of claim 6, wherein Qes Q, Qes -O (Q), Qes Q ', and Q' is C1-6 alkyl,

5. The compound of claim 1, wherein Q

is Q , preferably where Q it is halogen or hydroxy.

6. The compound of any one of claims 1-4, wherein Q is Q. 1a 1c

1 C

1d 1d 1 C 1e 1e 1e

optionally substituted by one or more Q1f. 1c 1e1e 1e1e

8.

The compound of claim 6, wherein Qes Q, Qes Q ', and Q' is heterocycloalkyl, optionally substituted by one or more Q1f.

9.

A compound of formula II according to claim 1:

image 1 wherein R1 is C1-6 alkyl, C1-6 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 1f1e1f1f1f Res -C (= O) O (R), -C (= O) CH2 (R), -S (R), -S (O) 2 (R) or -S (= O) (R), alkyl C1-6, C1-6 alkoxy, amino, amido, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or optionally heterocycloalkyloxy substituted by one or more R1d; R1d is H, halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy or C1-6 haloalkyl; R1e is H, C1-6 alkyl, C1-6 alkoxy, -CN, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R1f is H, C1-6 alkyl, C1-6 haloalkyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkyl; and Q1 has the meaning defined in any one of claims 1 to 8. 10. A compound of formula I according to claim 1, selected from the group consisting of: 1- [2- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -3-methyl-butane-1- ona; 1- (2-benzo [1,3] dioxol-5-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -3-methyl-butan-1-one; 2,2-dimethyl-1- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -5H-pyrrolo [2,3-b] pyrazin-7 -yl] -propan-1-one; 1- [2- (1H-indol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin-3- ona; 2,2-dimethyl-1- [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7 -yl] -propan-1-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] oxazin-3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4-methyl-4H-benzo [1,4] oxazin-3-one; 2,2-dimethyl-1- [2- (1-pyridin-3-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2,4-trimethyl-4H-benzo [1,4] oxazin- 3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4-ethyl-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; 4-benzyl-6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4H-benzo [1,4] oxazin-3-one; 1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-6-yl] -5H-pyrrolo [2,3-b] pyrazin-7-yl} -2,2- dimethylpropan-1-one; 2,2-dimethyl-1- {2- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1H-indol-6-yl] -5H-pyrrolo [2 , 3-b] pyrazin-7-yl} -propan-1-one; 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide; 2,2-dimethyl-1- [2- (1-piperidin-4-yl-1H-indol-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-6- [7- (1-methyl-cyclohexanecarbonyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] oxazin-3-one; 7- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4H-benzo [1,4] thiazin-3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4-pyridin-2-ylmethyl-4H-benzo [ 1,4] oxazin-3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,2-dimethyl-4- (2-morpholin-4-yl-ethyl ) -4H-benzo [1,4] oxazin-3-one; 6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -4- (3-hydroxy-2-hydroxymethyl-propyl) -2,2- dimethyl-4Hbenzo [1,4] oxazin-3-one; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -methanesulfonamide; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide; 1- [2- (4-benzenesulfonyl-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2, 2-dimethyl-propan-1-one; N- (4- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-ylsulfamoyl} -phenyl) -acetamide; N- (4- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -2,3-dihydro-benzo [1,4] oxazine-4-sulfonyl} -phenyl) acetamide; 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-yl } -benzenesulfonamide; 1- {2- [4- (4-amino-benzenesulfonyl) -3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] -5H-pyrrolo [2,3-b] pyrazin-7 -yl} -2,2-dimethylpropan-1-one; 4-chloro-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -benzenesulfonamide; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -4-fluorobenzenesulfonamide; N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -4-methoxybenzenesulfonamide; 6-Chloro-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide -3-sulfonic; Pyridine-3-sulfonic acid {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide ; 6-amino-pyridine {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -amide -3-sulfonic; (1-methyl-cyclohexyl) - [2- (4-methyl-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -5H-pyrrolo [2,3-b] pyrazin-7 -yl] -methanone; 2,2-dimethyl-1- (2-quinolin-5-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one; 1- [2- (1H-indazol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 1- [2- (1H-indazol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -2,2-dimethyl-propan-1-one; 2,2-dimethyl-1- (2-quinolin-6-yl-5H-pyrrolo [2,3-b] pyrazin-7-yl) -propan-1-one; 2,2-dimethyl-1- [2- (1-methyl-1H-indazol-4-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one; 2,2-dimethyl-1- [2- (3-methyl-1H-indazol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1-one; 2,2-dimethyl-1- [2- (1-pyridin-2-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 1- {2- [1- (1-benzyl-pyrrolidin-3-yl) -1H-indol-5-yl] -5H-pyrrolo [2,3-b] pyrazin-7-yl} -2,2- dimethylpropan-1-one; 2,2-dimethyl-1- [2- (1-pyridin-3-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- [2- (1-pyridin-4-ylmethyl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; 2,2-dimethyl-1- {2- [3- (1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1H-indol-5-yl] -5H-pyrrolo [2 , 3-b] pyrazin-7-yl} -propan-1-one; 2,2-dimethyl-1- [2- (3-piperidin-4-yl-1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] -propan-1- ona; [2- (1H-indol-5-yl) -5H-pyrrolo [2,3-b] pyrazin-7-yl] - (1-methyl-cyclohexyl) -methanone; 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1-methyl-1H-indol-4-yl } -N-methyl-benzenesulfonamide; and 4-amino-N- {6- [7- (2,2-dimethyl-propionyl) -5H-pyrrolo [2,3-b] pyrazin-2-yl] -1H-indol-4-yl} -N- methylbenzenesulfonamide. 11. A compound according to claim 1 or 9, wherein Q1 is dihydrobenzodioxynyl, benzodioxolyl, dihydrobenzoxazinyl, indolyl, dihydrobenzothiazinyl, quinolinyl or indazolyl, optionally substituted by one or more 1b 1c Q or Q defined in any one of claims 1 to 9. 12. A compound according to claim 1 or 9, wherein Q1 is indolyl, dihydrobenzoxazinyl or benzoxazinone, 1b 1c optionally substituted by one or more Qo Q defined in any one of claims 1 to 9.

13.

Use of the compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of an inflammatory disorder or an autoimmune disorder.

14.

Compound according to any one of claims 1 to 10 for use in treating an inflammatory disorder or an autoimmune disorder.