ES2377330T3 - Pyridine-methylene azolidinones and their use as phosphoinositide inhibitors - Google Patents

Abstract

A pyridine-methylene azolidinone derivative according to formula (I): wherein R1 is selected from H, halogen, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, C1-C6 alkoxy ), alkoxycarbonyl, acyl, sulfonyl, sulfanyl, sulfinyl, alkoxy and amino; R2 is selected from H; halogen; C1-C6 alkyl; C2-C6 alkenyl, C2-C6 alkynyl; aryl; heteroaryl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; aryl (C1-C6) alkyl; heteroaryl (C1-C6) alkyl; cycloalkyl (C3-C8) -alkyl (C1-C6), heterocycloalkyl (C3-C8) -alkyl (C1-C6); (C1-C6) alkoxy-alkyl; alkoxycarbonyl; acyl; sulfonyl; sulfanyl; sulfinyl; alkoxy and amino; X is selected from S, NH and O; Y is selected from O, S and NR3, wherein R3 is selected from H, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, aryl (C1 -C6) optionally substituted, cyano and optionally substituted sulfonyl; A is a heteroaryl group; n is an integer selected from 1 and 2; as well as its geometric isomers, its optically active forms such as enantiomers, diastereoisomers and its racemic forms, as well as its pharmaceutically acceptable salts.

Description

Pyridine-methylene azolidinones and their use as phosphoinositide inhibitors.

Field of the Invention

The present invention relates to the use of pyridine-methylene azolidinone derivatives of formula (I) for the treatment and / or prophylaxis of autoimmune diseases and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, graft rejection or lung lesions. Specifically, the present invention relates to pyridine-methylene-azolidinone derivatives for modulation, in particular the inhibition of the activity or function of phosphoinositide-3-kinases, PI3K.

Background of the invention

Phosphoinositide-3-kinases (PI3K) have a critical signaling function in cell proliferation, cell survival, vascularization, membrane traffic, glucose transport, neuritic growth, membrane undulation, superoxide production, actin reorganization and chemotaxis (Cantley, 2000, Science, 296, 1655-1657 and Vanhaesebroeck et al., 2001, Annu. Rev. Biochem. 70, 535-602).

The term PI3K is given to a family of lipid kinases which, in mammals, consists of eight identified PI3Ks that are divided into 3 subfamilies according to their structure and substrate specificity.

The class I group of PI3K consists of 2 subgroups, class IA and class IB.

Class IA consists of an 85 kDa regulatory unit (responsible for protein-protein interactions through the interaction of the 2 Src homology domain (SH2) with phosphotyrosine residues of other proteins) and a catalytic subunit of 110 kDa. For this class there are 3 catalytic forms (p100 !, p110∀ and p110 #) and 5 regulatory isoforms (p85 !, p85∀, p55∃, p55! And p50!).

Class IB is stimulated by ∀∃ subunits of the G protein of heterodimeric G proteins. The only characterized member of class IB is PI3K∃ (catalytic subunit p110∃ complexed with a 101 kDa regulatory protein, p101).

Class II of PI3K comprises isoforms!, ∀ and ∃, which have approximately 170 kDa and are characterized by the presence of a C2 C-terminal domain.

Class III of PI3K includes phosphatidylinositol specific 3-kinases.

The evolutionarily conserved isoforms p110! and ∀ are expressed ubiquitously, while # and ∃ are expressed more specifically in the hematopoietic cell system, smooth muscle cells, myocytes and endothelial cells (Vanhaesebroeck et al., 1997, Trends Biochem. Sci., 22 (7) , 267-72). Its expression can also be regulated in an inducible way depending on the type of cell, tissue and stimuli, as well as the context of the disease.

PI3Ks are enzymes involved in phospholipid signaling and are activated in response to a variety of extracellular signals such as growth factors, mitogens, integrins (cell-cell interactions), hormones, cytokines, viruses and neurotransmitters and also by cross-regulation. intracellular by other signaling molecules (interaction, in which the original signal can activate some parallel routes that in a second stage transmit signals to the PI3K by intracellular signaling events), such as small GTPases, kinases or phosphatases, for example.

Phosphatidylinositol (PtdIns) is the basic structural unit for intracellular inositol lipids in eukaryotic cells, consisting of D-myo-inositol-1-phosphate (Ins1P) linked by its diacylglycerol phosphate group. The inositol head group of PtdIns has 5 free hydroxy groups and 3 of them are found to be phosphorylated in the cells in different combinations. PtdIns and its phosphorylated derivatives are collectively referred to as inositol phospholipids or phosphoinositides (PI). Eight species of PI have been documented in eukaryotic cells (Vanhaesebroeck et al., 2001, see above). IPs all reside in membranes and are substrates for kinases, phosphatases and lipases.

In vitro, PI3K phosphorylates the 3-hydroxyl group of the inositol ring on 3 different substrates: phosphatidylinositol (PtdIn), phosphatidylinositol 4-phosphate (PI (4) P) and phosphatidylinositol 4,5-bisphosphate (PI (4, 5) P2), respectively, generating 3 lipid products, specifically phosphatidylinositol 3-monophosphate (PI (3) P), 3,4-phosphatidylinositol (PI (3,4) P2) bisphosphate and 3,4,5 - phosphatidylinositol triphosphate (PI (3,4,5) P3 (see scheme A, below).

Scheme A

The preferred substrate for class I of PI3K is PI (4,5) P2, class II of PIK has a strong preference for PtdIns as a substrate over PI (4) and PI (4,5) P2. Class III of PI3K can only use PtdIns as a substrate in vivo and is likely to be responsible for the generation of the majority of PI (3) P in eukaryotic cells (Vanhaesebroeck et al., 2001, see above).

The intracellular phosphoinositide signaling pathway begins with the binding of a signaling molecule (extracellular ligands, stimuli, receptor dimerization, heterologous receptor transactivation (e.g., tyrosine kinase receptor)) to a transmembrane receptor coupled to protein G integrated into the plasma membrane that results in the activation of PI3K.

Once activated, the PI3K converts the membrane phospholipid PI (4,5) P2 into PI (3,4,5) P3 which in turn can be converted to another 3'-phosphorylated form of phosphoinositides by specific phosphoinositide phosphatases of 5 ', thus the enzymatic activity of PI3K results directly or indirectly in the generation of two subtypes of 3'-phosphoinositides that function as second messengers in intracellular signal transduction (Leslie et al., 2001, Chem. Rev. 101 ( 8) 2365-80; Katso et al., 2001, Annu. Rev. Cell Dev. Biol. 1, 615-75 and Toker et al., 2002, Cell Mol. Life Sci. 59 (5) 761-79).

The role as second messengers of PtdIns phosphorylated products is involved in a variety of signal transduction pathways, including those essential for cell proliferation, cell differentiation, cell growth, cell size, cell survival, apoptosis, adhesion, cell mobility, Cellular migration, chemotaxis, invasion, cytoskeletal rearrangement, changes in cell form, vesicular traffic and metabolic pathway (Stein, 2000, Mol. Med. Today 6 (9) 347-57). Chemotaxis, the directed movement of cells towards a concentration gradient of chemical attractors, also called chemokines, is involved in many important diseases such as inflammation / autoimmunity, neurodegeneration, angiogenesis, invasion / metastasis and wound healing (Wyman et al. ., 2000, Immunol Today 21 (6) 260-4; Hirsch et al., 2000, Science 287 (5455) 104953; Hirsch et al., 2001, FASEB J. 15 (11) 2019-21 and Gerard et al. , 2001, Nat Immunol. 2 (2) 108-15).

Therefore, it is believed that activation of PI3-kinase is involved in a variety of cellular responses including cell growth, differentiation and apoptosis (Parker et al., 1995, Current Biology, 5, 577-99; Yao et al ., 1995, Science, 267, 2003-05).

Recent biochemical studies showed that class I of PI3K (e.g., PI3K∃ isoform of class IB) are double specificity kinase enzymes, that is, they have both lipid kinase activity (phosphoinositide phosphorylation) and protein activity kinase, since they are capable of inducing phosphorylation of other proteins as substrates, including autophosphorylation as an intramolecular regulatory mechanism.

It seems that PI3Ks are involved in a number of aspects of leukocyte activation. It has been shown that an activity of PI3-kinase associated with p85 is physically associated with the cytoplasmic domain of CD28, which is an important costimulatory molecule for the activation of T lymphocytes in response to antigen (Pages et al., 1994, Nature, 369 , 327-29). These effects are connected with increases in the transcription of a series of genes including interleukin-2 (IL-2), an important T lymphocyte growth factor (Fraser et al., 1991, Science, 251, 313-16). Mutation of CD28 so that it can no longer interact with PI3-kinase, leads to a failure to start the production of IL-2, suggesting a critical function for PI3-kinase in the activation of T lymphocytes.

Cellular processes in which PI3Ks have an essential function include suppression of apoptosis, reorganization of the actin skeleton, growth of cardiac myocytes, stimulation of glycogen synthase by insulin, neutrophil priming mediated by TNF! and generation of superoxides, and leukocyte migration and adhesion to endothelial cells.

PI3K∃ has been identified as a mediator of the G-beta-dependent regulation of JNK activity in which G beta-gamma are subunits of the heterotrimeric G proteins (Lopez-Ilasaca et al., 1998, J. Biol Chem. 273 (5) 2505-8).

Recently, it has been described that PI3K∃ transmits inflammatory signals through different receptors coupled to G (i) (Laffargue et al., 2002, Immunity 16 (3) 441-51) and is central to the function of primed cells , stimuli in the context of leukocytes, and immunology, and includes cytokines, chemokines, adenosines, antibodies, integrins, aggregation factors, growth factors, viruses or hormones, for example (Lawlor et al., 2001, J. Cell Sci., 114 (Pt 16) 2903-1 and Stephens el al., 2002, Curr. Opinion Cell Biol. 14 (2), 203-13).

Specific inhibitors against individual members of a family of enzymes provide valuable tools to decipher the functions of each enzyme.

Two compounds, LY294002 and wortmanin (see hereafter), have been widely used as PI3-kinase inhibitors. These compounds are not specific PI3K inhibitors, since they do not distinguish between the 4 members of class I of PI3-kinases.

The IC50 values of wortmanin against each of the different class I PI3-kinases are in the range of 1-10 nM and the IC50 values of LY294002 against each of these PI3-kinases are approximately 15-20% M (Fruman al., 1998, Ann. Rev. Biochem., 67, 481-507), also 5-10 mM in protein kinase CK2 and some inhibitory activity in phospholipases.

Wortmanin is a fungal metabolite that irreversibly inhibits the activity of PI3K by covalently binding to the catalytic domain of this enzyme. The inhibition of PI3K activity by wortmanin eliminates the subsequent cellular response to the extracellular factor (Thelen el al, 1994, Proc. Natl. Acad. Sci. USA, 91, 4960-64). Experiments with wortamanin show that the activity of PI3K in hematopoietic lineage cells, particularly neutrophils, monocytes and other types of leukocytes, is implicated in many immune memories not memorized with acute and chronic inflammation.

Based on studies using wortmanin, there is evidence that the role of PI3-kinase is also necessary for some aspects of leukocyte signaling through G-protein coupled receptors (Thelen et al., 1994). In addition, it has been shown that wortmanin and LY294002 block neutrophil migration and release of superoxides. However, insofar as these compounds do not distinguish between the different isoforms of PI3K, it remains unclear that particular isoforms or isoforms of PI3K are involved in these phenomena.

Some results have indicated that PI3K inhibitors, for example, LY294002, may increase the in vivo antitumor activity of certain cytotoxic agents (e.g., paclitaxel) (Grant, 2003, I Drugs, 6 (10), 946-948 ).

Recently, thiazolidine derivatives have been developed as PI3K inhibitors (WO 2004/007491; WO 2004/056820; WO 2004/052373).

WO 2004/007491 describes azolidinedione-vinyl derivatives fused with benzene of the following structure:

WO 2004/056820 describes benzoxazine derivatives of the following structure:

WO 2004/052373 describes benzoxazin-3-one derivatives of the following structure:

The great importance of the PI3K pathway in some widely spread diseases reinforces the need to develop inhibitors, including selective PIK inhibitors.

Summary of the Invention

An object of the invention is to provide substances that are suitable for the treatment and / or prevention of disorders related to phosphoinositide-3-kinases, PI3K.

It is also an object of the present invention to provide substances that are suitable for the treatment and / or prevention of autoimmune and / or inflammatory disorders.

It is also an object of the present invention to provide substances that are suitable for the treatment and / or prevention of cardiovascular diseases.

It is also an object of the present invention to provide substances that are suitable for the treatment and / or prevention of neurodegenerative disorders.

It is also an object of the present invention to provide substances that are suitable for the treatment and / or prevention of a disorder selected from bacterial and viral infections, kidney diseases, aggregation of

20 platelets, cancer, transplantation, graft rejection, lung lesions, respiratory diseases and ischemic conditions.

In particular it is an object of the present invention to provide chemical compounds that can modulate, in particular inhibit the activity or function of PI3K phosphoinositide-3-kinases in pathologies in mammals, especially in humans.

In addition, it is an object of the present invention to provide a new category of pharmaceutical formulations for the treatment and / or selected mediated diseases of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, kidney diseases, platelet aggregation , cancer, transplantation, graft rejection, lung lesions, respiratory diseases and ischemic conditions.

Furthermore, it is an object of the present invention to describe a method for the treatment and / or prevention of selected disorders of autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, kidney diseases, platelet aggregation, cancer, transplantation. , graft rejection or lung lesions, respiratory diseases and ischemic conditions.

In a first aspect, the invention provides pyridine methylene azolidinone derivatives of formula (I):

wherein A, R1, R2, X, Y and n are as defined in the detailed description below.

In a second aspect, the invention provides the use of a compound according to formula (I) for use as a medicament.

In a third aspect, the invention provides the use of a compound according to formula (I) to prepare a pharmaceutical composition for the treatment of a disorder selected from autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections. , kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung lesions, respiratory diseases and ischemic conditions and other diseases and disorders associated with PI3K phosphoinositide-3-kinases comprising PI3K! and ∃.

In a fourth aspect, the invention provides a pharmaceutical composition comprising at least one compound according to formula (I) and a pharmaceutically acceptable carrier, diluent or excipient thereof.

In a fifth aspect, the invention describes a method for treating a patient suffering from a disorder selected from autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, kidney diseases, platelet aggregation, cancer, transplantation, rejection. of graft or pulmonary lesions, respiratory diseases and ischemic conditions and other diseases and disorders associated with PI3K phosphoinositide-3-kinases. The method comprises administering a compound according to formula (I).

In a sixth aspect, the invention provides a method of synthesizing a compound according to formula (I).

In a seventh aspect, the invention provides compounds according to formula (II).

Detailed description of the invention

The following paragraphs provide definitions of the different chemical moieties that make up the compounds according to the invention and are intended to be applied uniformly throughout the specification and claims unless another expressly stated definition provides a broader definition.

"C1-C6 alkyl" refers to monovalent alkyl groups having 1 to 6 carbon atoms. This term is illustrated by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like. By analogy, C1-C12 alkyl refers to monovalent alkyl groups having 1 to 12 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.

"Aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring

(e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Aryl includes phenyl, naphthyl, phenanthrenyl and the like.

"Aryl (C1-C6) alkyl" refers to C1-C6 alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.

"Heteroaryl" refers to a monocyclic or heteroaromatic heteroaromatic group of bicyclic or tricyclic fused rings. Particular examples of heteroaromatic groups include pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3 -oxadiazolyl, oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydrojbenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, ptalazinyl, quinoxalinyl, cinolinyl, pyridyl, pyridyl pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl,

optionally substituted.

"Heteroaryl (C1-C6) alkyl" refers to C1-C6 alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2- (1H-indole-3-yl) ethyl and the like.

"C2-C6 alkenyl" refers to alkenyl groups that preferably have 2 to 6 carbon atoms and that have at least 1 or 2 alkenyl unsaturation sites. Preferred alkenyl groups include ethenyl (-CH = CH2), n-2-propenyl (allyl, -CH2CH = CH2) and the like.

"Aryl-C2-C6 alkenyl" refers to C2-C6 alkenyl groups having an aryl substituent, including 2-phenylvinyl and the like.

"Heteroaryl-C2-C6 alkenyl" refers to C2-C6 alkenyl groups having a heteroaryl substituent, including 2 (3-pyridinyl) vinyl and the like.

"C2-C6 alkynyl" refers to alkynyl groups preferably having 2 to 6 carbon atoms and having at least 1-2 alkynyl unsaturation sites, and preferred alkynyl groups include ethynyl (-C & CH), propargyl (- CH2C & CH), and the like.

 "Aryl (C2-C6) alkynyl" refers to C2-C6 alkynyl groups having an aryl substituent, including phenylethynyl and the like.

"Heteroaryl-C2-C6 alkynyl" refers to C2-C6 alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.

"C3-C8 cycloalkyl" refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring

(e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl), C3-C8 cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl and the like.

"Heterocycloalkyl" refers to a C3-C8 cycloalkyl group according to the above definition, in which up to 3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR, R being defined as hydrogen or methyl. The heterocycloalkyl includes pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, tetrahydrofuran and the like.

"Cycloalkyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclohexylpropyl, and the like.

"Heterocycloalkyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having a heterocycloalkyl substituent, including 2- (1-pyrrolidinyl) ethyl, morpholinylmethyl, morpholinyl ethyl, morpholinylpropyl, piperidinylethyl, tetrahydrofuranylmethyl and the like.

"Carboxy" refers to the group -C (O) OH.

"Carboxy-C1-C6 alkyl" refers to C1-C6 alkyl groups having a carboxy substituent, including 2-carboxy-ethyl and the like.

"Acyl" refers to the group -C (O) R in which R includes "C1-C6 alkyl", "aryl", "heteroaryl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl-C1 (alkyl) -C6) "or" heteroaryl (C1-C6) alkyl ".

"Acyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having an acyl substituent, including 2-acetylethyl and the like.

"Acyl-aryl" refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.

"Acyl-heteroaryl" refers to heteroaryl groups having an acyl substituent, including 2-acetylpyridyl and the like.

"Acyl- (hetero) (C3-C8) cycloalkyl" refers to 3- to 8-membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.

"Acyloxy" refers to the group -OC (O) R in which R includes H, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl "," Aryl "," heteroaryl "," aryl (C1-C6) alkyl "or" heteroaryl (C1-C6) alkyl "," arylalkyl (C2-C6) "," heteroaryl-alkenyl (C2-C6) "," Aryl (C2-C6) alkynyl "," heteroaryl (C2-C6) alkynyl "," (C1-C6) cycloalkylalkyl "," heterocycloalkyl (C1-C6) alkyl ".

"Acyloxy (C1-C6) alkyl" refers to C1-C6 alkyl groups having an acyloxy substituent, including aminopropionic acid ethyl ester.

"Alkoxy" refers to the group -OR in which R includes "C1-C6 alkyl" or "aryl" or "heteroaryl" or "aryl-C1-C6 alkyl" or "heteroaryl (C1-C6) alkyl" . Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.

"Alkoxy (C1-C6) alkyl" refers to C1-C6 alkyl groups having an alkoxy substituent, including methoxy, methoxyethyl and the like.

"Alkoxycarbonyl" refers to the group -C (O) OR in which R includes H, "C1-C6 alkyl" or "aryl" or "heteroaryl" or "arylalkyl (C1-C6)" or "heteroaryl-alkyl (C1 -C6) ”.

"Alkoxycarbonyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having an alkoxycarbonyl substituent, including 2- (benzyloxycarbonyl) ethyl and the like.

"Aminocarbonyl" refers to the group -C (O) NRR 'in which each of R, R' independently includes hydrogen

or C1-C6 alkyl or aryl or heteroaryl or "aryl (C1-C6) alkyl" or "heteroaryl (C1-C6) alkyl".

"Aminocarbonyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having an aminocarbonyl substituent, including 2- (dimethylaminocarbonyl) ethyl and the like.

"Acylamino" refers to the group -NRC (O) R 'in which each R, R' is independently hydrogen, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3 cycloalkyl -C8 "," heterocycloalkyl "," aryl "," heteroaryl "," aryl-C1-C6 alkyl "

or "heteroaryl (C1-C6) alkyl", "aryl (C2-C6) alkenyl", "heteroaryl (C2-C6) alkenyl", "aryl (C2-C6) alkynyl", "heteroarylalkyl (C2-) C6) "," cycloalkyl (C1-C6) alkyl "," heterocycloalkyl (C1-C6) alkyl ".

"Acylamino (C1-C6) alkyl" refers to C1-C6 alkyl groups having an acylamino substituent, including 2 (propionylamino) ethyl and the like.

"Ureido" refers to the group -NRC (O) NR'R "in which each R, R ', R" is independently hydrogen, "C1-C6 alkyl", "C2-C6 alkenyl", "C2 alkynyl- C6 "," C3-C8 cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl (C1-C6) "or" heteroaryl (C1-C6) alkyl "," aryl-alkenyl (C2 -C6) "," heteroaryl (C2-C6) alkenyl "," aryl (C2-C6) alkynyl "," heteroaryl (C2-C6) alkynyl "," "cycloalkyl (C1-C6) alkyl", " heterocycloalkyl (C1-C6) alkyl ", and wherein R 'and R", together with the nitrogen atom to which they are attached, may optionally form a 3-8 membered heterocycloalkyl ring.

"Ureido-C1-C6 alkyl" refers to C1-C6 alkyl groups having a ureido substituent, including 2- (N'methylureido) ethyl and the like.

"Carbamate" refers to the group -NRC (O) OR 'in which each R, R' is independently hydrogen, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3 cycloalkyl -C8 "," heterocycloalkyl "," aryl "," heteroaryl "," aryl-C1-C6 alkyl "

or "heteroaryl (C1-C6) alkyl", "aryl (C2-C6) alkenyl", "heteroaryl (C2-C6) alkenyl", "aryl (C2-C6) alkynyl", "heteroarylalkyl (C2-) C6) "," cycloalkyl (C1-C6) alkyl "," heterocycloalkyl (C1-C6) alkyl ".

"Amino" refers to the group -NRR 'in which each R, R' is independently hydrogen or "C1-C6 alkyl" or "aryl" or "heteroaryl" or "aryl-C1-C6 alkyl" or "heteroaryl - (C1-C6) alkyl ", or" cycloalkyl "or" heterocycloalkyl ", and in which R and R ', together with the nitrogen atom to which they are attached, can optionally form a 3-8 membered heterocycloalkyl ring .

"Amino (C1-C6) alkyl" refers to C1-C6 alkyl groups having an amino substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

"Ammonium" refers to a group with positive charge -N + RR'R ", in which each R, R ', R" is independently "C1-C6 alkyl" or "aryl-C1-C6 alkyl" or "heteroaryl (C1-C6) alkyl", or "cycloalkyl", or "heterocycloalkyl", and in which R and R ', together with the nitrogen atom to which they are attached, can optionally form a heterocycloalkyl ring of 3 -8 members.

"Ammonium (C1-C6) alkyl" refers to C1-C6 alkyl groups having an ammonium substituent, including 2- (1-pyrrolidinyl) ethyl and the like.

"Halogen" refers to fluorine, chlorine, bromine and iodine atoms.

"Sulfonyloxy" refers to a group -OSO2-R in which R is selected from H, "C1-C6 alkyl", "C1-C6 alkyl" substituted by halogens, p. eg, a group -OSO2-CF3, "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl-C1-alkyl C6) "or" heteroaryl (C1-C6) alkyl "," aryl (C2-C6) alkenyl "," heteroaryl (C2-C6) alkenyl "," aryl (C2-C6) alkynyl "," heteroaryl - (C2-C6) alkynyl "," cycloalkyl (C1-C6) alkyl "," heterocycloalkyl (C1-C6) alkyl ".

"Sulfonyloxy-(C1-C6) alkyl" refers to C1-C6 alkyl groups having a sulfonyloxy substituent, including 2 (methylsulfonyloxy) ethyl and the like.

"Sulfonyl" refers to the group "-SO2-R" in which R is selected from H, "aryl", "heteroaryl", "C1-C6 alkyl", "halogen-substituted C1-C6 alkyl", p. eg, a group -SO2-CF3, "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl-C1-alkyl C6) "or" heteroaryl (C1-C6) alkyl "," aryl (C2-C6) alkenyl "," heteroaryl (C2-C6) alkenyl "," aryl (C2-C6) alkynyl "," heteroaryl - (C2-C6) alkynyl "," cycloalkyl (C1-C6) alkyl ",

"heterocycloalkyl (C1-C6) alkyl".

"Sulfonyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having a sulfonyl substituent, including 2 (methylsulfonyl) ethyl and the like.

"Salinillo" refers to a group "-S (O) -R" in which R is selected from H, "C1-C6 alkyl", "C1-C6 alkyl" substituted by halogens, eg, a group -SO-CF3, "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl-C1-C6 alkyl" "," heteroaryl (C1-C6) alkyl, "" aryl (C2-C6) alkenyl "," heteroaryl (C2-C6) alkenyl "," aryl (C2-C6) alkynyl "," heteroaryl (C2-) alkynyl C6) "," cycloalkyl (C1-C6) alkyl "," heterocycloalkyl (C1-C6) alkyl ".

"Sulfinyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having a sulfinyl substituent, including 2 (methylsulfinyl) ethyl and the like.

"Sulfanyl" refers to -SR groups in which R includes H, "C1-C6 alkyl", "C1-C6 alkyl" substituted by halogens, eg, a -SO-CF3 group, "C2-C6 alkenyl "," C2-C6 alkynyl "," C3-C8 cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," aryl (C1-C6) alkyl "or" heteroaryl (C1-C6) alkyl ", "aryl (C2-C6) alkenyl", "heteroaryl (C2-C6) alkenyl", "aryl (C2-C6) alkynyl", "" heteroaryl (C2-C6) alkynyl "," cycloalkyl-C1-alkyl -C6) "," heterocycloalkyl (C1-C6) alkyl ". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

"Sulfanyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having a sulfanyl substituent, including 2 (etiIsulfanyl) ethyl and the like.

"Sulfonylamino" refers to a group -NRSO2-R 'in which each R, R' independently includes hydrogen, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3- cycloalkyl C8 "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl (C1-C6) "or" heteroaryl (C1-C6) alkyl "," aryl-alkenyl (C2-C6) "," heteroaryl-alkenyl (C2-C6) "," aryl (C2-C6) alkynyl "," heteroaryl (C2-C6) alkynyl "," cycloalkyl (C1-C6) alkyl "," heterocycloalkyl (C1-C6) alkyl " .

"Sulfonylamino (C1-C6) alkyl" refers to C1-C6 alkyl groups having a sulfonylamino substituent, including 2- (ethylsulfonylamino) ethyl and the like.

"Aminosulfonyl" refers to a group -SO2-NRR 'in which each R, R' independently includes, hydrogen, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3 cycloalkyl -C8 "," heterocycloalkyl "," aryl "," heteroaryl "," arylalkyl (C1-C6) "or" heteroaryl-alkyl (C1-C6) "," aryl-alkenyl (C2-C6) "," heteroaryl- (C2-C6) alkenyl, "" aryl (C2-C6) alkynyl "," heteroaryl (C2-C6) alkynyl "," "cycloalkyl (C1-C6) alkyl", "heterocycloalkyl (C1-C6) alkyl ".

"Aminosulfonyl (C1-C6) alkyl" refers to C1-C6 alkyl groups having an aminosulfonyl substituent, including 2- (cyclohexylaminosulfonyl) ethyl and the like.

"Substituted or unsubstituted": unless limited by the definition of the individual substituent, the groups set forth above, such as "alkenyl", "alkynyl", "aryl", "heteroaryl", "cycloalkyl", "heterocycloalkyl" etc groups . they may be optionally substituted with 1 to 5 substituents selected from the group consisting of "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "cycloalkyl", "heterocycloalkyl", '"aryl-alkyl ( C1-C6) "," heteroaryl (C1-C6) alkyl "," cycloalkyl (C1-C6) alkyl "," heterocycloalkyl (C1-C6) alkyl "," amino "," ammonium "," acyl " , "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "aryl", "carbamate", "heteroaryl", "sulfinyl", "sulfonyl", "alkoxy", "sulfanyl", " halogen "," carboxy ", trihalogenomethyl, cyano, hydroxy, mercapto, nitro, and the like.

"Substituted" refers to groups substituted with 1 to 5 substituents selected from the group consisting of "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "cycloalkyl", "heterocycloalkyl", '" aryl (C1-C6) alkyl "," heteroarylalkyl (C1-C6) "," cycloalkyl (C1-C6) alkyl "," heterocycloalkyl (C1-C6) alkyl "," amino "," aminosulfonyl "," ammonium "," acylamino "," aminocarbonyl "," aryl "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," alkoxycarbonyl "," carbamate "," sulfanyl "," halogen ", trihalogenomethyl, cyano , hydroxy, mercapto, nitro, and the like.

"Pharmaceutically acceptable salts or complexes" refers to salts or complexes of the compounds of formula (I) identified below that retain the desired biological activity. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. Such compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR, R ', R "+ Z-, wherein R, R', R "Are independently hydrogen, alkyl or benzyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl (C1-C6) alkyl, heteroaryl (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulphonate, phosphate or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

"Pharmaceutically active derivative" refers to any compound that, after administration to the recipient, is capable of directly or indirectly providing the activity described herein. The term

"Indirectly" also encompasses prodrugs that can be converted into the active form of the drug by endogenous enzymes or metabolism.

It has now been found that the compounds of the present invention are phosphoinositide-3-kinase (PI3K) modulators, which comprise PI3K! and ∃. When the phosphoinositide-3-kinase enzyme (PI3K) is inhibited by the compounds of the present invention, PI3K is unable to exert its enzymatic, biological and / or pharmacological effects. The compounds of the present invention are therefore useful in the treatment and prevention of autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung lesions.

The general formula (I) according to the present invention also comprises its tautomers, its geometric isomers, its optically active forms such as enantiomers, diastereoisomers and its racemic forms, as well as its pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of formula (I) are acid addition salts formed with pharmaceutically acceptable acids such as salts of hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, and / or para-toluenesulfonate.

The compounds according to formula (I) are suitable for modulation, in particular the inhibition of the activity of phosphoinositide-3-kinases (PI3K). Therefore, it is believed that the compounds of the present invention are particularly useful for the treatment and / or prevention of disorders that are mediated by PI3K, in particular PI3K! and / or PI3K ∃. Such treatment involves the modulation, in particular the inhibition or reduction, of phosphoinositide-3-kinases (PI3K).

The compounds according to formula (I) are suitable for use as a medicament.

In one embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I):

wherein R1 is selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted alkoxy-C1-C6 alkyl, optionally substituted alkoxycarbonyl, optionally substituted acyl , optionally substituted sulfonyl, optionally substituted sulfanyl, optionally substituted sulfinyl, optionally substituted alkoxy and optionally substituted amino;

R2 is selected from H; halogen; optionally substituted C1-C6 alkyl; optionally substituted C2-C6 alkenyl, C2-C6 alkynyl; optionally substituted aryl, such as phenyl and 3,5-dimethoxyphenyl; optionally substituted heteroaryl, such as optionally substituted 2,3-di-hydroindolyl (eg 2,3-dihydro-indole-1-carboxylic acid tert-butyl ester, 2,3-dihydro-1H-indole-5-yl, acetyl -2,3-dihydro-1H-indole-5-yl, 1- (4-dimethylamino-butyryl) -2,3-dihydro-1H-indole-5-yl, 1-methanesulfonyl-2,3-dihydro-1H-indole -5-yl, 1-chloromethanesulfonyl-2,3-dihydro-1H-indole-5-yl, 1- (3-morpholin-4-ylpropane-1-sulfonyl) -2,3-dihydro-1H-indole-5 -ilo); optionally substituted C3-C8 cycloalkyl; optionally substituted C3-C8 heterocycloalkyl, including optionally substituted piperidinyl such as 1-piperidinyl, 4-fluoro-1piperidinyl, 4- (trifluoromethyl) -1-piperidinyl; optionally substituted aryl (C1-C6) alkyl; optionally substituted heteroaryl (C1-C6) alkyl; optionally substituted cycloalkyl (C3-C8) -alkyl (C1-C6) and optionally substituted heterocycloalkyl (C3-C8) alkyl (C1-C6); optionally substituted (C1-C6) alkoxy-alkyl; optionally substituted alkoxycarbonyl; optionally substituted acyl; optionally substituted sulfonyl; optionally substituted sulfanyl; optionally substituted sulfinyl; optionally substituted alkoxy and optionally substituted amino.

X is selected from S, NH and O;

Y is selected from O, S and NR3, wherein R3 is selected from H, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, aryl (C1 -C6) optionally substituted, cyano and optionally substituted sulfonyl;

A is an optionally substituted heteroaryl group, including optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted furyl and optionally substituted imidazolyl;

n is an integer selected from 1 and 2; as well as its geometric isomers, its optically active forms such as enantiomers, diastereoisomers and its racemic forms, as well as its pharmaceutically acceptable salts.

In a specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R 1 is H.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R2 is H.

In another specific embodiment, the invention provides pyridine-methylene azolidinone derivatives of formula (I), wherein R2 is optionally substituted C3-C8 heterocycloalkyl.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R2 is selected from optionally substituted aryl and optionally substituted heteroaryl.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R 3 is H.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which X is S.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which Y is O.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which Y is S.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which n is 1.

In another specific embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein n is 2.

In a preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which A is such that together with the pyridine ring it forms the following group (Ia):

in which R1, R2 and n are as defined above.

In another preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which A is such that together with the pyridine ring it forms the following group (Ib):

In which R1, R2 and n are as defined above.

In another preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which A is such that together with the pyridine ring it forms the following group (Ic):

30 in which R1, R2 and n are as defined above.

In another preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), in which A is such that together with the pyridine ring it forms the following group (Id):

in which R1, R2 and n are as defined above.

In a preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R 1 is H; R2 is optionally substituted C3-C8 heterocycloalkyl; X is S; Y is O or S; A together with the pyridine ring forms a group of formula (Ia) in which n is 1.

In a preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R 1 is H; X is S; Y is O and A together with the pyridine ring forms a group of formula (Ib).

In a preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R 1 is H; X is S; Y is O and A together with the pyridine ring forms a group of formula (Ic).

In a preferred embodiment, the invention provides pyridine methylene azolidinone derivatives of formula (I), wherein R 1 is H; X is S; Y is O and A together with the pyridine ring forms a group of formula (Id).

The compounds of the present invention include in particular those of the group consisting of:

Example No.

Name

one

(5Z) -5 - {[4- (1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1,3-thiazolidine-2,4-dione;

2

(5Z) -5 - {[4- (4-fluoro-1-piperidinyl) pyrido [3,2-dlpyrimidin-6-yl] mctilene} -1,3-thiazolidine-2,4-dione;

3

(5Z) -5 - ({4- [4- (trifluoromethyl) -1-piperidinyl] pyrido [3,2-d] pyrimidin-6-yl} methylene} -1,3-thiazolidine-2,4-dione;

5-Pyrido [2,3-b] pyrazin-6-ylmethylene-thiazolidine-2,4-dione;

5

5-Furo [3,2-b] pyridin-5-ylmetliIen-thiazolidine-2,4-dione;

6

5- [4- (4-Fluoro-piperidin-1-yl) -pyrido [3,2 d] pyrimidin-6-ylmethylene] -2-thioxo-thiazolidin-4-one;

7

5- (3-Phenyl-3H-imidazo [4,5-b] pyridin-5-ylmethylene) -thiazolidine-2,4-dione;

8

5- [3- (3,5-Dimethoxy-phenyl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4-dione;

5- [5- (2,4-Dioxo-thiazolidin-5-ylidenemethyl) -imidazo [4,5-b] pyridin-3-yl] -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester;

10

5- [3- (2,3-Dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4-dione;

eleven

5- [3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-yl-methylene] -thiazolidine-2,4- diona;

5- {3- [1- (4-Dimethylamino-butyryl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridin-5-ylmethylene} thiazolidine-2 , 4-dione;

5- [3- (1-Methanesulfonyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4dione;

5- [3- (1-Chloromethanesulfonyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine2,4-dione;

5- {3- [1- (3-Morpholin-4-yl-propane-1-sulfonyl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridin -5-methylene} -thiazolidine-2,4-dione;

6- [5- (2,4-Dioxo-thiazolidin-5-ylidenemethyl) -imidazo [4,5-b] pyridin-3-yl] -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester;

5- [3- (1-Methanesulfonyl-2,3-dihydro-1H-indol-6-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4dione

The compounds of the present invention are useful as medicaments. They can be used to prepare a

15 medicine for the prophylaxis and / or treatment of autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung lesions.

In one embodiment, the compounds of formula (I) are useful for the treatment and / or prophylaxis of autoimmune diseases or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, lupus

20 systemic erythematosus, inflammatory bowel disease, pulmonary inflammation, thrombosis or cerebral infection / inflammation such as meningitis or encephalitis.

In another embodiment, the compounds of formula (I) are useful for the treatment and / or prophylaxis of neurodegenerative diseases including Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions.

In yet a further embodiment according to the invention, the compounds of formula (I) are useful for the treatment and / or prophylaxis of cardiovascular diseases such as atherosclerosis, cardiac hypertrophy, cardiac myocyte dysfunction, hypertension or vasoconstriction.

In yet another embodiment according to the invention, the compounds of formula (I) are useful for the treatment and / or prophylaxis of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, diseases

5 allergies, asthma, stroke or ischemic conditions, ischemia – reperfusion, platelet aggregation / activation, skeletal muscle atrophy / hypertrophy, leukocyte recruitment into cancer tissues, angiogenesis, invasive metastasis, particularly melanoma, Kaposi sarcoma, infections Acute and chronic bacterial and viral, sepsis, transplantation, graft rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial lesions in the lung or general pulmonary airway inflammation.

In another embodiment according to the invention, there is provided a process for preparing pyridinemethylene azolidinone derivatives according to formula (I), which comprises the step of reacting a compound of formula (II) with a derivative of formula ( III) in the presence of a base:

in which R1, R2, A, X, Y and n have been defined before. In another embodiment according to the invention, compounds according to formula (II) are provided:

wherein R1, R2, A, X, Y and n have been defined before and in which the compounds of formula II are selected from the group of formulas (IIa), (IIb) and (IIc):

In which R4 is selected from H and R2; R5 is a group R2 in which the first atom attached to the pyrimidine ring is selected from C, N, S and O and in which when R4 is NH2, R5 is not NH2; R1, R2 and n are as defined above;

in which R1, R2 and n are as defined above; 5

in which R1, R2 and n are as defined above and in which at least some of R1 or R2 is not H; Y

wherein R1, R2 and n are as defined above with the proviso that the compound of formula (IId) is not the 2- (4-Methoxyphenyl) -3H-Imidazo [4,5-b] pyridine-5-carboxaldehyde (RN 142764-79-2).

In a further embodiment according to the invention, compounds according to formula (II) are provided of the group:

4-Piperidin-1-yl-pyrido [3,2-d] pyrimidine-6-carbaldehyde; 4- (4-Fluoro-piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6-carbaldehyde; 4- (4-Methyl-piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6-carbaldehyde; Pyrido [2,3-b] pyrazine-6-carbaldehyde; 2-Trimethylsilanyl-furo [3,2-b] pyridine-5-carbaldehyde; 3-Phenyl-1H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- (3,5-Dimethoxyphenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; Tert-butyl 5- (5-Formyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate; 3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- {1- [4- (dimethylamino) butanoyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- {1 - [(chloromethyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- {1 - [(3-morpholin-4-ylpropyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; Tert-butyl 6- (5-formyl-3H-imidazo [4,5-b] pyridine-3-yl) indoline-1-carboxylate; 3- [1- (Methylsulfonyl) -2,3-dihydro-1H-indol-6-yl] -3H-imidazo [4,5-b] pyridine-5-carbaldehyde.

The pyridine methylene azolidinone derivatives illustrated in this invention can be prepared from materials. Easily available starting materials, using the following general methods and procedures. It will be noted that where typical or preferred experimental conditions occur (i.e. reaction temperatures, time, moles of reagents, solvents etc.), other experimental conditions may also be used unless indicated contrary. Optimum reaction conditions may vary with particular reactants or solvents. used, but such conditions can be determined by the person skilled in the art, using methods of routine optimization.

When used as pharmaceuticals, the compounds of the present invention are administered. typically in the form of a pharmaceutical composition. Therefore, the pharmaceutical compositions that they comprise a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient for the They are also within the scope of the present invention. A person skilled in the art is aware of the wide variety of said carrier compounds, diluents or excipients suitable for formulating a pharmaceutical composition

The compounds of the invention, together with an adjuvant, vehicle, diluent or excipient used in a manner conventional, can be put in the form of pharmaceutical compositions and unit dosages thereof, and in such form they can be used as solids, such as tablets or charged capsules, or liquids such as solutions, suspensions, emulsions, elixirs or capsules loaded therewith, all for oral use, or in form of sterile injectable solutions for parenteral use (including subcutaneous use). These compositions Pharmaceutical and unit dosage forms thereof may comprise ingredients in proportions. conventional, with or without additional compounds or active ingredients, and said unit dosage forms they may contain any suitable effective amount of the active ingredient in proportion to the range of purported daily dosage to be used.

The pharmaceutical compositions containing the pyridine methylene azolidinone derivatives of this invention can be prepared in a manner well known in the pharmaceutical art, and comprise at least one active compound. In general, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition to be treated, the route of administration chosen, the particular compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of the present invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Compositions for oral administration may have the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, the compositions are presented in unit dosage forms to facilitate precise dosing. The term "unit dosage forms" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled ampules or syringes and measures of liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the pyridine-methylene-azolidinone derivative is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) the rest being different vehicles or excipients and auxiliaries of the processing useful to form the desired dosage form.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispersing agents, colorants, flavorings and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a sliding agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable vehicles known in the art. As mentioned before, the pyridine-methylene-azolidinone derivatives of formula (I) in said compositions are typically a minor component, often in the range between 0.05 and 10% by weight, the remainder being the injectable vehicle, and Similar.

The components described above for orally administered or injectable compositions are simply representative. Additional materials as well as processing techniques and the like are set forth in part 5 of Remington's Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pa., Which is incorporated herein by reference.

The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A representative description of sustained release materials can also be found in the materials incorporated in Remington's Pharmaceutical Sciences.

Synthesis of the compounds of the invention:

The new pyridine-methylene azolidinone derivatives according to formula (I) can be prepared from readily available starting materials by various synthetic methods, using chemical protocols both in the dissolution phase and in the solid phase (Brummond et al. ., 1999, JOC, 64, 1723-1726). The condensed pyridine intermediates are described in Shiolani et al. J. Heterocyclic Chem. 34, 901 (1997) and in Lown et al., Chem. Res. Toxicol. 1992, 5, 597. Examples of synthetic routes will be described.

The following abbreviations refer respectively to the following definitions:

Å (Angstrom), cm (centimeters), eq (equivalent), h (hours), g (grams), M (molar), MHz (Megahertz), μl

(microliters), min (minutes), mg (milligrams), ml (milliliters), mm (millimeters), mmol (millimoles), mM (millimolar), nm (nanometers), t.a. (room temperature), ACN (acetonitrile), ATP (adenoside triphosphate), BSA (bovine serum albumin), DCM (dichloromethane), DIBAL (diisobutylaluminum hydride), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), HPLC (chromatography high performance liquid), Ins1P (D-myo-inositol-1-phosphate), IR (infrared), LC (liquid chromatography), MS (mass spectrometry), NMR (nuclear magnetic resonance), PBS (saline buffered with phosphate), PI (phosphoinositides), PI3K (phosphoinositide 3-kinases), PI (3) P (3-phosphatidylinositol monophosphate), PI (3,4) P2 (3,4-phosphatidylinositol bisphosphate), PI (3, 4,5) P3 (3,4,5-phosphatidylinositol trisphosphate), PI (4) P (4-phosphatidylinositol phosphate), PI (4,5) P2) (4,5-phosphatidylinositol bisphosphate), PtdIns ( phosphatidylinositol), PVT (polyvinyl toluene), SPA (proximity scintillation test), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), TMS (trimethylsilyl), UV (ultraviolet).

The pyridine methylene azolidinone derivatives illustrated in this invention can be prepared from materials.

5 readily available using the following general methods and procedures. It will be noted that where typical or preferred experimental conditions exist (ie, reaction temperatures, time, moles of reagents, solvents etc.), other experimental conditions can also be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art, using routine optimization procedures.

In the procedure illustrated the following schemes R1, R2, A, X, Y and n are each as defined above in the description.

In general, pyridine-methylene-azolidinone derivatives according to the general formula (I) can be obtained by various synthetic procedures, using chemistry protocols both in the dissolution phase and in the solid phase (Brummond et al., 1999, see before), either by conventional methods or by techniques assisted by

15 microwaves

In a first step, an aldehyde reactant P1 (P1a, P1b, P1c, P1d) and 1 or 2 equivalents of reactant P2 (in particular thiazolidinedione or rodanine) are heated in the presence of a preferably soft base to provide the corresponding olefin of formula ( I) as shown in the following scheme 1. In the first stage, P1 can be replaced by precursors P1a, P1b, P1c and P1d in order to obtain the final compounds (Ia),

20 (Ib) (Ic) and (Id) respectively, as described earlier in the description.

Particularly preferred processes according to the invention are illustrated by the following schemes 2, 3, 4 and 5 in which the compounds of formula (Ia), (lb), (Ic) and (Id) respectively, can be obtained using the same reaction conditions mentioned above.

Scheme 3:

30 Scheme 4:

Scheme 5:

Although this step can be carried out in the absence of a solvent at a temperature that is sufficiently high to produce at least partial fusion of the reaction mixture, it is preferable to carry it out in the presence of an inert solvent. A preferred temperature range is about 70 ° C to 250 ° C, and a temperature of about 80 ° C to 120 ° C is especially preferred.

Examples of such solvents for the above reaction include solvents such as dimethoxymethane, xylene, toluene, o-dichlorobenzene and methanol. Soft base examples suitable for the above reaction are alkali and alkaline earth metal salts of weak acids such as (C1-C12) alkylcarboxylic acids and benzoic acid, alkali and alkaline earth metal carbonates and bicarbonates such as calcium carbonate, carbonate magnesium, potassium bicarbonate and secondary amines such as piperidine, morpholine or pyrrolidine as well as tertiary amines such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, Nmethylpiperidine and the like. Especially preferred mild bases are sodium acetate or pyrrolidine for reasons of economy and efficacy.

In said typical reaction (Tietze et al., In "The Knoevenagel reaction", p. 341 ƒƒ, Pergamon Press, Oxford 1991, Eds .: Trost BM, Fleming I.) the aldehyde P1 and the other starting material (p. eg, thiazolidinedione) P2 are combined in approximately equimolar amounts with 0.5 to 1 equivalent of pyrrolidine in methanol or a similar solvent, and are heated between 70 and 200 ° C, at which temperature the reaction is substantially completed at approximately 15 minutes to 3 hours The desired olefin of formula (I) is then isolated by filtration, if it had precipitated from the reaction mixture after cooling, or for example, mixing it with water and subsequent filtration, to obtain the crude product. The crude product is purified, if desired, for example by crystallization or by conventional chromatographic methods.

Alternatively, the compounds of formula (I) can typically be obtained by mixing equimolar amounts of the thiazolidinedione P2 with the aldehyde P1 with a molar excess of anhydrous sodium acetate and the mixture is heated to a high temperature sufficient to perform the melting, temperature at which the reaction is completed practically in about 5 to 60 minutes.

Preferably, the above reaction is carried out in acidic medium such as acetic acid in the presence of sodium acetate or beta-alanine.

More preferably, the above reaction is carried out in methanol using 1.1 to 2.0 equivalents of thiazolidinedione P2, 1 equivalent of aldehyde P1 and 0.2 to 0.5 equivalents of pyrrolidine in methanol.

The reactions described above can alternatively be carried out under microwave conditions as a heating source. Typically, the aldehyde P1 and thiazolidinedione P2 starting material are combined in approximately equimolar amounts with 0.5 to 1 equivalent of piperidine in dimethoxyethane or a similar solvent, and are heated between 140 ° C and 240 ° C, temperature at which the reaction is substantially complete in about 3 to 10 minutes.

Pharmaceutically acceptable cationic salts of the compounds of the present invention are readily prepared by reacting the acidic forms with a suitable base, usually 1 equivalent, in a

co-solvent Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydroxide, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benetamine, diethylamine, piperazine and tromethamine. The salt is isolated by concentration to dryness or by the addition of a non-solvent. In some cases, the salts can be prepared by mixing a solution of the acid with a solution of the cation (sodium ethylhexanoate, magnesium oleate), using a solvent in which the desired cationic salt precipitates, or can be isolated in another way by concentration and addition of a non-solvent.

2,4-Azolidinone P2 derivatives are commercially available from different sources.

Methods of preparing intermediate compounds of the compounds formula (I)

Aldehydes of formula P1 are prepared by a variety of well known methods, for example, by oxidoreduction starting from the corresponding carboxylic acid alkyl ester or carboxylic acid.

Conventional techniques for reducing an alkyl ester of carboxylic acid, carboxylic halides or carboxylic acid to benzyl alcohols, use lithium aluminum hydride, diisopropyl aluminum, lithium aluminum tri-tert-butoxyhydride, etc.

Finally, the corresponding benzyl alcohol is re-oxidized to the corresponding aldehyde by mild oxidation with reactants such as manganese dioxide, chromic acid, Dess-Martin reagent or Swern oxidation, or under other conditions known to produce aldehydes from primary alcohols. . An alternative route may be the direct reduction of the corresponding alkyl ester of carboxylic acid or carboxylic acid to the corresponding aldehyde, using DIBAL at low temperature, or any other technique known in the field.

An alternative route to prepare the suitable aldehyde P1 is the selective reduction of a nitrile moiety to the corresponding aldehyde using methods known as, e.g. eg, DIBAL.

Another way of obtaining aldehydes of formula P1 is the selective reduction of the corresponding acyl chloride using, e.g. e.g., lithium aluminum tri-tert-butoxyhydride (Cha et al., 1993, J.O.C, 58, p. 4732-34).

Another way of synthesizing P1 aldehydes is starting from the corresponding 2-pyridine halides, which are subjected to an organometallic assisted reaction in order to provide the corresponding 2-vinyl pyridines, which can finally be oxidized to the corresponding aldehydes. P1 using conventional oxidation agents for olefinic bonds, such as osmium tetraoxide, ruthenium tetraoxide, ozone, ruthenium (III) chloride in the presence of sodium periodate and others, known to the person skilled in the art.

Another way of obtaining the corresponding P1 aldehydes is the oxidation of a 2-methylpyridine using oxidizing agents such as selenium dioxide or benzene-seleninic anhydride.

According to a particularly more preferred method of the invention, as illustrated in the following scheme 6, the reactant P1a can be obtained from a derivative of formula P3a in which R is selected from methyl, ethyl or any other group susceptible to reduction known to the person skilled in the art, optionally applying a reduction / oxidation sequence preferably using lithium aluminum hydride in tetrahydrofuran, followed by an oxidation step preferably using manganese dioxide in dichloromethane.

Scheme 6:

An intermediate compound that can be used for the above synthesis is methyl 2,4,8-trichloropyrido [3,2-d] pyrimidine-6-carboxylate (intermediate compound 1.3), the synthesis of which is described in the literature (Srinivasan et al. , 1979, JOC, 1979, 44, 3, p. 435), as shown in the following scheme 7.

Scheme 7:

The selective substitution of the 3 chlorine groups can allow the introduction of the R1 and R2 groups leading to different intermediate compounds of formula P3a (P3a (1), P3a (2), P3a (3), P3a (4), P3a (5 ), P3a (6), P3a (7)) as shown in the following scheme 8.

The reduction steps in scheme 8 can be carried out using conventional reducing agents, such as hydrogen or ditiation with Raney Nickel (Srinivasan et al., 1979, see above).

Preferably, the reduction is carried out under mild conditions using ammonium formate in the presence of 10 palladium. The amount of ammonium formate is determined by the number of chlorine atoms to be removed (212 eq.).

The introduction of the R2 and R1 groups is obtained by conventional reaction techniques known to those skilled in the art.

According to another particularly preferred process of the invention, as illustrated in the following scheme 9, the aldehyde P1b can be obtained starting from an intermediate compound P3b by oxidative breakage of an olefinic double bond.

Scheme 9:

where R is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl. In said reaction the olefinic double bond is broken using oxidation agents for olefinic bonds, such as osmium tetraoxide, ruthenium tetraoxide, ozone, ruthenium (III) chloride in the presence of sodium periodate and others

5 known to the person skilled in the art.

The intermediate compound P3b can be synthesized starting from 2-halogen-pyridine derivatives using organometallic assisted coupling reactions to introduce a vinyl moiety in a conventional manner known to those skilled in the art. The corresponding 2-halogen-pyridines are easily accessible from, e.g. eg, of 2-halogen-4-nitro-6-aminopyridine, as depicted in the following scheme 10, in which "Hal" represents a

10 halogen.

According to another particularly preferred process of the invention, as illustrated in the following scheme 11, wherein R is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, intermediate P1c can be obtained from the intermediate compound P3c by oxidation of 2-methylpyridines.

Scheme 11:

Said oxidation can be carried out using selenium dioxide or benzene seleninic anhydride in a solvent.

20 inert, at temperatures between 150 and 250 ° C. Preferably, said reaction is carried out using microwaves as a heating source. In a second stage, the desililation is carried out under conventional conditions as described in Kocienski, 1994 (see above) and Greene et al., 1999 (see above).

Preferably, the trimethylsilyl group is cleaved using 2 to 5 N sodium hydroxide.

The introduction of R2 can be performed as described in WO2004 / 007491.

According to another more preferred procedure, intermediate compound P1c can be obtained from intermediate compound P3c by a transposition of picolin N-oxide: typically intermediate compound P3c is subjected to N-oxidation leading to intermediate compound P3 ′, using oxidants such as m-chloroperbenzoic acid (m-CPBA) at room temperature, or any oxidant known to the person skilled in the art. The subsequent basic treatment and heating of P3c 'in acetic anhydride at 100 ° C for 5 to 15 min (Cava et al., 1958, JOC, 23, 1616) leads to the corresponding acetyl-protected alcohol, which in turn can be protected and Simulate simultaneously by treatment with sodium hydroxide (2 N) in methanol at room temperature. Finally, the primary alcohol P3c "can be oxidized to the corresponding intermediate aldehyde P1c using oxidants such as manganese dioxide in dichloromethane or any oxidant known to those skilled in the art (scheme 11, above).

According to another particularly preferred process of the invention, when azabenzimidazoles are represented, intermediate compound P4d can be obtained from intermediate compound P5d, as depicted in the following scheme 12, in which "Hal" represents a halogen.

Substitution of 2-halogen with R2NH2 in alcohols (eg, ethanol) in the presence of a base, is followed by the reduction of the nitro group catalyzed by indium metal in the presence of a hydrogen source. P4d is obtained by subsequent cyclization by condensation with amidines, followed by the introduction of a vinyl moiety using organometallic-assisted coupling reactions in a conventional manner, known to the person skilled in the art.

When R2 in intermediate P4d is a chemical moiety that is going to undergo synthetic transformations, these transformations are carried out after completion of the coupling with the vinyl moiety. These synthetic transformations include, but are not limited to, deprotections, coupling, oxidations, reductions.

In accordance with a particularly preferred method of the invention, the vinyl olefinic bond introduced from intermediate P3d (scheme 13 above) is cleaved using oxidation agents for olefinic bonds such as osmium tetraoxide or ruthenium (III) chloride in the presence of sodium, ozone, and other known periodate for the person skilled in the art

According to another general procedure, the compounds of formula (I) can be converted into alternative compounds of formula (I) using suitable interconversion techniques known to those skilled in the art.

If the set of general synthetic methods above is not applicable to obtain compounds according to formula (I) and / or intermediate compounds necessary for the synthesis of the compounds of formula (I), suitable methods for the preparation, known, should be used by the person skilled in the art. In general, the synthetic routes for any individual compound of formula (I) will depend on the specific substituents of each molecule and the easy availability of the necessary intermediates; said factors being again appreciated by the person skilled in the art. For all protection and deprotection methods, see Kocienski, 1994 (see above) and Greene et al., 1999 (see above).

The compounds of this invention can be isolated associated with solvent molecules by crystallization by evaporation of a suitable solvent. Pharmaceutically acceptable acid addition salts of the compounds of formula (I), which contain a basic center, can be prepared in a conventional manner. For example, a solution of the free base can be treated with a suitable acid, either alone or in a suitable solution, and the resulting salt isolated by filtration or by evaporation under vacuum of the reaction solvent. The salts of

Pharmaceutically acceptable base addition can be obtained in an analogous manner by treating a solution of the compound of formula (I) with a suitable base. Both types of salts can be formed or interconverted using ion exchange resin techniques.

Next, the present invention will be illustrated by some examples that should not be considered as limiting the scope of the invention.

Examples:

The following commercially available starting materials were used:

5-Aminouracil available commercially in Aldrich; Dimethyl acetylenedicarboxylate commercially available from Aldrich; N, N-diethylaniline commercially available from Aldrich; Phosphorus oxychloride commercially available in Aldrich; N-ethyldiisopropylamine commercially available from Aldrich; Commercially available ammonium formate in Aldrich; Lithium aluminum hydride commercially available in Aldrich; Commercially available manganese oxide in Aldrich; 2,4-Thiazolidinedione available commercially in Aldrich; Rodanina commercially available in Aldrich; Commercially available beta-alanine in Aldrich; 4-Fluoro-piperidine commercially available from Fluorochem; Commercially available 4-Trifluoromethyl-piperidine in Lancaster; Glioxal (oxaldehyde) commercially available in Aldrich; Tetrakis (triphenylphosphine) palladium available commercially in Aldrich; Vinyltributilestannano commercially available in Aldrich; 6-Yodo-2-picolin-5-ol commercially available in Acros; (Trimethylsilyl) acetylene commercially available from Aldrich; Dichlorobis (triphenyl phosphine) palladium (II) commercially available from Aldrich; 1,2-Dichlorobenzene commercially available from Aldrich; 2-Amino-3-nitro-6-chloropyridine commercially available from ACROS; Commercially available Indian powder in Aldrich; Commercially available formamidine acetate in Aldrich; Tributyl (vinyl) tin commercially available in Aldrich; Commercially available osmium tetraoxide in Aldrich; Commercially available sodium periodate in Aldrich; 2,6-Dichloro-3-nitropyridine commercially available from Aldrich; 3,5-Dimethoxyaniline commercially available from Aldrich; 5-Nitroindoline commercially available in Aldrich; 6-Nitroindoline commercially available in Aldrich; 4- (dimethylamino) butyric acid hydrochloride commercially available from Aldrich; Commercially available 3-chloropropanesulfonyl chloride in Aldrich; Chloromethanesulfonyl chloride commercially available in Alfa Aesar.

The HPLC, NMR and MS data provided in the examples described below are obtained as follows: HPLC: Waters Symmetry C8 50 × 4.6 mm column, Conditions: MeCN / H2O, 5 to 100% (8 min), max. 230 400 nm; Mass spectra: PE-SCIEX API 150 EX (APCI and ESI), LC / MS spectra: Waters ZMD (ES); NMR of 1H: Bruker DPX-300 MHz.

Purifications by preparative HPLC are carried out with the Waters Prep LC 4000 HPLC system equipped with Prep Nova-Pak® HR C186 μm 60 Å, 40 × 30 mm (up to 100 mg) columns or with XTerra® Prep MS C8, 10 μm, 50 × 300 mm (up to 1 g). All purifications are carried out with a gradient of 0.09% MeCN / H2O TFA. Semi-preparative reverse phase HPLCs are carried out with the Biotage Parallex Flex system equipped with Supelcosil ™ ABZ + Plus columns (25 cm × 21.2 mm, 12 μm); UV detection at 254 nm and 220 nm; flow rate 20 ml / min (up to 50 mg). TLC analysis is carried out on Merck Precoated 60 F254 plates. The purifications by Flash chromatography is carried out on SiO2 support, using cyclohexane / EtOAc or DCM / MeOH mixtures as eluents.

Intermediate 1.1: (2E) -2 - [(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl-amino] -2-dimethyl butenedioate (Scheme 7)

To a suspension of 5-aminouracil (B) (4.0 g; 31.5 mmol; 1 eq.) In MeOH (120.00 ml) was added dimethyl acetylenedicarboxylate (C) (5.0 g; 35.2 mmol; 1.1 eq.). The suspension was stirred at room temperature for 46 h. The reaction was followed by NMR. The solid was filtered to provide (2E) -2 - [(2,4-dioxo-2,2,3,4-tetrahydro-5-pyrimidinyl) amino] -2-dimethyl butanedioate (8.0 g, 95%) (Intermediate compound 1.1).

Quantity: 8.0 g; Yield: 95%; Formula: C10H11O6N3; HPLC purity: 95%; HPLC (0.1% H2O TFA -0.05% TFA ACN): Rt (min); Rea?% = 1.37; 93.61; 1H NMR (DMSO-d6) # 3.64 (s, 3H), 3.66 (s, 3H), 5.21 (s, 1H), 7.42 (s, 1H), 9.07 (s, 1H), 10.86 (width, 1H), 11.31 (width, 1H); LC-MS: M / Z ESI: Rt (min) 0.85; 210, 238, 270 (M + 1); 208, 236, 268 (M − 1).

Intermediate compound 1.2: methyl 2,4,8-trioxo-1,2,3,4,5,8-hexahydropyrid [3,2-d] pyrimidine-6-carboxylate (Scheme 7)

(2E) -2 - [(2,4-dioxo-1,2,3,4 tetrahydro-5-pyrimidinyl) amino] -2-butanedioate was placed in a 2-liter 4-liter flask provided with a reflux coolant. dimethyl (Intermediate 1.1) (38.5 g; 0.14 mol; 1 eq.) Dowtherm® A (1 liter) (eutectic mixture phenyl biphenyl ether). The suspension was stirred with a mechanical stirrer under an argon atmosphere and heated to 220 ° C. The reaction was followed by HPLC / LC / MS. After 3 hours, the reaction was stopped by cooling followed by the addition of 300 ml of petroleum ether. The resulting precipitate was filtered and washed with DMF (2 × 100 ml). Methyl 2,4,8-trioxo-1,2,3,4,5,8 hexahydropyrid [3,2-d] pyrimidine-6-carboxylate (21.02 g; 62%) (Intermediate 1.2) isolated in the form of a yellow powder with 100% purity by HPLC. Quantity: 21.0 g; Yield: 62%; Formula: C9H7O5N3; 1H NMR (DMSO-d6) # 3.87 (s, 3H), 7.58 (s, 1H), 10.90 (s, 1H), 11.56 (s, 1H), 12.10 (width, 1 HOUR).

Intermediate compound 1.3: Methyl 2,4,8-trichloropyrido [3,2-d] pyrimidine-6-carboxylate (Scheme 7)

A solution of methyl 2,4,8-trioxo-1,2,3,4,5,8-hexahydropyrid [3,2-d] pyrimidine-6-carboxylate (Intermediate 1.2) (9 g; 37.95 mmol; 1 eq.) and N, N-diethylaniline (10 ml) in phosphorus oxychloride (174 ml) was heated at reflux overnight. The solution was concentrated in vacuo. The black oil was slowly poured on ice. Ethyl acetate was added and the organic phase was washed with water until pH = 6. The organic layers were dried over magnesium sulfate, filtered and concentrated. Methyl 2,4,8-trichloropyrido [3,2-d] pyrimidine-6-carboxylate (Intermediate 1.3) (6.5 g, 59%) precipitated in cyclohexane as a pink solid with 98% purity by HPLC. Quantity: 6.5 g; Yield: 59%; Formula: C9H4O2Cl3N3; 1H NMR (CDCl3) # 4.12 (s, 3H), 8.70 (s, 1H); HPLC (0.1% H2O TFA -0.05% TFA ACN): Rt (min); �?% = 3.07; 98; LC-MS: M / Z ESI: Rt (min) 1.58; 293 (M + 1).

Intermediate 1.4: 2,8-Dichloro-4- (1-piperidinyl) pyrido [3,2-d] pyrimidine-6-carboxylate methyl (Scheme 8)

To a solution of methyl 2,4,8-trichloropyrido [3,2-d] pyrimidine-6-carboxylate (4.65 g; 15.9 mmol; 1 eq.) (Intermediate 1.3) in acetonitrile (140 ml ) N-ethyldiisopropylamine (4 ml; 23.8 mmol; 1.5 eq.) was added. The mixture was cooled to 0 ° C. A solution of piperidine (1.57 ml; 15.9 mmol; 1 eq.) In acetonitrile (20 ml) was added dropwise. The mixture was stirred 15 min at 0 ° C. The mixture was partially concentrated and the precipitate was filtered, washed with MeOH and dried in vacuo to provide methyl 2,8-dichloro-4- (1-piperidinyl) pyrido [3,2-d] pyrimidine-6-carboxylate ( Intermediate 1.4) (3.98 g; 73%) in the form of a pink solid with 98.8% HPLC purity; Quantity: 3.98 g; Yield: 73%; Formula: C14H14O2Cl2N4; 1H NMR (DMSO-d6) # 1.71 (s1, 6H), 3.92 (s, 3H), 4.01 (s1, 2H), 4.82 (s1, 2H), 8.42 (s, 1 HOUR); LC-MS: M / Z ESI: Rt (min) 2.02; 341.02, 342.89 (M + 1); HPLC (0.1% TFA H2O - 0.05% TFA ACN): Rt (min); �?% = 4.27; 98.84.

Intermediate compound 1.5: 4- (1-Piperidinyl) pyrido [3,2-d] pyrimidine-6-carboxylate (Scheme 8)

Palladium (540 mg; 0.51 mmol; 0.05 eq.) And isopropanol (90 ml) were added in a round bottom flask. Ar was bubbled in this mixture. A solution of ammonium formate in degassed water (2.56 g, 40.6 mmol, 4 eq., In 4 ml of water) was added, followed by 2,8-dichloro-4- (1-piperidinyl) pyrido [3 , Methyl 2-d] pyrimidine-6-carboxylate (Intermediate 1.4) (3.46 g; 10.5 mmol; 1 eq.) And degassed isopropanol (10 ml). After 30 min, a second batch of ammonium formate was added as a solution in water (2.56 g, 40.6 mmol, 4 eq., In 4 ml of water). Finally, after an additional 30 min, another 8 equivalents of ammonium formate in water (5.12 g, 81.2 mmol, 8 eq., In 8 ml of water) were added. Then, the mixture was stirred at t.a. overnight and leaked through Celite. The filtrate was evaporated. The crude product was dissolved in DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give methyl 4- (1-piperidinyl) pyrido [3,2-d] pyrimidine-6-carboxylate (2.29 g; 83%) (Compound intermediate 1.5), in the form of a yellow solid with 92.9% purity by HPLC. This product was used in the next stage without further purification. Quantity: 2.29 g; Yield: 82%; Formula: C14H16O2N4; 1H NMR (DMSO-d6) # 1.70 (s1, 6H), 3.92 (s, 3H), 4.42 (s1, 4H), 8.19 (d, J = 9 Hz, 1H), 8 , 30 (d, J = 9 Hz, 1H), 8.52 (s, 1H); HPLC (0.1% H2O TFA -0.05% TFA ACN): Rt (min); Rea?% = 1.83; 92.88; LC-MS: M / Z ESI: Rt (min) 1.58; 273.10 (M + 1).

Intermediate 1.6: [4- (1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methanol (Scheme 6)

Methyl 4- (1-piperidinyl) pyrido [3,2-d] pyrimidine-6-carboxylate (Intermediate 1.5) (4.4 g; 16.2 mmol; 1 eq.) Was dissolved in THF (176 ml ) and the solution was cooled to −35 ° C (indoor temperature). Lithium aluminum hydride (8.1 ml; 1.00 M; 8.1 mmol; 0.50 eq.) Was added dropwise. After 2 h 30 at −35 ° C the reaction was complete. Water (8.1 ml) was added and the temperature was allowed to rise to t.a. After adding MeOH (8 ml), the mixture was filtered through Celite, and rinsed extensively with 1: 1 DCM / MeOH mixture. The solvents were removed under reduced pressure to give [4- (1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methanol (Intermediate 1.6) (3.99 g; quantitative yield) with 92, 9% purity by HPLC. This product was used in the next stage

Without further purification. Quantity: 3.99 g; Yield: 100%; Formula: C13H16ON4; 1H NMR (DMSO-d6) # 1.64 (m, 6H), 4.32 (s1, 4H), 4.66 (s, 2H), 7.86 (d, J = 9 Hz, 1H), 8 , 06 (d, J = 9 Hz, 1H), 8.44 (s, 1H); LC-MS: M / Z ESI: Rt (min) 1.24; 245.08 (M + 1); HPLC H2O 0.1% TFA -0.05% TFA NAC): Rt (min); �?% = 1.39; 92.88.

Intermediate 1.7: 4- (1-piperidinyl) pyrido [3,2-d] pyrimidine-6-carbaldehyde (Scheme 6)

[4- (1-Piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methanol (Intermediate 1.6) (3.95 g; 16.2 mmol; 1.00 eq.) Was dissolved in DCM (160 ml). The solution was cooled to 0 ° C and manganese oxide (16.5 g; 0.162 mol; 10 eq.) Was added. The reaction was stirred 5 min at 0 ° C and then overnight at t.a. To complete the conversion, MnO2 was added after 12 hours and 20 hours (2 batches of 4.96 g; 48.48 mmol; 3 eq.). After 20 hours, the reaction was complete. MeOH (100 ml) was added and the mixture was filtered through Celite and rinsed extensively with 1: 1 DCM / MeOH mixture. The solvents were removed under reduced pressure to give 4- (1-piperidinyl) pyrido [3,2d] pyrimidine-6-carbaldehyde (Intermediate 1.7). This product was used in the next stage without further purification. Quantity: 4.1 g; Formula: C13H14ON4; HPLC purity: 58.84%; LC-MS: M / Z ESI: Rt (min) 1.53; 243.06 (M + 1); HPLC (0.1% H2O TFA -0.05% TFA ACN): Rt (min); �?% = 1.39; 58.84. 1H NMR (DMSO-d6) # 9.95 (s, 1H), 8.52 (s, 1H), 8.16 (m, 2H), 4.46 (1, 4H), 1.70 (1, 6H).

Intermediate 2.1: 4- (4-fluoro-piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6-carbaldehyde (Schemes 6 and 8)

The title compound was obtained using 4-fluoro-piperidine following the general procedure described for the synthesis of intermediate 1.7 (Schemes 5 and 7). Quantity: 4.15 g; Formula: C13H13FON4; HPLC purity: 89.16%; LC-MS: M / Z ESI: Rt (10 min) 2.26; 261.08 (M + 1); HPLC H2O 0.1% TFA -0.05% TFA ACN); Rt (min); �?% = 1.19; 89.16; 1H NMR (DMSO-d6) # 10.01 (s, 1H), 8.60 (s, 1H), 8.23 (m, 2H), 5.00 (m, 1H), 4.51 (1, 4H), 1.91 (1, 4H).

Intermediate 3.1: 4- (4- (trifluoromethyl) -piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6-carbaldehyde (Schemes 6 and 8)

The title compound was obtained using 4-trifluoromethyl-piperidine following the general procedure described for the synthesis of intermediate 1.7 (Schemes 5 and 7). Quantity: 4.8 g; Formula: C14H13OF3N4; HPLC purity: 67.12%; LC-MS: M / Z ESI: Rt (3 min) 1.75; 311.04 (M + 1); HPLC: 0.1% TFA H2O -0.05% TFA ACN); Rt (min); �?% = 1.89; 67.12; 1H NMR (DMSO-d6) # 10.03 (s, 1H), 8.62 (s, 1H), 8.18 (s, 2H), 3.22 (t, 2H), 2.48 (m, 2H), 2.08 (d, 2H), 1.80 (m, 3H).

Intermediate 4.1: 6-Chloro-pyridine-2,3-diamine (Scheme 10)

The 2-amino-3-nitro-6-chloropyridine (3 g, 17.3 mmol, 1 eq.) Was dissolved in THF (50 ml) at t.a. Tin chloride dihydrate (15.6 g, 70 mmol, 4 eq.) Previously dissolved in HCl∋ (5 ml) was added slowly and the reaction mixture was stirred at t.a. During 4 hours. When the reaction was over, the reaction mixture was cooled to 0 ° C and treated with 5M sodium hydroxide (12 ml) to pH 14 and the corresponding compound was extracted with ethyl acetate. The organic phases were dried with magnesium sulfate, evaporated in vacuo and the resulting crude material was purified by flash chromatography using cyclohexane / ethyl acetate (1/1) to give 1.5 g of a red oil (Intermediate 4.1). Quantity: 1.5 g; Yield: 60%; C5H6N3Cl; HPLC purity: 98%; HPLC: H2O TFA 0.1% -ACN TFA 0.05%): Rt (min); �?% = 0.5 min; 98%; 1H NMR (DMSO-d6) # 6.67 (d, 1H, H5, J = 8 Hz), 6.36 (d, 1H, H4, J = 8 Hz), 5.78 (m, 2H, NH2) , 4.75 (m, 2H, NH2): LC-MS: M / Z ESI: Rt (min) 0.1 min, 144.0 (M + 1).

Intermediate 4.2: 6-Chloro-pyrido [2,3-b] pyrazine (Scheme 10)

6-Chloro-2,3-pyridinadiamine (Intermediate 4.1) (1 g, 6.96 mmol, 1 eq.) Was dissolved in THF (15 ml). Glyoxal (0.84 ml, 18.1 mmol, 2.5 eq.) Was added and the reaction mixture was stirred at t.a. for 2 hours The reaction was followed by RP-HPLC. THF was evaporated, the residue was re-dissolved in ethyl acetate (30 ml). The organic phases were washed twice with saturated Na2CO3 solution, dried over magnesium sulfate and evaporated in vacuo to give 1.15 g of the expected compound as a white solid (Intermediate 4.2). Quantity: 1.15 g; Yield: 100%; Formula: C7H4N3Cl; HPLC purity: 98%; HPLC H2O 0.1% TFA -0.05% TFA NAC): Rt (min); �?% = 1.2 min; 98%; 1H NMR (CDCl3) # 9.0 (s, 1H), 8.88 (s, 1H), 8.36 (d, 1H, J = 8 Hz), 7.67 (d, 1H, J = 8 Hz ); LC-MS: M / Z ESI: Rt (min) 0.68 min, 167.0 (M + 1).

Intermediate 4.3: 6-Vinyl-pyrido [2,3-b] pyrazine (Scheme 10)

The 6-chloropyrido [2,3-b] pyrazine (Intermediate 4.2) (3 g, 18.12 mmol, 1.00 eq.) Was dissolved in THF (150 ml) and degassed with nitrogen at t.a. for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (1.46 g, 1.27 mmol, 0.07 eq.) And vinyltributyl ethannan (7.47 ml, 23.5 mmol, 1.3 eq.) And the mixture of The reaction was stirred at 65 ° C for 3 hours. THF was evaporated and the crude product was purified directly by flash chromatography using cyclohexane / ethyl acetate (8/2) to give 2.3 g of the expected compound (Intermediate 4.3) in the form of an orange oil. Quantity: 2.3 g; Yield: 81%; Formula: C9H7N3; HPLC purity: 98%; HPLC: H2O TFA 0.1% -ACN TFA 0.05%): Rt (min); Rea?% = 1.32 min; 98%; 1H NMR (DMSO-d6) # 9.10 (s, 1H), 8.98 (s, 1H), 8.46 (d, 1H, J = 8 Hz), 7.95 (d, 1H, J = 8 Hz), 6.90 (dd, 1H, Jtrans = 17 Hz, Jcis = 10 Hz), 6.50 (dd, 1H, Jtrans = 17 Hz, Jgem = 1.5 Hz), 5.80 (dd, 1H, Jcis = 10 Hz, Jgem = 1.5 Hz). LC-MS: M / Z ESI: Rt (min) 0.78 min, 158.13 (M + 1).

Intermediate 4.4: Pyrido [2,3-b] pyrazine-6-carbaldehyde (Scheme 9)

The 6-vinylpyrido [2,3-b] pyrazine (Intermediate 4.3) (1 g, 6.37 mmol, 1 eq.) Was dissolved in methanol (20 ml) and cooled to -70 ° C. Then a gentle flow of an oxygen / ozone mixture was bubbled for 20 minutes. The reaction was followed by TLC using cyclohexane / ethyl acetate (8/2). When the reaction was over, dimethyl sulfide (0.1 ml) was added and the reaction was left at t.a. for 30 minutes The methanol was evaporated in vacuo and 600 mg of pyrido [2,3-b] pyrazine-6-carbaldehyde was recovered. The crude material was analyzed without further purification (Intermediate 4.4). Quantity: 0.60 g; Yield: 60%; Formula: C8H5N3O; HPLC purity: 90%; HPLC: H2O TFA 0.1% -ACN TFA 0.05%): Rt (min); �?% = 0.90 min; 90%; 1H NMR (DMSO-d6) # 10.1 (1, 1H), 9.05 (s, 1H), 8.95 (s, 1H), 8.70 (d, 1H, J = 8 Hz), 8 , 20 (d, 1H, J = 8 Hz); LC-MS: M / Z ESI: Rt (min) 0.76 min, 158.13 (M + 1).

Intermediate 5.1: 5-Methyl-2-trimethylsilanyl-furo [3,2-b] pyridine (Scheme 11)

To a degassed solution of 6-iodo-2-picolin-5-ol (855 mg; 3.64 mmol; 1.00 eq.) In triethylamine (20.00 ml) were added (trimethylsilyl) acetylene (1 g; 10 , 19 mmol; 2.80 eq.), Copper iodide (90.07 mg; 0.47 mmol; 0.13 eq.) And dichlorobis (triphenylphosphine) palladium (II) (229.82 mg; 0.33 mmol ; 0.09 eq.). The solution was heated to reflux. After 3 h, the reaction was complete and allowed to cool to t.a. The solution was filtered through Celite (washed with AcOEt and MeOH). The solvents were separated. AcOEt and water were added and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the expected compound. The crude product was purified by short flash chromatography using cyclohexane and then AcOEt / cyclohexane 20/80 to provide 603 mg of the desired compound as a solid (Intermediate 5.1). Amount: 603 mg; Yield: 81%; Formula: C11H15NOSi; HPLC purity: 93.14%; HPLC: H2O TFA 0.1% -ACN TFA 0.05%): Rt (min); Rea?% = 2.17 min; 93.14%; 1H NMR (CDCl3) # 7.65 (d, 1H, J = 8.5 Hz), 7.10 (s, 1H), 7.06 (d, 1H, J = 8.5 Hz), 2.67 (s, 3H), 0.36 (s, 9H); LC-MS: M / Z ESI: Rt (min) 1.89 min, 206.06 (M + 1).

Intermediate 5.2: 2-Trimethylsilanyl-furo [3,2-b] pyridine-5-carbaldehyde (Scheme 11)

To a solution of 5-methyl-2- (trimemethylsilyl) furo [3,2-b] pyridine (Intermediate 5.1) (600 mg; 2.92 mmol; 1 eq.) In 1,2-dichlorobenzene (12 ml) Selenium dioxide (486 mg; 4.38 mmol; 1.5 eq.) was added. The reaction mixture was heated in a microwave at 220 ° C for 6 h. The solution was concentrated in vacuo. Et2O was added and the black solid was filtered. The filtrate was concentrated and purified by flash chromatography using cyclohexane and then cyclohexane / AcOEt 90/10 to provide a solid (Intermediate 5.2). Quantity: 130 mg; Yield: 20%; Formula: C11H13NO2Si; HPLC purity: 81.8%; HPLC H2O 0.1% TFA -0.05% TFA NAC): Rt (min); Rea?% = 3.84 min; 81.83%; 1H NMR (CDCl3) # 10.19 (s, 1H), 7.99 (d, 1H, J = 8.50 Hz), 7.89 (d, 1H, J = 8.50 Hz), 7.27 (s, 1H), 0.40 (s, 9H); LC-MS: M / Z ESI: Rt (min) 1.86 min, 220 (M + 1).

General procedures for the synthesis of intermediate compounds 6 to 16.3:

General procedure I for the substitution with R2NH2 in intermediate compound P5d (Scheme 12):

A solution of 2,6-dibromo-3-nitropyridine (Intermediate 6 of formula P5d in which Hal is Br and R1 is H) (1 eq.), Arylamine (1.0-1.2 eq.) And triethylamine (2 eq.) In ethanol (5 ml / mmol) is stirred for 48 h at room temperature. Filtration of the resulting precipitate provides the respective substitution product with high purity.

General procedure II for reduction (Scheme 12):

A mixture of bromopyridine (1 eq.), Indium powder (3-6 eq.), Saturated aqueous solution of ammonium chloride (8 ml / mmol) and ethanol (20 ml / mmol) is stirred by heating under reflux for 4 h . Filtration through Celite® and the concentration of the vacuum filtrate is followed by basic extraction. The organic layer is dried over sodium sulfate and concentrated in vacuo. The resulting corresponding diaminopyridine is used in the next step without further purification.

General procedure III for cyclization (Scheme 12):

A mixture of diaminopyridine (1 eq.), Formamidine acetate (3-5 eq.) And 2-methoxyethanol (30 ml / mmol) is stirred by heating under reflux for 15 h. The mixture is concentrated in vacuo and purified by chromatography (gradient of EtOAc / hexane) to provide the corresponding bromoimidazo [4,5-b] pyridine.

General procedure IV for coupling (Scheme 12):

A solution of bromoimidazo [4,5-b] pyridine (1 eq.), Tributyl (vinyl) tin (1.5-3 eq.) And tetrakis (triphenylphosphine) palladium (0) (0.1 eq.) In toluene (deoxygenated with N2, 20 ml / mmol ml) is stirred by heating at reflux for 4 h. Concentration in vacuo and chromatographic purification (gradient of EtOAc / hexane) provides the corresponding vinylimidazo [4,5-b] pyridine.

General procedure V for the oxidation of intermediate compound 4 (Scheme 13): resulting is diluted with uniform amounts of water and ethyl acetate. After filtration through Celite®, the organic phase is dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give the respective formylimidazo [4,5-b] pyridine.

5 Intermediate 6: 2,6-dibromo-3-nitropyridine (Scheme 12)

A mixture of commercially available 2,6-dichloro-3-nitropyridine (10.0 g; 51.8 mmol) and 33% by weight HBr / AcOH (120 ml) is heated at 80 ° C for 3 h. The solution is concentrated in vacuo, the resulting residue is taken up in EtOAc and washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated in vacuo. The resulting product 14.4 g (99%) is used without further purification (Compound

10 intermediate 6). GC / MS: 94% purity, tR 7.56 min (tR (MP) 6.93 min), m / z (C5H2Br2N2) 280/282/284 (M, 38), 222/224/226 (35) , 76 (100) Finnegan LCQ.

Intermediate 7.1: 6-Bromo-3-nitro-2-phenylaminopyridine (Scheme 12)

The title compound is obtained from 2,6-dibromo-3-nitropyridine (Intermediate 6) and aniline in a 95% yield following the general procedure I (Intermediate 7.1). GC / MS: 99% purity, tR 9.28 min (tR (MP: nitropyridine) 7.62 min), m / z 293/295 (M, 12), 168 (25), 140 (25), 77 (100) Finnegan LCQ.

Intermediate 7.2: 6-Bromo-N2-phenylpyridine-2,3-diamine (Scheme 12)

The title compound is obtained from N- (5-bromo-2-nitrophenyl) -N-phenylamine (Intermediate 7.1) 20 in 97% yield, following general procedure II. GC / MS: 99% purity, tR 9.69 min (tR (MP) 9.27 min), m / z 263/265 (M, 45), 183 (19), 104 (18), 92 (23 ), 77 (42) Finnegan LCQ.

Intermediate 7.3: 5-Bromo-3-phenyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

The title compound is obtained from 6-bromo-N2-phenylpyridine-2,3-diamine (Intermediate 7.2) in 25 71% yield following the general procedure III. GC / MS: 99% purity, tR 9.23 min (tR (SM) 9.72 min), m / z 273/275 (M, 55), 194 (36), 167 (30), 77 (100 ) Finnegan LCQ.

Intermediate 7.4: 3-Phenyl-5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

The title compound is obtained from 5-bromo-3-phenyl-3H-imidazo [4,5-b] pyridine (Intermediate 7.3) in 92% yield following the general procedure IV. GC / MS: 97% purity, tR 8.94 min (tR (MP) 9.23 min), m / z 221 (M, 100), 77 (58) Finnegan LCQ.

Intermediate 7.5: 3-Phenyl-3H-imidazo [4,5-b] pyridine-5-carbaldehyde (Scheme 13)

The title compound is obtained from 3-phenyl-5-vinyl-3H-imidazo [4,5-b] pyridine (Intermediate 7.4) in 36% yield following the general procedure V. GC / MS: 97 % purity, tR 9.20 min (tR (MP) 9.04 min), m / z 223 (M, 55), 195 (63), 77 (100) Finnegan LCQ.

Intermediate 8.1: 6-Bromo-3-nitro-2- (2,5-dimethoxyphenyl) aminopyridine (Scheme 12)

The title compound is obtained from commercially available 2,6-dibromo-3-nitropyridine and 3,5-dimethoxyaniline in 85% yield following the general procedure I. HPLC (over 10 min MeCN / NaOAc ac 100 mM at 10-85%): 98% purity, tR 10.12 min (tR (MP: nitropyridine) 7.98 min). GC / MS: 99% of

15 purity, tR 10.88 min (tR (MP: nitropyridine) 7.50 min), m / z 253/255 (M, 100), 228 (72), 122 (41), 77 (53) Finnegan LCQ. 1H NMR (400 MHz, DMSO-d6): # 10.04 (s, 1H), 8.42 (d, 1H), 7.19 (d, 1H), 6.94 (s, 2H), 6, 33 (s, 1H), 3.76 (s, 6H) ppm.

Intermediate 8.2: 6-Bromo-N2- (3,5-dimethoxyphenyl) pyridine-2,3-diamine (Scheme 12)

The title compound is obtained from N- (5-Bromo-2-nitrophenyl) -N- (3,5-dimethoxyphenyl) amine (Intermediate 8.1) in 93% yield using general procedure II. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAc): 96% purity, tR 8.38 min (t R (MP) 10.12 min). GC / MS: 97% purity, tR 11.47 min (tR (MP) 10.15 min), m / z 323/325 (M, 100), 310/308 (33), 292/294 (39) Finnegan LCQ.

Intermediate 8.3: 5-Bromo-3- (3,5-dimethoxyphenyl) -3H-imidazo [4,5-b] pyridine (Scheme 12)

The title compound is obtained from 6-Bromo-N2- (3,5-dimethoxyphenyl) pyridine-2,3-diamine (Intermediate 8.2) in 43% yield following general procedure III. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAc): 98% purity, tR 8.51 min (tR (MP) 8.40 min). GC / MS: 98% purity, tR

10.56 min (tR (MP) 11.47 min), m / z 333/335 (M, 79), 207 (100) Finnegan LCQ.

Intermediate 8.4: 3- (3,5-Dimethoxyphenyl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

The title compound is obtained from 5-bromo-3- (3,5-dimethoxyphenyl) -3H-imidazo [4,5-b] pyridine (Compound

5 intermediate 8.3) with 57% yield following the general procedure IV. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAc): 99% purity, tR 8.39 min (tR (MP) 8.51 min). GC / MS: 99% purity, tR 10.36 min (tR (MP) 10.56 min), m / z 281 (M, 100) Finnegan LCQ.

Intermediate 8.5: 3- (3,5-Dimethoxyphenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (Scheme 13)

The title compound is obtained from 3- (3,5-dimethoxyphenyl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Intermediate 8.4) in 56% yield following the general procedure V. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 98% purity, tR 7.26 min (tR (MP) 8.39 min). GC / MS: 99% purity, tR 10.32 min (tR (MP) 10.36 min), m / z 283 (M, 100) Finnegan LCQ.

Intermediate compound 9.1: 5 - [(6-bromo-3-nitro-pyridin-2-yl) amino] indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert-butyl 2,6-dibromo-3-nitropyridine and 5-aminoindoline-1-carboxylate (5-nitroindoline derivative commercially available for protection with N-Boc and subsequent reduction of nitro group with H2 / Pd / C in MeOH / EtOAc) with 97% yield following the general procedure I. HPLC (over 10 min MeCN / 0.1% TFA / 10-85% H2O): 99 % purity, t R 10.35 min (t R (SM: nitropyridine) 6.79 min). 1H NMR

20 (400 MHz, CDCl3): # 10.16 (s, 1H), 8.31 (d, 1H), 7.86 (broad s, 0.4H), 7.49 (s, 1H), 7, 45 (wide s, 0.6H), 7.31 (d, 1H), 6.92 (d, 1H), 4.03 (wide t, 2H), 3.14 (t, 2H), 1.56 (s, 9H) ppm. MS (ESI) m / z (C18H19O4BrN4) 435.2 / 437.1 (M + 1, 100) Finnegan LCQ.

Intermediate 9.2: 5 - [(3-amino-6-bromopyridin-2-yl) amino] indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert-butyl 5 - [(5-bromo-2-nitrophenyl) amino] indoline-1-carboxylate (Intermediate 9.1) in 96% yield following general procedure II. HPLC (over 10 5 min MeCN / 10-85% 100 mM aq. NaOAC): 98% purity, tR 9.86 min (t R (MP) 11.66 min). MS (ESI) m / z (C18H21BrN4O2) 405.1 / 407.0 (M + 1, 100), 349.1 / 351.1 (82) Finnegan LCQ.

Intermediate 9.3: 5- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert-butyl 5 - [(3-amino-6-bromopyridin-2-yl) amino] indoline-1-carboxylate (Intermediate 9.2) in 91% yield following the general procedure III . HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 97% purity, tR 10.08 min (tR (MP) 9.85 min). MS (ESI) m / z (C19H19BrN4O2) 415.0 / 416.9 (M + 1, 91), 359.1 / 361.0 (100), 315.1 / 317.2 (51) Finnegan LCQ.

Intermediate compound 9.4: 5- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert-butyl 5- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate (intermediate Compound 9.3) in 94% yield following the general procedure IV. HPLC (over 10 min MeCN / 0.1% TFA / 10-85% H2O): 96% purity, tR 7.21 min (tR (MP) 8.51 min). 1H NMR (400 MHz, CDCl3) # 8.21 (s, 1H), 8.04 (d, 1H), 7.98 (broad s, 0.5H), 7.56 (s, 1H), 7, 55 (wide s, 0.5H), 7.48 (d, 1H), 7.35 (d,

1H), 6.89 (dd, 1H), 6.19 (d, 1H), 5.42 (d, 1H), 4.05 (t, 2H), 3.18 (t, 2H), 1 , 55 (s, 9H) ppm.

Intermediate 9.5: 5- (5-formyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylic acid tert-butyl ester (Scheme 13)

The title compound is obtained from tert-butyl 5- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate (Intermediate 9.4) in 69% yield following the general procedure V. HPLC (over 10 min MeCN / 0.1% TFA / 10-85% H2O): 96% purity, tR 7.31 min (tR (MP) 7.21 min) .

Intermediate 10.1: 3- (2,3-dihydro-1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

A mixture of tert-butyl 5- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate (Intermediate 9.4) (9.50 g, 26.21 mmol ) (intermediate 9.4), 4M HCl in 1,4-dioxane (200 ml), 2-propanol (30 ml) and dioxane (50 ml) is stirred for 1.5 h at room temperature. The mixture is concentrated to dryness to provide 9.50 10 g (98% yield) of the trihydrochloride salt of the corresponding free amine. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 6.64 min (t R (MP) 10.06 min). 1H NMR (400 MHz, methanold4) # 9.97 (s, 1H), 8.34 (d, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.85 (d , 1H), 7.82 (d, 1H), 7.63 (m, 1H), 7.54 (m, 1H), 6.98 (dd, 1H), 6.37 (d, 1H), 5 , 63 (d, 1H), 4.02 (t, 2H), 3.52 (t, 2H) ppm. MS (ESI) m / z (C16H14N4) 263.2 (M + 1, 100), 219.2

(32) Finnegan LCQ.

Intermediate 10.2: 3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

A mixture of 3- (2,3-dihydro-1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Intermediate 10.1) (150.0 mg, 0.57 mmol), glacial acetic acid (39.3 μl, 0.69 mmol), N-ethyl-N ′ - (3-dimethylaminopropyl) carbodiimide hydrochloride (175.4 mg, 0.91 mmol), 4-dimethylaminopyridine 419, 2 mg, 3.43 mmol) and dichloromethane (10 ml) is stirred for 24 h

20 room temperature. The mixture is successively extracted with saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 139.1 mg (80%) of the respective amide. HPLC (over 10 min MeCN / 1085% 100 mM aq. NaOAC): 99% purity, tR 6.43 min (tR (MP) 6.64 min). GC / MS: 96% purity, tR 13.98 min, m / z 304 (M, 58), 262 (100), 207 (62) Finnegan LCQ.

Intermediate 10.3: 3- (1-Acetyl-2,3-dihydro-1 H -indole-5-yl) -3 H -imidazo [4,5-b] pyridine-5-carbaldehyde (Scheme 13)

The title compound is obtained from 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Intermediate 10.2) with 44% yield following the general procedure V. HPLC (over 10 30 min MeCN / NaOAC 100 mM at 10-85%): 95% purity, tR 5.38 min (tR (MP ) 6.43 min). GC / MS: tR 14.98 min (tR (MP)

25 13.98 min), m / z 306 (M, 60), 264 (100) Finnegan LCQ.

Intermediate 11.1: N, N-dimethyl-N- {4-oxo-4- [5- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) -2,3-dihydro- 1H-indole-1yl] butyl} amine (Scheme 12)

A mixture of 3- (2,3-dihydro-1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (48.0 mg, 0.14 mmol) (Intermediate 10.1), 4- (dimethylamino) butyric acid hydrochloride (36.3 mg, 0.21 mmol), N-ethyl-N ′ hydrochloride - (3dimethylaminopropyl) carbodiimide (54.9 mg, 0.29 mmol), 4 -dimethylaminopyridine (122.5 mg, 1.00 mmol) and dichloromethane (8 ml) is stirred for 24 h at room temperature. The mixture is successively extracted with saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 50.4 mg (94%) of the respective amide. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 92% purity, tR 6.27 min (t R (MP) 6.61 min).

Intermediate 11.2: 3- {1- [4- (dimethylamino) butanoyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5carbaldehyde (Scheme 13)

The title compound is obtained from N, N-dimethyl-N- {4-oxo-4- [5- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) - 2,3-dihydro-1-indole-1-yl] butyl} amine (Intermediate 11.1) in 45% yield following the general procedure V. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC). : 94% purity, tR 5.02 min (tR (MP) 6.27 min).

Intermediate 12.1: 3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

A solution of 3- (2,3-dihydro-1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (2.53 g, 9.64 mmol) (Intermediate 10.1), methanesulfonyl chloride (1.12 ml, 14.47 mmol) and triethylamine (2.94 ml, 21.22 mmol) in dichloromethane (50 ml) is stirred for 30 min at room temperature. The mixture is successively extracted with saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 3.24 g (99%) of the respective sulfonamide. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 92% purity, tR 7.16 min (t R (MP) 6.64 min). MS (ESI) m / z (C17H16N4O2S) 341.1 (M + 1, 100) Finnegan LCQ.

Intermediate 12.2: 3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (Scheme 13)

The title compound is obtained from 3- [1- (methylsulfonyl) -2,3-dihydro1H-indol-5-yl] -5-vinyl-3H-imidazo [4,5b] pyridine (Intermediate 12.1) with 60% yield following the general procedure V. HPLC (over 10 min MeCN / NaOAC 100 mM at 10-85%): 98% purity, tR 6.13 min (tR (MP) 7, 16 min)

Intermediate 13.1: 3- {1 - [(chloromethyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

A solution of 3- (2,3-dihydro-1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (2.57 g, 9.80 mmol) (Compound intermediate 10.1), chloromethanesulfonyl chloride (2.00 ml, 19.59 mmol) and N, N-diisopropylethylamine (11.98 ml, 68.58 mmol) in dichloromethane (100 ml) is stirred for 20 min at room temperature. The mixture is successively extracted with saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 3.61 g (98%) of the sulfonamide.

15 respectively. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 92% purity, tR 8.05 min (t R (MP) 6.64 min). 1H NMR (400 MHz, DMSO-d6) # 9.03 (s, 1H), 8.22 (d, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.56 (m, 2H), 6.93 (dd, 1H), 6.25 (d, 1H), 5.50 (d, 1H), 5.41 (s, 2H), 4.21 (t, 2H) , 3.28 (t, 2H) ppm. MS (ESI) m / z (C17H15ClN4O2S) 375.0 (M + 1, 100) Finnegan LCQ.

Intermediate compound 13.2: 3- {1 - [(chloromethyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5carbaldehyde (Scheme 13)

The title compound is obtained from 3- {1 - [(chloromethyl) sulfonyl] -2,3-dihydro1H-indol-5-yl} -5-vinyl-3Himidazo [4,5-b] pyridine (Compound intermediate 13.1) with 86% yield following the general procedure V. HPLC (over 10 min MeCN / NaOAC 100 mM at 10-85%): 97% purity, tR 7.03 min (tR (MP ) 8.05 min). MS

25 (ESI) m / z (C16H13ClN4O3S) 377.0 (M + 1, 100) Finnegan LCQ.

Intermediate 14.1: 3- {1 - [(3-chloropropyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

A solution of 3- (2,3-dihydro1H-indol-5-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (270 mg, 1.03 mmol) (Intermediate 10.1), chloride of 3-chloropropanesulfonyl (0.25 ml, 2.06 mmol) and N, N-diisopropylethylamine (1.08 ml, 6.18 mmol) in dichloromethane (15 ml) is stirred for 10 min at room temperature. The mixture is successively extracted with saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 351 mg (85%) of the respective sulfonamide. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 92% purity, tR 8.44 min (tR (MP) 6.59 min). MS (ESI) m / z (C19H19ClN4O2S) 403.0 (M, 100), 294.9 (65) Finnegan LCQ.

Intermediate 14.2: 3- {1 - [(3-morpholin-4-ylpropyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -5-vinyl-3H-imidazo [4,5b] pyridine (Scheme 12)

A mixture of 3- {1 - [(3-chloropropyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -5-vinyl-3H-imidazo [4,5-b] pyridine (Intermediate 14.1) (351 mg, 0.87 mmol), morpholine (0.46 ml, 5.23 mmol), potassium iodide (144.6 mg, 0.87 mmol) and N, N-dimethylformamide (10 ml) is stir for 24 h at room temperature. The mixture is extracted with saturated aqueous ammonium chloride solution and the organic layer is dried over sodium sulfate. Concentration under vacuum provides 382 mg (97%) of the respective morpholino derivative. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 91% purity, tR 8.44 min (tR (MP) 8.44 min). 1H NMR (400 MHz, CDCl3) # 8.32 (s, 1H), 8.09 (d, 1H), 7.68 (s, 1H), 7.55 (m, 2H), 7.41 (d , 1H), 6.90 (dd, 1H), 6.22 (d, 1H), 5.48 (d, 1H), 4.14 (t, 2H), 3.70 (m, 4H), 3 , 40-3.18 (m, 8H), 2.36 (m, 2H) ppm. MS (ESI) m / z (C23H27N5O3S) 454.0 (M, 10) Finnegan LCQ.

Intermediate 14.3: 3- {1 - [(3-morpholin-4-ylpropyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5carbaldehyde (Scheme 13)

The title compound is obtained from 3- {1 - [(3-morpholin-4-ylpropyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -5-vinyl3H-imidazo [4 , 5-b] pyridine (Intermediate 14.2) with 82% yield following the general procedure

V. HPLC (over 10 min MeCN / NaOAC 100 mM at 10-85%): tR 7.55 min (tR (MP) 8.44 min). MS (ESI) m / z (C22H25N5O4S) 456.1 (M + 1, 100) Finnegan LCQ.

Intermediate compound 15.1: 6 - [(5-bromo-2-nitrophenyl) amino] indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert-butyl 2,6-dibromo-3-nitropyridine and 6-aminoindoline-1-carboxylate (obtained from commercially available 6-nitroindoline for protection with N-Boc and subsequent reduction of the nitro group with H2 / Pd / C in MeOH / EtOAc) with 51% yield following the general procedure

I. HPLC (over 10 min MeCN / 0.1% TFA / 10-85% H2O): 99% purity, tR 10.45 min (t R (SM: nitropyridine) 7.98 min). MS (ESI) m / z (C18H19O4BrN4) 435.2 / 437.1 (M + 1, 100) Finnegan LCQ.

Intermediate compound 15.2: 6 - [(3-amino-6-bromopyridin-2-yl) amino] indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert-butyl 6 - [(5-bromo-2-nitrophenyl) amino] indoline-1-carboxylate (Intermediate 15.1) in 98% yield following general procedure II. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 9.72 min (t R (MP) 11.38 min). MS (ESI) m / z (C18H21BrN4O2) 426.8 / 428.9 (M + Na +, 87), 405.1 / 407.0 (M + H +, 23), 349.1 / 351.0 (100) , 305.1 / 307.1 (56) Finnegan LCQ.

Intermediate 15.3: 6- (5-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert-butyl 6 - [(3-amino-6-bromopyridin-2-yl) amino] indoline-1-carboxylate (Intermediate 15.2) in 76% yield following general procedure III. HPLC (throughout

20 of 10 min MeCN / NaOAC ac. 100 mM at 10-85%): 99% purity, tR 9.78 min (tR (MP) 9.72 min). MS (ESI) m / z (C19H19BrN4O2) 415.0 / 416.9 (M + 1, 74), 359.1 / 361.0 (100), 315.1 / 317.2 (51) Finnegan LCQ.

Intermediate 15.4: 6- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylic acid tert-butyl ester (Scheme 12)

The title compound is obtained from tert 6- (5-bromo-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate

25 butyl (Intermediate 15.3) with 69% yield following the general procedure IV. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 9.76 min (tR (MP) 9.78 min). MS (ESI) m / z (C21H21N4O2) 363.0 (M + 1, 100), 307.0 (92) Finnegan LCQ.

Intermediate 15.5: 6- (5-formyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate tert-butyl (Scheme 13)

The title compound is obtained from tert-butyl 6- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate (Intermediate 15.4) in 95% yield following the general procedure V. HPLC (over 10 min MeCN / NaOAC 100 mM at 10-85%): 88% purity, tR 8.61 min (tR (MP) 9.76 min). MS (ESI) m / z (C20H20N4O3) 365.1 (M + 1, 100) Finnegan LCQ.

Intermediate 16.1: 3- (2,3-dihydro-1H-indole-6-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

A mixture of tert-butyl 6- (5-vinyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate (4.90 g, 13.52 mmol)

10 (Intermediate 15.3), 4M HCl in 1,4-dioxane (200 ml), 2-propanol (30 ml) and dioxane (50 ml) is stirred for 1 h at room temperature. The mixture is concentrated to dryness to provide 4.00 g (99% yield) of the monohydrochloride salt of the corresponding free amine. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 7.06 min (tR (MP) 9.78 min). MS (ESI) m / z (C16H14N4) 263.3 (M + 1, 100) Finnegan LCQ.

Intermediate 16.2: 3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-6-yl] -5-vinyl-3H-imidazo [4,5-b] pyridine (Scheme 12)

A solution of 3- (2,3-dihydro-1H-indol-6-yl) -5-vinyl-3H-imidazo [4,5-b] pyridine (Intermediate 16.1) (1.10 g, 4.19 mmol), methanesulfonyl chloride (0.65 ml, 8.39 mmol) and triethylamine (3.49 ml, 25.16 mmol) in dichloromethane

20 (50 ml) is stirred for 15 min at room temperature. The mixture is successively extracted with saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 1.40 g (98%) of the respective sulfonamide. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 7.03 min (tR (MP) 7.06 min). MS (ESI) m / z (C17H16N4O2S) 341.0 (M + 1, 100) Finnegan LCQ.

Intermediate 16.3: 3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-6-yl] -3H-imidazo [4,5-b] pyridine-5-carbaldehyde (Scheme 13)

The title compound is obtained from 3- [1- (methylsulfonyl) -2,3-dihydro1H-indol-6-yl] -5-vinyl-3H-imidazo [4,5b] pyridine (Intermediate 16.2) with 99% yield following the general procedure V. HPLC (at

30 long 10 min MeCN / NaOAC ac. 100 mM at 10-85%): 93% purity, tR 6.09 min (tR (MP) 7.03 min). MS (ESI) m / z (C16H14N4O3S) 343.0 (M + 1, 100) Finnegan LCQ.

Example 1: Potassium salt of (5Z) -5 - {[4- (1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1,3-thiazolidine-2,4dione ( 1) (Scheme 2)

A mixture of 2,4-thiazolidinedione (3.4 g; 29.1 mmol; 1.80 eq.), Pyrrolidine (269.80 µl; 3.2 mmol; 0.2 eq.) In MeOH

5 (50 ml) was heated to 70 ° C. A solution of 4- (1-piperidinyl) pyrido [3,2-d] pyrimidine-6carbaldehyde (Intermediate 1.7) (3.9 g; 16.2 mmol; 1 eq.) In MeOH (50 ml) was added slowly over 1.5 hours at 70 ° C. After 2 h heating at reflux after the addition, the reaction was complete. A precipitate formed. The hot reaction mixture was filtered and the solid was washed with cold MeOH to give the (5Z) -5 - {[4- (1piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1, 3-thiazolidine-2,4-dione (1) (2.70 g; 48%) as an orange solid

10 with 98% purity by HPLC.

(5Z) -5 - {[4- (1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1,3-thiazolidine-2,4-dione (2.7 g; 8.1 mmol; 1 eq.) Was suspended in THF (80 ml) and water (80 ml). Potassium hydroxide (16.2 ml; 0.50 M; 8.1 mmol; 1 eq.) Was added and the solution was filtered through cotton and rinsed with water. After lyophilization, the potassium salt of (5Z) -5 {[4- (1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1,3-thiazolidine-2,4 -diona (1) (3.06 g, 98%) was isolated as a

15 yellow solid with 99.36% purity by HPLC. Quantity: 3.06 g; Yield: 99%; Melting point: 319 ° C; Formula: C16H14O2SN5K; IR (only) (3355.1, 2932.9, 2852.7, 1674.1, 1519.6 cm − 1; 1 H NMR (DMSO-d6) # 1.68 (s1, 6H), 4.34 (s1 , 4H), 7.44 (s, 1H), 7.93 (d, J = 9 Hz, 1H), 8.04 (d, J = 9 Hz, 1H), 8.45 (s, 1H); HPLC H2O 0.1% TFA -0.05% TFA NAC): Rt (min); �?% = 2.07; 99.10; LC-MS: M / Z ESI: Rt (min) 1.36; 342.04 (M + 1); 340.08 (M − 1).

Example 2: (5Z) -5 - {[4- (4-fluoro-1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1,320 thiazolidine-2,4 potassium salt -diona (2) (Scheme 2)

The title compound was obtained following the general procedure described for Example 1, using intermediate 2.1, 4- (4-fluoro-piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6-carbaldehyde. After lyophilization, the potassium salt of (5Z) -5 - {[4- (4-fluoro-1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1, 3-thiazolidine-2,4

Dione (2) in the form of an orange solid with 98.8% HPLC purity; Formula: C16H13FO2SN5.K; 1H NMR (DMSOd6) # 1.86 (m, 2H), 2.07 (m, 2H), 4.39 (m, 4H), 5.00 (m, 1H), 7.44 (s, 1H) , 7.97 (d, J = 9 Hz, 1H), 8.07 (d, J = 9 Hz, 1H), 8.50 (s, 1H); HPLC (0.1% TFA H2O -0.05% TFA ACN). Rt (min); Rea?% = 1.92; 98.76; LC-MS: M / Z ESI: Rt (min) 1.27; 360.07 (M + 1); 358.07 (M-1).

Example 3: Potassium salt of (5Z) -5 - ({4- [4- (trifluoromethyl) -1-piperidinyl] pyrido [3,2-d] pyrimidin-6-yl} methylene) -1,330 thiazolidine-2 , 4-dione (3) (Scheme 2)

The title compound was obtained following the general procedure described for Example 1, using intermediate 3.1, 4- (4- (trifluoromethyl) -piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6- carbaldehyde After lyophilization, the potassium salt of (5Z) -5 - ({4- [4- (trifluoromethyl) -1-piperidinyl] pyrido [3,2-d] pyrimidin-6-yl} methylene) was isolated 1 , 3-thiazolidine-2,4-dione (3) in the form of an orange solid with 99.5% HPLC purity; Formula: C17H13O2SF3N5.K; 1H NMR (DMSO-d6) # 1.39 (m, 2H), 1.76 (m, 2H), 2.59 (m, 1H), 3.05 (m, 2H), 5.44 (m, 2H), 7.24 (s, 1H), 7.76 (d, J = 9 Hz, 1H), 7.87 (d, J = 9 Hz, 1H), 8.30 (s, 1H); HPLC (0.1% H2O TFA -0.05% TFA ACN): Rt (min); �?% = 244; 80.47; LC-MS: M / Z ESI: Rt (min) 1.55; 410.09 (M + 1); 408.09 (M − 1).

Example 4: 5-Pyrido [2,3-b] pyrazin-6-ylmethylene-thiazolidine-2,4-dione (4) (Scheme 3)

Pyrido [2,3-b] pyrazine-6-carbaldehyde (Intermediate 4.4) (300 mg, 1.89 mmol, 1 eq.), 2,5-thiazolidinedione (397 mg, 3.4 mmol, 1.8 eq.) and pyrrolidine (0.03 ml, 0.38 mmol, 0.2 eq.) were heated in methanol (10 ml) for 3 h at 65 ° C. When the reaction was over, water (3 ml) was added and the corresponding brown precipitate was filtered off, washed with methanol, water and then diethyl ether to give 200 mg of the expected pure compound (4). From the free base (200 mg, 0.78 mmol, 1 eq.), A potassium salt was synthesized using KOH (1 M, V = 0.78 ml, 1 eq.) To give 231 mg of the corresponding potassium salt Amount: 231 mg (potassium salt); Yield: 41%; Formula: C11H6O2SN4.K; HPLC purity: 98.7%; HPLC H2O 0.1% TFA -0.05% TFA NAC): Rt (min); Rea?% = 1.89 min; 98.7%; 1H NMR (DMSO-d6) # 9.09 (s, 1H), 8.95 (s, 1H), 8.46 (d, 1H, J = 8 Hz), 8.02 (d, 1H, J = 8 Hz), 7.52 (s, 1H): LC-MS: M / Z ESI: Rt (min) 0.76 min, 259.07 (M + 1).

Example 5: 5-Furo [3,2-b] pyridin-5-ylmethylene-thiazolidine-2,4-dione (5) (Scheme 4)

A solution of 2- (trimethylsilyl) furo [3,2-b] pyridine-5-carbaldehyde (Intermediate 5.2) (130 mg; 0.59 mmol; 1 eq.), 2,4-thiazolidinedione (125 mg; 1 , 07 mmol; 1.8 eq.) And beta-alanine (95 mg; 1.07 mmol; 1.8 eq.) In acetic acid (2 ml) was heated at 100 ° C for 7 h. Water was added and the precipitate was filtered and washed with Et2O to provide a solid (purity: 98.14%, yield: 25%). Then, the (5Z) -5 - {[2- (trimethylsilyl) furo [3,2-b] pyridin-5yl] methylene} -1,3-thiazolidine-2,4-dione (41 mg; 0, 13 mmol; 1 eq.) In MeOH (5 ml). NaOH (5 N aqueous) (150.00 µl) was added. The solution was stirred at t.a. After 24 hours the reaction was complete. AcOH (1 ml) was added and the solution was concentrated in vacuo. Water was added and the precipitate was filtered, washed with water, Et2O and MeOH to provide a solid (5). From the free base (24 mg, 0.097 mmol, 1 eq.) A potassium salt was synthesized using KOH (1 M, V = 0.097 ml, 1 eq.) Providing 24 mg of the corresponding potassium salt. Quantity: 24 mg (potassium salt); Yield: 75%; Formula: C11H6N2O3S.K; HPLC purity: 98.03%; HPLC (0.1% TFA H2O -0.05% TFA ACN). Rt (min); Rea?% = 2.96 min; 98.03%; 1H NMR (DMSO-d6) # 8.30 (s, 1H), 8.00 (d, 1H, J = 9 Hz), 7.51 (d, 1H, J = 9 Hz), 7.37 (s , 1H), 7.13 (s, 1H); LC-MS: M / Z ESI: Rt (min) 1.31 min, 246.95 (M + 1).

Example 6: 5- [4- (4-Fluoro-piperidin-1-yl) -pyrido [3,2-d] pyrimidin-6-ylmethylene] -2-thioxo-thiazolidin-4-one (Scheme 2)

The title compound was obtained following the general procedure described for Example 1, using rodanin (instead of thiazolidinedione) and intermediate 2.1, 4- (4-fluoro-piperidin-1-yl) -pyrido [3,2- d] pyrimidine-6 carbaldehyde. After lyophilization, the potassium salt of 5 - [(4- (4-fluoro-piperidin-1-yl) -pyrido [3,2d] pyrimidin-6-ylmethylene] -2-thioxo-thiazolidin-4 was isolated -one (6) in the form of an orange solid with 95.5% HPLC purity; Formula: C16H13FOS2N5.K; 1H NMR (DMSO-d6) # 1.89 (m, 4H), 4.42 (m, 4H), 5.00 (m, 1H), 7.29 (s, 1H), 8.07 (d, J = 9 Hz, 2H), 8.52 (s, 1H); HPLC H2O TFA at 0, 1% -05% TFA NAC): Rt (min); Rea?% = 2.37 min; 95.54%; LC-MS: M / Z ESI: Rt (min) 1.38 min; 376.11 (M + 1); 374.11 (M-1).

Example 7: (5Z) -5 - [(3-phenyl-3H-imidazo [4,5-b] pyridin-5-yl) methylene] -1,3-thiazolidine-2,4-dione (Scheme 5)

The title compound was obtained from 3-phenyl-3H-imidazo [4,5-b] pyridine-5-carbaldehyde in 55% yield following the general procedure described for Example 1. HPLC (over 10 min. MeCN / 10-85% 100 mM aq. NaOAC): 96% purity, Rt 4.95 min. MS (ESI) m / z (C16H10N4O2S) 361.2 (M + K +, 100). 1H NMR (JEOL 400 MHz, DMSO-d6): # 8.97 (s, 1H), 8.23 (d, 1H), 8.13 (d, 2H), 7.70-7.45 (m, 5H).

Example 8: Preparation of (5Z) -5 - {[3- (3,5-dimethoxyphenyl) -3H-imidazo [4,5-b] pyridin-5-yl] methylene} -1,3 thiazolidine-2, 4-diona (Scheme 5)

The title compound is obtained from 3- (3,5-dimethoxyphenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde in 85% yield following the general procedure VI. HPLC (over 10 min MeCN / NaOAC ac. 100 mM at 10

20 85%): 96% purity, tR 5.12 min (tR (MP) 7.26 min). 1H NMR (JEOL 400 MHz, DMSO-d6): # 8.90 (s, 1H), 8.16 (d, 1H), 7.58 (d, 1H), 7.41 (s, 1H), 7 , 24 (s, 2H), 6.60 (s, 1H), 3.87 (s, 6H).

Example 9: 5- {5 - [(Z) - (2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -3H-imidazo [4,5-b] pyridin-3-yl} indoline -1-tert-butyl carboxylate (Scheme 5)

The title compound is obtained from tert-butyl 5- (5-formyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate in 65% yield following the general procedure VI. HPLC (over 10 min MeCN / 0.1% TFA / 10-85% H2O): 94% purity, tR 6.50 min (tR (MP) 7.31 min). 1H NMR (JEOL 400 MHz, DMSO-d6) # 8.89 (s, 1H), 8.17 (s, 1H), 8.12 (d, 1H), 7.92 (wide s, 0.5H) , 7.88 (s, 1H), 7.59 (wide s, 0.5H), 7.58 (d, 1H), 7.28 (d, 1H), 4.06 (wide t, 2H), 3.24 (t, 2H), 1.54 (s, 9H) ppm. MS (ESI) m / z (C23H20N5O4S) 464.1 (M + 1, 100), 408.1 (60) Finnegan LCQ.

Example 10: (5Z) -5 - {[3- (2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-yl] methylene} -1, 3-thiazolidine-2,4-dione (Scheme 5)

A mixture of 5- {5 - [(Z) - (2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -3H-imidazo [4,5-b] pyridin-3-yl} indoline -1-tert-butyl carboxylate (35.0 mg, 75.5 mmol) (Example 9), 4M HCl in 1,4-dioxane (3 ml) and 2-propanol (1 ml) is stirred for 1, 5 h at room temperature. The mixture is concentrated to dryness, washed with water and dried under vacuum to provide 27.3 mg (89% yield) of the monohydrochloride salt of the corresponding free amine. HPLC

15 (over 10 min MeCN / NaOAC 100 mM at 10-85%): 98% purity, tR 4.44 min (tR (MP) 6.23 min). 1H NMR (JEOL 400 MHz, DMSO-d6) # 9.03 (s, 1H), 8.33 (d, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7, 91 (d, 1H), 7.75 (d, 1H), 7.34 (d, 1H), 3.97 (wide s, 4H), 3.74 (t, 2H), 3.22 (t, 2H) ppm. MS (ESI) m / z (C18H13N5O2S) 364.1 (M + 1, 100), 329.2 (21) Finnegan LCQ.

Example 11: (5Z) -5 - {[3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-yl] methylene } -1,3-thiazolidine20 2,4-dione (Scheme 5)

The title compound is obtained from 3- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridine-5carbaldehyde (intermediate compound 10.3) with 55% yield following the general procedure VI. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 4.46 min (t R (MP) 5.38 min). 1H NMR

25 (JEOL 400 MHz, DMSO-d6, 65 ° C) # 12.23 (wide s, 1H), 8.89 (s, 1H), 8.27 (d, 1H), 8.22 (wide s, 1H) , 7.93 (s, 1H), 7.90 (s, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 4.23 (t, 2H), 3.29 ( t, 2H), 2.23 (s, 3H) ppm. MS (ESI) m / z (C20H15N5O3S) 406.3 (M + 1, 100) Finnegan LCQ.

Example 12: (5Z) -5 - [(3- {1- [4- (dimethylamino) butanoyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridin-5il) methylene] -1,3-thiazolidine-2,4-dione

The title compound is obtained from 3- {1- [4- (dimethylamino) butanoyl] -2,3-dihydro-1H-indole-5-yl} -3H

5 imidazo [4,5-b] pyridine-5-carbaldehyde (intermediate 11.2) in 78% yield following the general procedure VI. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 98% purity, tR 4.14 min (t R (MP) 5.02 min). 1H NMR (JEOL 400 MHz, DMSO-d6) # 8.94 (s, 1H), 8.28 (d, 1H), 8.22 (d, 1H), 7.98 (s, 1H), 7, 76 (wide s, 3H), 4.23 (t, 2H), 3.45 (wide s, mH), 3.31 (t, 2H), 2.71 (t, 2H), 2.59 (t , 2H), 2.52 (s, 6H), 1.88 (m, 2H) ppm. MS (ESI) m / z (C24H24N6O3S) 477.1 (M + 1, 100), 432.2 (49), 272.3 (19), 260.4 (21) Finnegan LCQ.

Example 13: (5Z) -5 - ({3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridin-5- il} methylene) -1,3 thiazolidine-2,4-dione (Scheme 5)

The title compound is obtained from 3- [1- (methylsulfonyl) -2,3-dihydro1H-indol-5-yl] -3H-imidazo [4,5-b] pyridine-5carbaldehyde (intermediate compound 12.2) with 62% yield following the general procedure VI. HPLC (a

15 over 10 min MeCN / NaOAC ac. 100 mM at 10-85%): 99% purity, tR 4.80 min (tR (MP) 6.13 min). 1H NMR (JEOL 400 MHz, DMSO-d6) # 8.97 (s, 1H), 8.32 (d, 1H), 7.96 (s, 2H), 7.87 (d, 1H), 7, 74 (d, 1H), 7.45 (d, 1H), 4.09 (t, 2H), 3.28 (t, 2H), 3.10 (s, 3H) ppm. MS (ESI) m / z (C19H15N5O4S2) 442.1 (M + 1, 100), 363.0 (27), 291.3 (22).

Example 14: Preparation of (5Z) -5 - [(3- {l1 - [(chloromethyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5b] pyridin -5-yl) methylene] -1,3-thiazolidine-2,4-dione (Scheme 5)

The title compound is obtained from 3- {1 - [(chloromethyl) sulfonyl] -2,3-dihydro1H-indol-5-yl} -3H-imidazo [4,5b] pyridine-5-carbaldehyde (intermediate compound 13.2) with 60% yield following the general procedure

SAW. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 5.37 min (t R (MP) 7.03 min).

1H NMR (JEOL 400 MHz, DMSO-d6) # 8.92 (s, 1H), 8.31 (d, 1H), 7.98 (d, 2H), 7.88 (d, 1H), 7, 75 (d, 1H), 7.52 (d, 1H), 25 5.38 (s, 2H), 4.22 (t, 2H), 3.30 (t, 2H) ppm. MS (ESI) m / z (C19H14ClN5O4S2) 477.0 (M + 1, 100) Finnegan LCQ.

Example 15: (5Z) -5 - [(3- {1 - [(3-morpholin-4-ylpropyl) sulfonyl] -2,3-dihydro-1H-indole-5-yl} -3H-imidazo [4, 5-b] pyridin-5il) methylene] -1,3-thiazolidine-2,4-dione (Scheme 5)

The title compound is obtained from 3- {1 - [(3-morpholin-4-ylpropyl) sulfonyl] -2,3-dihydro-1H-indole-5-yl} -3H

5 imidazo [4,5-b] pyridine-5-carbaldehyde in 39% yield following the general procedure VI. HPLC (over 10 min MeCN / NaOAC 100 mM at 10-85%): tR 5.50 min (tR (MP) 7.55 min). 1H NMR (JEOL 400 MHz, DMSO-d6) # 8.93 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.85 (d, 1H), 7, 66 (d, 1H), 7.56 (s, 1H), 7.42 (d, 1H), 4.13 (t, 2H), 3.74 (m, 2H), 3.50-3.20 (m, 12H), 2.18 (m, 2H) ppm. MS (ESI) m / z (C23H27N5O3S) 454.0 (M, 10) Finnegan LCQ.

Example 16: 6- {5 - [(Z) - (2,4-dioxo-1,3-thiazolidin-5-ylidene) methyl] -3H-imidazo [4,5-b] pyridin-3-yl} indoline -110 tert-butyl carboxylate (Scheme 5)

The title compound is obtained from tert-butyl 6- (5-formyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate in 22% yield following the general procedure VI. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 6.49 min (tR (MP) 8.61 min). 1H NMR (JEOL 400 MHz, DMSO-d6) # 8.87 (s,

15 1H), 8.24 (d, 1H), 8.02 (broad d, 1H), 7.74 (d, 1H), 7.72 (s, 1H), 7.50 (wide s, 1H) , 7.41 (d, 1H), 4.05 (t, 2H), 3.20 (t, 2H), 1.45 (s, 9H) ppm. MS (ESI) m / z (C23H20N5O4S) 464.0 (M + 1, 100), 408.1 (42) Finnegan LCQ.

Example 17: (5Z) -5 - ({3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-6-yl] -3H-imidazo [4,5-b] pyridin-5-yl } methylene) -1,3 thiazolidine-2,4-dione (Scheme 5)

The title compound is obtained from 3- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-6-yl] -3H-imidazo [4,5-b] pyridine-5-carbaldehyde with 29% of performance following the general procedure VI. HPLC (over 10 min MeCN / 10-85% 100 mM aq. NaOAC): 99% purity, tR 4.68 min (t R (MP) 6.09 min). 1H NMR (JEOL 400 MHz, DMSO-d6) # 8.87 (s, 1H), 8.17 (d, 1H), 7.82 (d, 1H), 7.65-7.50 (m, 3H ), 7.42 (s, 1H), 4.09 (t, 2H), 3.24 (t, 2H), 3.15 (s, 3H) ppm. MS (ESI) m / z (C19H15N5O4S2) 442.0 (M + 1, 100), 362.8 (21) Finnegan LCQ.

25 Example 18: Biological tests

The compounds of the present invention can be subjected to the following tests:

a) High performance PI3K lipid kinase assay (binding assay):

The efficacy of the compounds of the invention in the inhibition of lipid phosphorylation induced by PI3K can be tested in the following binding assay.

The assay combines the technology of the proximity scintillation assay (SPA, Amersham) with the ability of neomycin (a polycationic antibiotic) to bind phospholipids with high affinity and specificity. The proximity scintillation assay is based on the properties of weakly emitting isotopes (such as 3H, 125I, 33P). The coating of SPA beads with neomycin allows the detection of phosphorylated lipid substrates after incubation with recombinant PI3K and radioactive ATP in the same well, capturing radioactive phospholipids in SPA beads for their specific binding to neomycin.

In a 384-well MTP plate containing 5% 1 of the test compound of formula (I) (solubilized with 6% DMSO; test compound 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001 μM), the following test components are added. 1) 5 μl (58 ng) of recombinant human GST-PI3K∃ (in 40 mM Hepes, pH 7.4, 1 mM DTT and 5% ethylene glycol), 2) 10% 1 of lipid micelles and 3) 10% l of kinase buffer ([33P] ∃-ATP 45 μM / 60 nCi, 30 mM MgCl2, 1 mM DTT, 1 mM lic-Glycerophosphate, 100% M Na3VO4, 0.3% Na collate, in 40 mM Hepes , pH 7.4). After incubation at room temperature for 180 minutes, with gentle stirring, the reaction is stopped by adding 60% 1 of a solution containing 100% g of neomycin coated SPA PVT beads in PBS containing 10 mM ATP and EDTA 5 mM. The assay is further incubated at room temperature for 60 minutes with gentle agitation to allow phospholipid binding to SPA-neomycin beads. After precipitation of the neomycin coated SPA PVT beads for 5 minutes at 1500 x g, the radioactive PtIns (3) P is quantified by scintillation counting on a Wallac MicroBetaTM plate counter.

The values indicated in the following table I refer to the IC50 (nM) with respect to the PI3K∃, that is, the amount necessary to achieve 50% inhibition of said objective. These values show considerable inhibitory potency of thiazole compounds with respect to PI3K∃.

Examples of inhibitory activities for the compounds of the invention are presented in Table I.

Table I: IC50 values of thiazole derivatives against PI3K∃

Example No.

PI3K∃ IC50 (nM)

one

4

3

6

4

twenty

5

35

6

2

8

10

12

7

fifteen

twenty

b) Cell-based ELISA for monitoring PI3K inhibition:

The efficacy of the compounds of the invention to inhibit the phosphorylation of Akt / PKB induced by PI3K can be tested in the following cell-based assay.

Measurement of phosphorylation of Akt / PKB in macrophages after stimulation with complement 5a: Raw 264: Raw macrophages 264-7 (grown in DMEM-F12 medium containing 10% fetal calf serum and antibiotics) are grown with 20,000 cells / well in a MTP 96 plate 24 h before cell stimulation. Before stimulation with the complement at 50 mM for 5 minutes, the serum cells are deprived for 2 h, and are previously treated with inhibitors for 20 minutes. After stimulation, the cells are fixed in 4% formaldehyde for 20 minutes and washed 3 times in PBS containing 1% Triton X-100 (PBS / Triton). The endogenous peroxidase is blocked by a 20 minute incubation in 0.6% H2O2 and 0.1% sodium azide in PBS / Triton and washed 3 times in PBS / Triton. The cells are then blocked by incubation 60 minutes with 10% fetal calf serum in PBS / Triton. The phosphorylated Akt / PKB is then detected by overnight incubation at 4 ° C with the first antibody (directed against phosphoserine 473 Akt IHC, cell signaling) diluted 800 times in PBS / Triton, containing 5% bovine serum albumin (BSA) . After 3 washes in PBS / Triton, the cells are incubated for 60 minutes with a peroxidase-conjugated goat anti-rabbit antibody (1/400 dilution in PBS / Triton, containing 5% BSA), washed 3 times in PBS / Triton, and 2 times in PBS and further incubate in 100% l of reagent and substrate solution (R&D) for 20 minutes. The reaction is stopped by the addition of 50% 1 of 1M SO4H2 and the absorbance is read at 450 nm.

The values indicated in the following Table II reflect the percent inhibition of AKT phosphorylation

compared to baseline level. These values show a clear effect of thiazole compounds on activation. of phosphorylation of AKT in macrophages. Examples of inhibitory activities of the compounds of the invention are presented in the following table II. Table II: IC50 values of thiazole derivatives in cell assay

Example No.

Cell assay (P-Akt, Elisa) IC50 (nM)

one

<10

3

<10

Example 19: Thioglycolate-induced peritoneal cell recruitment model

The in vivo efficacy of the compounds of the invention in inhibiting leukocyte migration by intraperitoneal thioglycolate stimulation can be tested with the following assay.

Experimental protocol:

Female C3H mice, 8-10 weeks old, were fasted for 18 hours. 15 minutes before intraperitoneal injection of thioglycolate (1.5%, 40 ml / kg), the mice were treated orally with pyridine-methylenenazolidinones of formula (I). Control mice received CMC / Tween as a vehicle (10 ml / kg). The mice were then sacrificed by CO2 inhalation and the peritoneal cavity was washed twice with 5 ml of ice cold PBS / 1 mM EDTA. Washings were done 4 h and 48 h after stimulation with thioglycolate to evaluate the recruitment of neutrophils or macrophages, respectively. Leukocytes (neutrophils, lymphocytes or macrophages) were counted using a Beckman Coulter® ACT 5diff ™. Dexamethasone was used as the reference drug.

Example 20: Preparation of a pharmaceutical formulation

Formulation 1 - Tablets

A compound of formula (I) is mixed as a dry powder with dried gelatin as a binder in a weight ratio of about 1: 2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg, of active pyridine-methylene azolidinone compound per tablet) in a tablet press.

Formulation 2 - Capsules

A compound of formula (I) is mixed as a dry powder with starch as a diluent in a weight ratio of about 1: 1. The mixture is loaded into 250 mg capsules (125 mg of active pyridine-methylenazolidinone compound per capsule).

Formulation 3 - Liquid

A compound of formula (I) (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are mixed, passed through a U.S. sieve. standard mesh No. 10, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Dilute sodium benzoate (10 mg), flavor and color with water and add with stirring. Then, enough water is added to produce a total volume of 5 ml.

Formulation 4 - Tablets

A compound of formula (I) is mixed as a dry powder with dried gelatin as a binder in a weight ratio of about 1: 2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active pyridine methylene azolidinone compound per tablet) in a tablet press.

Formulation 5 - Injection

A compound of formula (I) is dissolved in an injectable aqueous medium of buffered saline, with a concentration of approximately 5 mg / ml.

Claims (23)

1.-A derivative of pyridine-methylene-azolidinone according to formula (I): wherein R 1 is selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, alkoxycarbonyl, acyl, sulfonyl, sulfanyl, sulfinyl, alkoxy and amino; R2 is selected from H; halogen; C1-C6 alkyl; C2-C6 alkenyl, C2-C6 alkynyl; aryl; heteroaryl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl; aryl (C1-C6) alkyl; heteroaryl (C1-C6) alkyl; cycloalkyl (C3-C8) -alkyl (C1-C6), heterocycloalkyl (C3-C8) -alkyl (C1-C6); (C1-C6) alkoxy-alkyl; alkoxycarbonyl; acyl; sulfonyl; sulfanyl; sulfinyl; alkoxy and not me; X is selected from S, NH and O; Y is selected from O, S and NR3, wherein R3 is selected from H, optionally substituted C1-C6 alkoxy, C1-C6 alkyl optionally substituted, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl (C1-C6) alkyl, cyano and optionally substituted sulfonyl; A is a heteroaryl group; n is an integer selected from 1 and 2; as well as its geometric isomers, its optically active forms such as enantiomers, diastereoisomers and their racemic forms, as well as their pharmaceutically acceptable salts. 2. A pyridine-methylene-azolidinone derivative according to claim 1, wherein R1 is H. 3.-A pyridine-methylene-azolidinone derivative according to claims 1 to 2, wherein R2 is H. 4. A pyridine-methylene-azolidinone derivative according to claims 1 to 2, wherein R2 is C3-C8 heterocycloalkyl. 5. A pyridine-methylene-azolidinone derivative according to claims 1 to 2, wherein R2 is Select from aryl and heteroaryl. 6. A pyridine-methylene-azolidinone derivative according to any of the preceding claims, in which X is S. 7. A pyridine-methylene-azolidinone derivative according to any of the preceding claims, in which Y is O. 8. A pyridine-methylene-azolidinone derivative according to any of the preceding claims, in which Y is S. 9. A pyridine-methylene-azolidinone derivative according to any of the preceding claims, in which n is 1. 10.-A pyridine-methylene-azolidinone derivative according to any of the preceding claims, in which A together with the pyridine ring forms the following group (Ia): wherein R1 and R2 are as defined in any of the preceding claims. 11. A pyridine-methylene-azolidinone derivative according to any one of claims 1 to 9, wherein A together with the pyridine ring forms the following group (Ib): wherein R1 and R2 are as defined in any of the preceding claims. 12. A pyridine-methylene azolidinone derivative according to any one of claims 1 to 9, wherein A together with the pyridine ring forms the following group (Ic): wherein R1 and R2 are as defined in any of the preceding claims. 13. A pyridine-methylene-azolidinone derivative according to any one of claims 1 to 9, wherein A together with the pyridine ring forms the following group (Id): wherein R1 and R2 are as defined in any of the preceding claims. 14. A pyridine methylene azolidinone derivative according to any one of claims 1 to 10, in the that R1 is H; R2 is C3-C8 heterocycloalkyl; X is S; Y is O or S, and A together with the pyridine ring forms a group of formula (Ia). 15.-A pyridine-methylene-azolidinone derivative according to any of the preceding claims, wherein R1 is H; X is S; Y is O and A together with the pyridine ring forms a group of formula (Ib). 16.-A pyridine-methylene-azolidinone derivative according to any of the preceding claims, wherein R1 is H; X is S; Y is O and A together with the pyridine ring forms a group of formula (Ic). 17.-A pyridine-methylene-azolidinone derivative according to any of the preceding claims, wherein R1 is H; X is S; Y is O and A together with the pyridine ring forms a group of formula (Id). 18.-A pyridine-methylene-azolidinone derivative according to any of the preceding claims, selected from the following group: (5Z) -5 - {[4- (1-piperidinyl) pyrido [3,2-d] pyrimidin-6-yl] methylene} -1,3-thiazolidine-2,4-dione; (5Z) -5 - {[4- (4-fluoro-1-piperidinyl) pyrido [3,2-dlpyrimidin-6-yl] mctilene} -1,3-thiazolidine-2,4-dione; (5Z) -5 - ({4- [4- (trifluoromethyl) -1-piperidinyl] pyrido [3,2-d] pyrimidin-6-yl} methylene} -1,3-thiazolidine-2,4-dione; 5-Pyrido [2,3-b] pyrazin-6-ylmethylene-thiazolidine-2,4-dione; 5-Furo [3,2-b] pyridin-5-ylmetliIen-thiazolidine-2,4-dione; 5- [4- (4-Fluoro-piperidin-1-yl) -pyrido [3,2 d] pyrimidin-6-ylmethylene] -2-thioxo-thiazolidin-4-one; 5- (3-Phenyl-3H-imidazo [4,5-b] pyridin-5-ylmethylene) -thiazolidine-2,4-dione; 5- [3- (3,5-Dimethoxy-phenyl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4-dione; 5- [5- (2,4-Dioxo-thiazolidin-5-ylidenemethyl) -imidazo [4,5-b] pyridin-3-yl] -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester; 5- [3- (2,3-Dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4-dione; 5- [3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-yl-methylene] -thiazolidine-2,4- diona; 5- {3- [1- (4-Dimethylamino-butyryl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridin-5-ylmethylene} -thiazolidine- 2,4-dione; 5- [3- (1-Methanesulfonyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4-dione; 5- [3- (1-Chloromethanesulfonyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4-dione; 5- {3- [1- (3-Morpholin-4-yl-propane-1-sulfonyl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridin -5-ylmethylene} -thiazolidine 2,4-dione; 6- [5- (2,4-Dioxo-thiazolidin-5-ylidenemethyl) -imidazo [4,5-b] pyridin-3-yl] -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester; 5- [3- (1-Methanesulfonyl-2,3-dihydro-1H-indol-6-yl) -3H-imidazo [4,5-b] pyridin-5-ylmethylene] -thiazolidine-2,4-dione 19.-A pyridine-methylene-azolidinone derivative according to claims 1 to 18, for use as a medicament. 20. Use of a pyridine-methylene azolidinone derivative according to claims 1 to 18, as well as mixtures thereof, to prepare a medicament for the prophylaxis and / or treatment of autoimmune disorders and / or inflammatory diseases, diseases cardiovascular, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung lesions. 21. Use according to claim 20, wherein said diseases are selected from the group that includes multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pulmonary inflammation, thrombosis or cerebral infection / inflammation such as meningitis or encephalitis. 22. Use according to claim 20, wherein said diseases are selected from the group that includes Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic conditions. 23. Use according to claim 20, wherein said diseases are selected from the group that includes atherosclerosis, cardiac hypertrophy, cardiac myocyte dysfunction, hypertension or vasoconstriction. 24. Use according to claim 20, wherein said diseases are selected from the group that includes chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia-reperfusion, aggregation / platelet activation, skeletal muscle atrophy / hypertrophy, leukocyte recruitment in cancer tissues, angiogenesis, invasive metastases, melanoma, Kaposi sarcoma, acute and chronic bacterial and viral infections, sepsis, transplantation, graft rejection, glomerulosclerosis, glomerulonephritis , progressive renal fibrosis, endothelial and epithelial lesions in the lung or inflammation of the pulmonary airways in general. 25. Use according to any of claims 20 to 24 for the modulation, in particular for the inhibition, of the activity of PI3 kinase. 26. Use according to claim 25, wherein said PI3 kinase is a PI3 kinase ∃. 27. A pharmaceutical composition containing at least one pyridine methylene azolidinone derivative according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier, diluent or excipient therefor. 28. A process for preparing a pyridine methylene azolidinone derivative according to any one of claims 1 to 18, comprising the step of reacting a compound of formula (II) with a derivative of formula (III) in the presence of a base: wherein R1, R2, A, X, Y and n are as defined in any of the preceding claims. 29.-A compound according to formula (IIa), (IIb), (IIc) and (IId): wherein R4 is selected from H and R2; R5 is a group R2 in which the first atom attached to the pyrimidine ring is selected from C, N, S and O and in which when R4 is NH2, R5 is not NH2; R1, R2 and n are as defined in any of the preceding claims; wherein R1, R2 and n are as defined in any of the preceding claims; wherein R1, R2 and n are as defined in any of the preceding claims and wherein at least some of R1 or R2 is not H; Y wherein R1, R2 and n are as defined in any of the preceding claims and with the proviso that the compound of formula (IId) is not 2- (4-methoxyphenyl) -3H-Imidazo [4,5-b ] pyridine-5-carboxaldehyde. 30. A compound according to claim 29 selected from the group: 4-Piperidin-1-yl-pyrido [3,2-d] pyrimidine-6-carbaldehyde; 4- (4-Fluoro-piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6-carbaldehyde; 4- (4-Methyl-piperidin-1-yl) -pyrido [3,2-d] pyrimidine-6-carbaldehyde; Pyrido [2,3-b] pyrazine-6-carbaldehyde; 2-Trimethylsilanyl-furo [3,2-b] pyridine-5-carbaldehyde; 3-Phenyl-1H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- (3,5-Dimethoxyphenyl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; Tert-butyl 5- (5-Formyl-3H-imidazo [4,5-b] pyridin-3-yl) indoline-1-carboxylate; 3- (1-Acetyl-2,3-dihydro-1H-indol-5-yl) -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- {1- [4- (Dimethylamino) butanoyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- [1- (Methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- {1 - [(Chloromethyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; 3- {1 - [(3-Morpholin-4-ylpropyl) sulfonyl] -2,3-dihydro-1H-indol-5-yl} -3H-imidazo [4,5-b] pyridine-5-carbaldehyde; Tert-butyl 6- (5-Formyl-3H-imidazo [4,5-b] pyridine-3-yl) indoline-1-carboxylate; 3- [1- (Methylsulfonyl) -2,3-dihydro-1H-indol-6-yl] -3H-imidazo [4,5-b] pyridine-5-carbaldehyde.