WO2010092015A1 - Dérivés d'urée-triazolo[1,5-a]pyridine en tant qu'inhibiteurs de pi3k - Google Patents

Dérivés d'urée-triazolo[1,5-a]pyridine en tant qu'inhibiteurs de pi3k Download PDF

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WO2010092015A1
WO2010092015A1 PCT/EP2010/051462 EP2010051462W WO2010092015A1 WO 2010092015 A1 WO2010092015 A1 WO 2010092015A1 EP 2010051462 W EP2010051462 W EP 2010051462W WO 2010092015 A1 WO2010092015 A1 WO 2010092015A1
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compound
pyridin
alkyl
triazolo
tert
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WO2010092015A8 (fr
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Nigel Ramsden
Kathryn Bell
Jess Taylor
Mihiro Sunose
David Middlemiss
Katie Ellard
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Cellzome Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a novel class of kinase inhibitors, including pharmaceutically acceptable salts, prodrugs and metabolites thereof, which are useful for modulating protein kinase activity for modulating cellular activities such as signal transduction, proliferation, differentiation, programmed cell death, migration and cytokine secretion. More specifically the invention provides compounds which inhibit, regulate and/or modulate kinase activity, in particular PBK activity, and signal transduction pathways relating to cellular activities as mentioned above. Furthermore, the present invention relates to pharmaceutical compositions comprising said compounds, e.g. for the treatment of diseases such as immunological, inflammatory, autoimmune and allergic disorders, and processes for preparing said compounds.
  • diseases such as immunological, inflammatory, autoimmune and allergic disorders
  • Protein and lipid kinases participate in the signaling events which control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines.
  • protein kinases are classified in two groups, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues in their protein substrates.
  • lipid kinases phosphorylate a variety of lipid substrates.
  • Inappropriately high protein or lipid kinase activity is involved in many diseases including cancer, metabolic diseases, immunological diseases and inflammatory disorders. This can be caused either directly or indirectly by the failure of control mechanisms due to mutation, overexpression or inappropriate activation of the enzyme. In all of these instances, selective inhibition of the kinase is expected to have a beneficial therapeutic effect.
  • Phosphoinositide 3-kinases also called Phosphatidylinositol 3-kinases, PDKs
  • Phosphoinositide 3-kinases represent a group of lipid kinases that play pivotal roles in numerous intracellular signaling events, for example in T-cell receptor signaling.
  • Some members of the PI3K family also display protein kinase activity (Vanhaesebroeck et al, 2001, Annu. Rev. Biochem. 70:535-602).
  • PI3Ks belong to a superfamily of signaling lipid kinases that catalyse the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2 or phosphatidylinositol (Ptdlns) at the 3'-OH group, giving rise to the second messengers phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) or phosphatidylinositol-3- phosphate (PtdIns(3)P).
  • PtdIns(3,4,5)P3 can be converted into PtdIns(3,4)P2 by SH2- containing inositol phosphatase (SHIP), or can be dephosphorylated by phosphatase and tensin homologue (PTEN) phosphatase to regenerate PtdIns(4,5)P2.
  • SHIP inositol phosphatase
  • PTEN tensin homologue
  • PtdIns(3,4,5)P3, PtdIns(3,4)P2 PtdIns(4,5)P2, PtdIns(5)P and PtdIns(3)P recruit and activate various signaling proteins (Ptdlnsbinding proteins; Ptdlns-BPs) through direct lipid-protein interactions (Hawkins et al., 2006, Biochem. Soc. Trans. 34:647-62).
  • Phosphatidylinositol-3,4,5-trisphosphate has an important role as second messenger by working as a docking platform for lipid-binding domains, such as the pleckstrin homology (PH) domains of various cellular proteins.
  • lipid-binding domains such as the pleckstrin homology (PH) domains of various cellular proteins.
  • kinases such as 3-phosphoinositide-dependent protein kinase 1 (PDKl) and protein kinase B (PKB)/Akt
  • guanine-nucleotide exchange factors such as Vav and P-Rex
  • PI3 -kinase activation is believed to be involved in a variety of signal transduction pathways, including those essential to cell proliferation, cell differentiation, cell growth, cell survival, apoptosis, adhesion, chemotaxis, invasion, cytoskeletal rearrangement, contraction, phagocytosis vesicle trafficking, receptor internalization, secretion, protein synthesis and metabolic pathways.
  • PI3K gamma ( ⁇ ) and delta ( ⁇ ) isoforms appear to be involved in a number of aspects of leukocyte activation (Rommel et al., 2007, Nat. Rev. Immunol. 7(3):191-201; Ruckle et al., 2006, Nat. Rev. Drug Discov. 5(11):903-18).
  • PBK PBK-derived neuropeptide kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase (Kadlns) as in vivo substrate, yielding phosphatidylinositol-3-phosphate (PtdIns(3)P).
  • PtdIns(3)P phosphatidylinositol-3-phosphate
  • class II enzymes similarly to class I can be activated by external stimuli via receptor tyrosine kinases (RTKs), cytokine receptors and integrins, suggesting roles in cancer, wound healing and insulin signaling.
  • RTKs receptor tyrosine kinases
  • cytokine receptors cytokine receptors
  • integrins integrins
  • the class III represents the most ancient form of PBK and it uses exclusively Ptdlns as a substrate to produce PtdIns(3)P. This class of PBKs is involved in endocytic membrane traffic, phagosom maturation and autophagy (Falasca et al, 2007, Biochem. Soc. Trans. 35:211-4; Lindmo et al, 2006, J. Cell Sci. 119:605-14).
  • the class IA PBKs - PBK ⁇ , ⁇ and ⁇ consist of a SH2-domain-containing regulatory subunit (p85; five distinct isoforms of which have been identified) that forms a complex with one of three catalytic subunits, pi 10a, pi lO ⁇ or pl lO ⁇ (Bader et al., 2005, Nat. Rev. Cancer 5(12):921-9).
  • PBK pathway Genetic polymorphisms within the PBK pathway are also associated with an increased risk of type 2 diabetes. Downstream of the insulin-like growth factor 1 (IGFl) receptor, signaling through class I PBK controls growth and development. Amplification and point mutations of the gene encoding PBK ⁇ that increase the enzymatic activity of the protein have been frequently found in human cancers (Bader et al., 2005, Nat. Rev. Cancer 5(12):921-9).
  • IGFl insulin-like growth factor 1
  • PBK activation and PIP3 production are fundamental for most biological responses exerted by insulin.
  • Activated insulin receptor (IR) triggers PBK activity by binding and phosphorylating adaptor proteins of the insulin receptor substrate (IRS) family.
  • IRS insulin receptor substrate
  • PIP3 production in turn activates downstream effectors that control various metabolic processes such as glucose uptake, triglyceride formation, glycogen synthesis, lipolysis and hepatic gluconeogenesis inhibition (Knight et al., 2006, Cell 125(4): 733-747; Foukas et al., 2006, Nature, 441(7091):366-70).
  • PBK ⁇ has been implicated in regulating the formation and stability of integrin ⁇ (IIb) ⁇ (3), which is necessary for the activation and aggregation of platelets.
  • Isoform- selective PI3K pi lO ⁇ inhibitors have been developed which in vivo eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K pi lO ⁇ as an important new target for antithrombotic therapy (Jackson et al., 2005, Nat. Med. 11 (5):507-14).
  • PI3K ⁇ is predominantly expressed in the haematopoietic system and PBK ⁇ -def ⁇ cient mice are viable, fertile, apparently healthy and have a normal life span (Vanhaesebroeck et al., 2005. Trends in Biochemical Sciences 30, 194-204).
  • PI3K ⁇ has important roles in T- and B-cell signaling, mast-cell-mediated allergic responses, the neutrophils oxidative burst and, possibly, extravasation.
  • PBK inhibitors selective for PBK ⁇ were reported to block neutrophil activation in an animal model for neutrophil activation, thus pointing to PBk ⁇ as a target for the development of anti- inflammatory drugs (Sadhu et al., 2003, Biochem. Biophys. Res. Communications 308, 764-769).
  • PBK ⁇ the only member of class IB (PIK3CG), associates with either of two regulatory subunits, plOl and p84, that control its activation and subcellular location.
  • PBK ⁇ activation is driven by the direct association of its catalytic domain with the ⁇ subunits of G proteins following activation of pertussis-toxin-sensitive G ⁇ i-coupled G-protein- coupled receptors (GPCRs).
  • GPCRs pertussis-toxin-sensitive G ⁇ i-coupled G-protein- coupled receptors
  • PBK ⁇ can be activated by Ras by a direct interaction with the catalytic subunit. Beside its lipid kinase activity, PBK ⁇ has a protein kinase activity.
  • lipid kinase activity uses the regulatory subunits as well as itself as substrate and both events result in an increase of the lipid kinase activity (Leopoldt et al., 1998, J. Biol. Chem. 273(12):7024-9).
  • Other proteins for example phosphodiesterases (PDEs) can bind to PI3K ⁇ , indicating a protein-scaffold function in addition to its enzymatic activity.
  • PBK ⁇ was also shown to activate MEK kinase as well as to mediate shear-sensitive triggering of the JNK kinase pathway in endothelial cells (Patrucco et al, 2004, Cell 118(3):375-87; Voigt et al., 2006, J. Biol. Chem. 281(15):9977-86).
  • mice lacking functional PBK ⁇ were viable, fertile, and displayed a normal life span in a conventional mouse facility. Further studies revealed that neutrophils of these mice were unable to produce Ptdlns (3,4,5) P3 when stimulated with GPCR agonists such as formylated bacterial peptides (N-formyl-Met-Leu-Phe, fMLP), complement C5a or interleukin 8 (IL-8). This observation demonstrates that PBK ⁇ is the sole PBK isoform that is coupled to these GPCRs in neutrophils (Vanhaesebroeck et al., 2005. Trends in Biochemical Sciences 30, 194-204).
  • GPCR agonists such as formylated bacterial peptides (N-formyl-Met-Leu-Phe, fMLP), complement C5a or interleukin 8 (IL-8).
  • Ptdlns (3, 4, 5) P3-dependent activation of protein kinase B (PKB) was also absent in those neutrophils, while PKB could still be activated by GM-CSF or IgG/C3b- coated zymosan.
  • Pi3kcg-/- mice showed impaired thymocyte development and increases in neutrophil, monocyte, and eosinophil populations.
  • neutrophils and macrophages isolated from Pi3kcg-/-mice exhibited severe defects in migration and respiratory burst in response to GPCR agonists and chemotactic agents.
  • PBK ⁇ is required for the homing of dendritic cells to lymph nodes and in the development and activation of T lymphocytes (together with PBK ⁇ ).
  • PBK ⁇ also contributes to the activation of mast cell secretion by adenosine. Its involvement in the stimulation of autocrine and paracrine regulatory loops by purines has also been observed in other cell types.
  • PBK ⁇ also contributes to the activation of platelet aggregation by ADP in concert with PBK ⁇ (Ferguson et al., 2007, Nat. Cell Biol. 9(1):86-91).
  • PI3K ⁇ plays a crucial role in both vascular cells and white blood cells. It controls diverse immune modulatory and vascular functions like respiratory burst, cell recruitment, mast cell reactivity, platelet aggregation, endothelial activation as well as smooth muscle contractility.
  • PBK ⁇ plays a role in a mouse model for pancreatitis.
  • the lethality of the choline-deficient/ethionine-supplemented diet-induced pancreatitis was significantly reduced in mice lacking PBK ⁇ (Lupia et al., 2004. Am. J. Pathol. 165(6):2003-2011).
  • PI-3 Kinase inhibitors are described in WO-A 2007/095588 and WO-A 2008/025821.
  • Triazolopyridine derivatives are described WO-A 2006/038116 as antibacterial agents.
  • an object of the present invention is to provide a new class of compounds as kinase inhibitors, especially as PBK inhibitors, which may be effective in the treatment or prophylaxis of immunological, inflammatory, autoimmune, allergic disorders or other diseases or disorders associated with PBK. Furthermore, another object of the present invention is to provide said compounds, which may be effective in the treatment or prophylaxis of cancer or cardiovascular disorders associated with PBK.
  • R is N(R 5a R 5 );
  • R 5 is (CH 2 ) n -C(O)N(R 6a R 6 );
  • n 1; 2; or 3;
  • R 5a , R 6a are independently selected from the group consisting of H; and Ci_ ⁇ alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • R 6 is T; or CH 2 T;
  • R 6 , R 6a are joined together with the nitrogen atom to which they are attached to form a ring T 1 .
  • T is C3_7 cycloalkyl; 4 to 7 membered heterocyclyl; 7 to 11 membered heterobicyclyl; phenyl; naphthyl; indenyl; or indanyl, wherein T is optionally substituted with one or more R 7 , which are the same or different;
  • T 1 is an at least the nitrogen atom as ring heteroatom containing at least partially saturated 4 to 7 membered heterocycle; or an at least the nitrogen atom as ring heteroatom containing at least partially saturated 7 to 11 membered heterobicycle, wherein T 1 is optionally substituted with one or more R 7 , which are the same or different;
  • R 8 , R 8a , R 8b are independently selected from the group consisting of H; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more R 9 , which are the same or different;
  • R 9 is halogen; CN; C(O)OR 10 ; OR 10 ; C(O)R 10 ; C(O)N(R 10 R 103 ); S(O) 2 N(R 10 R 10a ); S(O)N(R 10 R 10a ); S(O) 2 R 10 ; S(O)R 10 ; N(R 10 )S(O) 2 N(R 10a R 10b ); SR 10 ; N(R 10 R 10a ); OC(O)R 10 ; N(R 10 )C(O)R 10a ; N(R 10 )S(O) 2 R 10a ; N(R 10 )S(O)R 10a ; N(R 10 )C(O)N(R 10a R 10b ); N(R 10 )C(O)OR 10a ; or OC(O)N(R 10 R 10a );
  • R 10 , R 1Oa , R 10b are independently selected from the group consisting of H; and C 1 ⁇ alkyl, wherein Ci_6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • R 1 , R 2 , R 3 are independently selected from the group consisting of H; halogen; CN; C(O)OR 11 ; OR 11 ; C(O)R 11 ; C(O)N(R 11 R 113 ); S(O) 2 N(R 11 R 113 ); S(O)N(R 11 R 113 ); S(O) 2 R 11 ; S(O)R 11 ; N(R n )S(0) 2 N(R l la R l lb ); N(R 11 JS(O)N(R 110 R 1 lb ); SR 11 ; N(R n R l la ); OC(O)R 11 ; N(R 1 ⁇ C(O)R 11 "; N(R 1 ⁇ S(O) 2 R 11 "; N(R n )S(O)R lla ; N(R n )C(0)N(R lla R l lb ); N(R 1 ⁇ C(O)OR
  • X 1 is N; or C(R 12 );
  • R 4 is H; or R 13 ;
  • R 12 is H; or R 14 ;
  • R 13 , R 14 are independently selected from the group consisting of halogen; CN; C(O)OR 15 ; OR 15 ; C(O)R 15 ; C(O)N(R 15 R 15a ); S(O) 2 N(R 15 R 15a ); S(O)N(R 15 R 15a ); S(O) 2 R 15 ; S(O)R 15 ; N(R 15 )S(O) 2 N(R 15a R 15b ); N(R ⁇ )S(O)N(R 153 R 15b ); SR 15 ; N(R 15 R 15a ); OC(O)R 15 ; N(R 15 )C(O)R 15a ; N(R 15 )S(O) 2 R 15a ; N(R 15 )S(O)R 15a ; N(R 15 )C(O)N(R 15a R 15b ); N(R 15 )C(O)OR 15a ; OC(O)N(R 15 R 15
  • R 15 , R 15a , R 15b are independently selected from the group consisting of H; and Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted with one or more R 16 ;
  • R 16 is halogen; CN; C(O)OR 17 ; OR 17 ; C(O)R 17 ; C(O)N(R 17 R 17a ); S (O) 2 N(R 17 R 17a ); S(O)N(R 17 R 17a ); S(O) 2 R 17 ; S(O)R 17 ; N(R 1 ⁇ S(O) 2 N(R 17a R 17b ); N(R 17 )S(O)N(R 17a R 17b ); SR 17 ; N(R 17 R 17a ); OC(O)R 17 ; N(R 17 )C(O)R 17a ; N(R 17 )S(O) 2 R 17a ; N(R 17 )S(O)R 17a ; N(R 17 )C(O)N(R 17a R 17b ); N(R 17 )C(O)OR 17a ; or OC(O)N(R 17 R 17a );
  • R 17 , R 17a , R 17b are independently selected from the group consisting of H; and Ci_ 6 alkyl, wherein Ci_ ⁇ alkyl is optionally substituted with one or more halogen, which are the same or different.
  • variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
  • the terms are used as follows:
  • Alkyl means a straight-chain or branched hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent.
  • Ci 4 alkyl means an alkyl chain having 1 to 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g.
  • Ci_6 alkyl means an alkyl chain having 1 to 6 carbon atoms, e.g. if present at the end of a molecule: Ci_ 4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, or e.g. -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -
  • Ci_6 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent.
  • C 3 _ 7 cycloalkyl or “C 3 _ 7 cycloalkyl ring” means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fiuoro or chloro.
  • Examples for a 4 to 7 membered heterocycles are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofliran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine,
  • Examples for a saturated 4 to 7 membered heterocycles are azetidine, oxetane, thietane, tetrahydrofliran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, tetrahydropyran, imidazolidine, piperidine, morpholine, triazolidine, tetrazolidine, diazepane, or homopiperazine.
  • Examples for a 7 to 11 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydro isoquinoline, benzazepine, purine or pteridine.
  • 7 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane.
  • saturated 7 to 1 1 membered heterobicycle examples are decahydroquinoline, or decahydroisoquinoline.
  • saturated 7 to 11 membered heterobicycle also includes saturated spiro structures of two rings like l,4-dioxa-8- azaspiro[4.5]decane or bridged saturated heterocycles like 8-aza-bicyclo[3.2.1]octane.
  • Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention.
  • the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.
  • substituents mentioned below independently have the following meaning. Hence, one or more of these substituents can have the preferred or more preferred meanings given below.
  • R 5a is H.
  • n is 1; or 2.
  • R 6a is H; or CH 3 .
  • R 6 is T.
  • T is C 3 _ ⁇ cycloalkyl; or saturated 4 to 7 membered heterocyclyl, wherein T is unsubstituted or substituted with one or more R 7 , which are the same or different.
  • T is cyclopropyl; pyrrolidinyl; piperidinyl; or morpholinyl, wherein T is unsubstituted or substituted with one or more R 7 , which are the same or different.
  • R 6 , R 6a are joined together with the nitrogen atom to which they are attached to form a ring T 1 .
  • T 1 is an at least the nitrogen atom as ring heteroatom containing saturated 4 to 7 membered heterocycle and wherein T 1 is unsubstituted or substituted with one or more R 7 , which are the same or different.
  • T 1 is pyrrolidine; morpholine; piperidine; or piperazine, and wherein T 1 is unsubstituted or substituted with one or more R 7 , which are the same or different.
  • R 7 is OCi_6 alkyl; N(C 1 ⁇ alkyl) 2 ; or Ci_6 alkyl, which is unsubstituted or ssuubbssttiittuutteedd wwiitthh oonnee oorr mmoorree RR 99 ,, wwhhiicchh aarree tthhee ssaammee oorr ddiifffferent and selected from the group consisting of halogen; OCi_6 alkyl; and N(Ci_6 alkyl)2.
  • R 3 is H; CH 3 ; or halogen. Even more preferably, R 3 is H; or F.
  • R 2 is H.
  • R 1 is H.
  • R 4 is R 13 .
  • R 13 is SO 2 N(R 15 R 15a ); SO 2 R 15 ; or Ci_ 6 alkyl, optionally substituted with one or more halogen, which are the same or different.
  • R 13a is H; or CH 3 .
  • R 15 is Ci_ 6 alkyl.
  • X 1 is N.
  • X J is C(R IZ ) it is preferred that R u is H.
  • Prodrug means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g.
  • Metabolites of compounds of formula (I) are also within the scope of the present invention.
  • metabolites refers to all molecules derived from any of the compounds according to the present invention in a cell or organism, preferably mammal.
  • the term relates to molecules which differ from any molecule which is present in any such cell or organism under physiological conditions.
  • tautomerism like e.g. keto-enol tautomerism
  • the individual forms like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio.
  • stereoisomers like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography.
  • enantiomers by using e.g. chiral stationary phases.
  • enantiomers may be isolated by converting them into diastereomers, i.e.
  • any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable means approved by a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably in humans.
  • the present invention furthermore includes all solvates of the compounds according to the invention.
  • the present invention provides compounds of formula (I) as kinase inhibitors, especially as PBK inhibitors.
  • the compounds of the present invention are useful for the prevention or treatment of immunological disorders (e.g. immune or autoimmune diseases), inflammatory disorders or allergic disorders.
  • another aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.
  • Another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof according to the present invention for use in a method of treating or preventing diseases and disorders associated with PI3K.
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with PDK, preferably PBK ⁇ and/or PBK ⁇ .
  • Compounds of the invention may be selective for one PB kinase isoform (for example gamma or delta) over a different isoform. Such compounds may preferentially inhibit one isoform. For example, a compound may preferentially inhibit the gamma isoform over the alpha isoform.
  • the compound's activity can be determined according to the Biological Assays as described herein. For example, the IC50 value of a compound is determined for four PI3 kinase iso forms (e.g. alpha, beta, gamma, delta). The obtained values should then be compared to determine the selectivity of the tested compound.
  • PIKK PI3K-like kinases
  • DNA-PK DNA-dependent kinase
  • the obtained value should then be compared to the value of the target of interest, for example PBK gamma, to determine the selectivity of the tested compound.
  • PBK or "PB kinase” includes all members of the PBK family comprising class IA (e.g. PBK alpha, beta and delta), class IB (e.g. PBK gamma), class II (e.g. PI3KC2 alpha, beta and gamma) and class III (e.g. Vps34 yeast homologue).
  • class IA e.g. PBK alpha, beta and delta
  • class IB e.g. PBK gamma
  • class II e.g. PI3KC2 alpha, beta and gamma
  • class III e.g. Vps34 yeast homologue
  • PBK ⁇ means PBK ⁇ protein (also referred to as pl lO-beta).
  • a human cDNA encoding the PBK ⁇ protein was described (Hu et al., 1993. MoI. Cell Biol. 13(12):7677-88).
  • the human PBK ⁇ protein is encoded by the PBKCB gene on chromosome 3q22.3.
  • PBKy means PBK ⁇ protein, the only member of PBK class IB (also referred to as pl lO-gamma).
  • PBK ⁇ protein, the only member of PBK class IB (also referred to as pl lO-gamma).
  • a human cDNA encoding the PBK ⁇ protein of a 1050 amino acid residue long polypeptide was described (Stoyanow et al., 1995, Science 269:690-693).
  • the human PBK ⁇ protein is encoded by the PBKCG gene which comprises 10 exons and is located on chromosome 7q22 (Kratz et al., 2002, Blood 99:372-374).
  • PDK ⁇ means PDK ⁇ protein, a member of PI3K class class IA (also referred to as pl lO-delta).
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of immunological, inflammatory, autoimmune, or allergic disorders.
  • preferred disorders are autoimmune diseases; organ and bone marrow transplant rejection; graft-versus-host disease; acute or chronic inflammation; pancreatitis; contact dermatitis; psoriasis; rheumatoid arthritis; multiple sclerosis; type I diabetes; inflammatory bowel disease; Crohn's disease; ulcerative colitis; systemic lupus erythematosus; asthma; chronic obstructive pulmonary disease (COPD); acute respiratory distress syndrome (ARDS); bronchitis; conjunctivitis; dermatitis; allergic rhinitis; acute gouty inflammation; cystic fibrosis; familial Mediterranean fever; tissue damage after bacterial infection; Sweet's syndrome; or anaphylaxis.
  • autoimmune diseases include organ and bone marrow transplant rejection; graft-versus-host disease; acute or chronic inflammation; pancreatitis; contact dermatitis; psoriasis; rheumatoid arthritis; multiple sclerosis; type I diabetes
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus
  • psoriasis psoriasis
  • MS multiple sclerosis
  • COPD chronic obstructive pulmonary disease
  • RA Rheumatoid arthritis
  • IBD Inflammatory bowel disease
  • ulcerative colitis In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers. In approximately 10% of cases confined to the rectum and colon, definitive classification of Crohn disease or ulcerative colitis cannot be made and are designated 'indeterminate colitis.' Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Neutrophil- induced injuries may be prevented by the use of neutrophils migration inhibitors (Asakura et al., 2007, World J. Gastroenterol. 13(15):2145-9).
  • SLE Systemic lupus erythematosus
  • T cell-mediated B-cell activation results in glomerulonephritis and renal failure.
  • Human SLE is characterized at early stages by the expansion of long-lasting autoreactive CD4 + memory cells (D'Cruz et al., 2007, Lancet 369(9561):587-596).
  • Psoriasis is a chronic inflammatory dermatosis that affects approximately 2% of the population. It is characterized by red, scaly skin patches that are usually found on the scalp, elbows, and knees, and may be associated with severe arthritis. The lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis (Sch ⁇ n et al., 2005, New Engl. J. Med. 352: 1899-1912).
  • MS Multiple sclerosis
  • Asthma is a complex syndrome with many clinical phenotypes in both adults and children. Its major characteristics include a variable degree of air flow obstruction, bronchial hyperresponsiveness, and airway inflammation (Busse and Lemanske, 2001, N. Engl. J. Med. 344:350-362).
  • COPD chronic obstructive pulmonary disease
  • COPD chronic inhalation of irritants causes an abnormal inflammatory response, remodeling of the airways, and restriction of airflow in the lungs.
  • the inhaled irritant is usually tobacco smoke, but occupational dust and environmental pollution are variably implicated (Shapiro 2005, N. Engl. J. Med. 352, 2016-2019).
  • Pancreatitis is the inflammation of the pancreas.
  • Acute pancreatitis is a condition that develops when the pancreas is damaged by inflammation that leads to swelling and sometimes to necrosis of part of the pancreas (Carroll et al., 2007. American Family Physiscian 75(1): 1513-1520).
  • acute pancreatitis widespread injury to the pancreas over many years may cause extensive scarring and destruction of the pancreas. It was demonstrated that PI3K ⁇ plays a role in a mouse model for pancreatitis.
  • mice lacking PI3K ⁇ The lethality of of the choline-deficient/ethionine-supplemented diet-induced pancreatitis was significantly reduced in mice lacking PI3K ⁇ (Lupia et al., 2004. Am. J. Pathol. 165(6):2003-2011).
  • Acute gouty inflammation is the consequence of the deposition of monosodium urate crystals in joints. Neutrophils appear to be the major effector of acute gout, accumulating in the joint fluid where they actively ingest urate crystals, aggregate and degranulate. Acute gouty inflammation as well as other diseases associated with crystal deposition like articular chondrocalcinosis, silicosis, soft tissue calcium deposit in patients with chronic renal failure, may be prevented by inhibition of neutrophils chemotaxis (Ryckman et al., 2003, Arthritis & Rheumatism 48 (8): 2310-20).
  • Cystic fibrosis is a hereditary disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), the product of which is a membrane protein thought to function as a chloride channel.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the lethal clinical manifestations are clearly related to the thick, infected mucous and chronic neutrophils-dominated airway inflammation.
  • An anti-inflammatory agent with direct effects on neutrophils may represent a good drug candidate for the clinical management of CF (Mclntosh et al., 1992, FASEB J 6:2775-82).
  • Familial Mediterranean Fever FMF is an autosomal recessive disorder characterised by recurrent and reversible attacks of fever and serositis.
  • the inflammatory episodes are characterized by massive influx of neutrophils into the serosal and synovial membranes. Secondary amyloidosis, a consequence of long-standing inflammation, is the most sever complication of the disease. Inhibitors of neutrophils activation may result beneficial for the amelioration of the disease (Molad et al., 2004, J. Investig. Med. 52(1):58-61).
  • Tissue damage after acute bacterial infection may partly result from excessive neutrophils infiltration and activation in the infected tissue.
  • bacteria in the kidney parenchyma trigger a burst of neutrophils extravascular migration.
  • renal scarring after acute bacterial pyelonephritis results from parenchymal damage by neutrophils.
  • Tissue damages following infections in pyelonephritis, osteomyelitis, endocaditis, endotoxic shock and acute respiratory distress syndrome may be prevented by inhibition of neutrophils activation (Bille et al., 1982, J. Infect. Dis. 146:220-6).
  • Sweet's syndrome (named acute febrile neutrophilic dermatosis) is characterized by a constellation of clinical symptoms which include pyrexia, elevated neutrophil count, tender erythematous skin lesions and a diffuse infiltrate consisting predominantly of mature neutrophils typically located in the upper dermis. Inhibition of neutrophils activation may represent a therapy for patient suffering from Sweet's syndrome (Cohen, 2007, Orphanet J. Rare Dis. 2:34).
  • Anaphylaxis is an acute systemic and severe type I hypersensitivity allergic reaction.
  • Anaphylactic shock is the most severe type of anaphylaxis.
  • Anaphylactic shock is a sudden, life-threatening allergic reaction associated with severe hypotension.
  • Platelet- activating factor (PAF) is implicated in the cardiovascular dysfunctions occurring in various shock syndromes, including anaphylaxis. Excessive production of the vasodilator NO causes inflammatory hypotension and shock.
  • eNOS the endothelial isoform of nitric oxide synthase, as a mediator of anaphylaxis and defines PI3K as new potential targets for treating anaphylaxis (Cauwels et al, 2006, J. Clin. Invest. 116(8):2244-51).
  • PBK diseases and disorders associated especially with PBK are cancer, cardiovascular disorders metabolic diseases, neurodegenerative disorders or infectious diseases.
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of cancer, metabolic diseases, neurodegenerative disorders, infectious diseases or cardiovascular disorders, more specifically myocardial infarction, stroke, ischemia or atherosclerosis.
  • Cancer comprises a group of diseases characterized by uncontrolled growth and spread of abnormal cells. All types of cancers generally involve some abnormality in the control of cell growth, division and survival, resulting in the malignant growth of cells. Key factors contributing to said malignant growth of cells are independence from growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, and genome instability (Hanahan and Weinberg, 2000. The Hallmarks of Cancer. Cell 100, 57-70).
  • cancers are classified as hematological cancers (for example leukemias and lymphomas) and solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • hematological cancers for example leukemias and lymphomas
  • solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • Obesity and diabetes mellitus type 2 represent metabolic diseases with a steadily increasing health risk worldwide.
  • Leptin secreted by adipose tissue and acting in part through its hypothalamic receptor, integrates the energy state of peripheral organs and the action of the central nervous system inhibiting food intake and stimulating energy expenditure.
  • the pancreas-derived peptide hormone insulin enters the central nervous system (CNS) through the blood-brain barrier by receptor-mediated transport to regulate food intake, sympathetic activity and peripheral insulin action through the inhibition of hepatic gluconeogenesis and reproductive endocrinology.
  • PI3K phosphatidylinositol 3-kinase
  • neuronal IR signaling has a direct role in the link between energy homeostasis, reproduction and the development of neurodegenerative diseases such as Alzheimer's disease (Plum et al., 2005, Trends Endocrinol. Metab. 16(2):59-65).
  • Leptin causes a delayed apoptosis of mature neutrophils through a signaling cascade involving PI3K (Bruno et al., 2005, J. Immunol. 174: 8090-96).
  • PI3K inhibitors may be beneficial in the treatment of diseases where the processes mentioned above are involved.
  • Obesity is associated with a state of chronic inflammation believed to play a role in the development of insulin resistance.
  • This low-grade state of inflammation is characterized by macrophage infiltration into adipose tissue and the chemokine Monocyte Chemoattractant Protein- 1 (MCPl) has been identified as a key player in this process.
  • MCPl Monocyte Chemoattractant Protein- 1
  • Signaling downstream of the chemokine receptor CCR2, a MCPl receptor is partly controlled by PI3K ⁇ .
  • Pi3K ⁇ -/- knockout mice kept on high-fat diet have shown an obesity resistant phenotype, with a decreased efficiency of weight-gain per food intake and improved glucose and insulin tolerance (Solinas et al., 2008.
  • PI3K phosphoinositide 3-kinase signaling pathway
  • Activation of PI3K in virus-infected cells is mediated by the viral NS l protein, which binds directly to the p85beta regulatory subunit of PBK and causes the PI3K-dependent phosphorylation of Akt (protein kinase B).
  • Akt protein kinase B
  • the PDK pathway could be a novel target for the development of future anti-influenza drugs (Ehrhardt et al., 2007, J. Virol. 81 (7): 3058-67; Hale et al., 2006, PNAS 103, 14194-14199).
  • Another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with PI3K, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of immunological; inflammatory; and allergic disorders, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.
  • the one or more conditions are selected from the group consisting of autoimmune diseases; organ and bone marrow transplant rejection; graft-versus-host disease; acute or chronic inflammation; pancreatitis; contact dermatitis; psoriasis; rheumatoid arthritis; multiple sclerosis; type I diabetes; inflammatory bowel disease; Crohn's disease; ulcerative colitis; systemic lupus erythematosus; asthma; chronic obstructive pulmonary disease (COPD); acute respiratory distress syndrome (ARDS); bronchitis; conjunctivitis; dermatitis; and allergic rhinitis; acute gouty inflammation; cystic fibrosis; familial Mediterranean fever; tissue damage after bacterial infection; Sweet's syndrome; or anaphylaxis.
  • autoimmune diseases include organ and bone marrow transplant rejection; graft-versus-host disease; acute or chronic inflammation; pancreatitis; contact dermatitis; psoriasis; rheumatoi
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus
  • psoriasis psoriasis
  • MS multiple sclerosis
  • COPD chronic obstructive pulmonary disease
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of cancer; metabolic diseases; neurodegenerative disorders; infectious diseases and cardiovascular disorders, more specifically myocardial infarction, stroke, ischemia or atherosclerosis, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.
  • treating or “treatment” is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • the compounds of the invention may also modulate in addition or alternatively immune cell activation via inhibition of PI3K.
  • PI3K immune cell activation via inhibition of PI3K.
  • PBK ⁇ and PI3K ⁇ important roles of PBK ⁇ and PI3K ⁇ in signaling and other functions of T cells, B cells, neutrophils, macrophages and mast cells indicate that these kinases are valid therapeutic targets for several inflammation-mediated diseases.
  • These diseases comprise rheumatoid arthritis (in which T cells, B cells and neutrophils are involved), systemic lupus erythematosus (in which neutrophils are involved), psoriasis (in which T cells, neutrophils and macrophages are engaged), multiple sclerosis (in which T cells, B cells and mast cells are implicated), asthma (for which T cell and mast cells are important), and chronic obstructive pulmonary disease (which involves neutrophils, macrophages and T cells) (Rommel et al., 2007, Nat. Rev. Immunology 7:191-201).
  • the link between PBK ⁇ and PI3K ⁇ as potential drug targets for specific diseases has been experimentally established by testing the respective PI3K-null mice in animal disease models. Additional pharmacological confirmation was obtained by using small molecule PI3K inhibitors in wild-type mice in which inflammatory diseases were experimentally induced.
  • Camps and colleagues used structure-based drug design to develop a potent small molecule inhibitor of PIK3 ⁇ referred to as AS-605240 (Camps et al, 2005. Nat. Med. 11 (9): 936-43). It was observed that Pik3cg-null mice were protected against arthritis induced by collagen Il-specific antibodies, a murine model of lymphocyte-independent rheumatoid arthritis (RA) associated with neutrophil activation. The effect was associated with impaired neutrophil chemotaxis. Treatment of wildtype mice with oral AS-605420 resulted in reduced clinical and histologic signs of collagen II-antibody- induced arthritis, similar to that seen in the Pik3cg-null mice.
  • RA lymphocyte-independent rheumatoid arthritis
  • Oral AS-605240 also resulted in decreased joint inflammation and damage in a distinct mouse model of lymphocyte-dependent rheumatoid arthritis induced by direct collagen II injection.
  • the authors concluded that PIK3CG inhibition operates on both the neutrophil and lymphocyte arms of chemokine signaling pathways, and thus may be of therapeutic value in various chronic inflammatory diseases.
  • PI3 kinases The involvement of PI3 kinases in allergic inflammatory diseases such as asthma was demonstrated through pharmacological inhibition by non-selective PI3K inhibitors such as wortmannin and LY294002. However, these compounds were not selective enough to discriminate between distinct PI3K isoforms (Walker et al., 2006, Drug Discovery Today: Disease Mechanisms, 3(l):63-69).
  • PBK ⁇ plays a role in neutrophil inflammatory responses. Inhibition of PBK ⁇ blocked both fMLP- and TNF l ⁇ - induced neutrophil superoxide generation and elastase exocytosis (Sadhu et al., 2003, Biochem. Biophys. Res. Commun. 2003 Sep 5; 308(4):764-769).
  • PBK ⁇ The essential role of PBK ⁇ in allergic responses was demonstrated by genetic and pharmacological inactivation of PBK ⁇ in mast cells. This inhibition leads to to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Moreover, inactivation of PBK ⁇ protects mice against anaphylactic allergic responses. Taken together, these studies suggest PBK ⁇ as a target for therapeutic intervention in allergy and mast-cell- related diseases (AIi et al., 2004, Nature 431 :1007-1011).
  • diseases and disorders are preferred which are associated with PBK delta and/or PBK gamma.
  • diseases and disorders are preferred which are associated with PBK delta and/or PBK gamma.
  • inflammatory and immunoregulatory disorders rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, multiple sclerosis, asthma and chronic obstructive pulmonary disease.
  • PBK also plays a role with regard to cancer and cardiovascular disorders.
  • PDK ⁇ has been proposed as a possible target for pharmacological intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.
  • Atherosclerosis and its sequelae, including myocardial infarction and stroke, are the leading causes of mortality and morbidity in the developed world.
  • PBK ⁇ is activated in macrophages by oxidized LDL, agonists, chemokines and inflammatory mediators commonly implicated in atherogenesis.
  • Genetic ablation of PI3Kg in hypercholesterolemic mice (apoE-/-) results in reduced atherosclerotic lesions.
  • apoE-/- hypercholesterolemic mice
  • it is of clinical relevance the possibility that the inhibition of PBK might affect plaque stability (Chang et al., 2007, PNAS 104 (19):8077-82).
  • PBK ⁇ phosphatidylinositol(3,4,5)-trisphosphate
  • PIP3 phosphatidylinositol(3,4,5)-trisphosphate
  • the study of mice lacking PBK ⁇ revealed that the PIP3 signaling pathway controls immune cell and vascular functions such as respiratory burst, cell recruitment, mast cell reactivity, platelet aggregation, endothelial activation and smooth muscle cell contractility. The specificity of these events suggests that inhibition of PBK ⁇ may be beneficial for major cardiovascular disorders such as hypertension (Hirsch et al., 2006, Thromb. Haemost. 95(l):29-35).
  • MI Myocardial infarction
  • I/R biphasic ischemia/reperfusion
  • This compound potently inhibits edema and inflammation in response to multiple mediators known to play a role in myocardial infarction. Importantly, this was achieved when dosing after myocardial reperfusion (up to 3 hours later), the same time period when patients are most accessible for therapeutic intervention (Doukas et al., 2006, PNAS 103(52): 19866- 19871; Doukas et al., 2007, Biochem. Soc. Trans. 35(Pt2):204-206; Palanki et al., 2007, J. Med. Chem. 50(18)4279-4294).
  • PIK3CA mutants promote cell growth and invasion of human cancer cells and that treatment with the non-selective PI3K inhibitor LY294002 abrogated PIK3 A signaling and preferentially inhibited growth of PI3KCA mutant cells (Samuels et al., 2005, Cancer Cell 7(6):561-573), thus suggesting PI3K proteins as promising drug targets for cancer therapy.
  • pl lObeta protein has an important physiological function in metabolic regulation and glucose homeostasis, cell proliferation and trafficking, partially via a kinase-independent mechanism.
  • the kinase activity of pl lObeta drives oncogenic transformation as shown in a mouse prostate tumour model identifying pl lObeta as a promising drug target for kinase inhibitors useful for the treatment of cancer (Jia et al., 2008. Nature 454(7205):776- 779).
  • PI3K ⁇ inhibitors may be useful for stem cell mobilization.
  • HPCs hematopoietic progenitor/stem cells
  • Recruitment of HPCs from the marrow into the blood is termed mobilization, or, more commonly, stem cell mobilization.
  • PBSC peripheral blood stem cell transplant is commonly employed in the treatment of myeloma patients in order to restore the immune system after high-dose chemotherapy treatments.
  • stromal cell-derived factor (SDF l ) binding to its receptor CXCR4 has been shown to induce rapid mobilization of hematopoietic stem cells (Chavakis et al., 2008. Circulation Research 102(8):942-949).
  • SDF l stromal cell-derived factor
  • PI3K ⁇ is involved in the signaling downstream CXCR4
  • small molecule PI3K ⁇ inhibitors may be useful for the mobilization of stem cells.
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally.
  • Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other PI3K inhibitors.
  • Other active ingredients for use in combination with other therapies for the treatment of immune, inflammatory, allergic disorders may include steroids, leukotriene antagonists, anti-histamines, cyclosporine or rapamycin.
  • a pharmaceutical composition of the present comprises one or more active ingredients. It is also possible that a combination of two or more pharmaceutical compositions is used with at least one pharmaceutical composition of the present invention.
  • combination of a compound of formula (I) or pharmaceutically acceptable salt, prodrug or metabolite thereof with another active ingredient may be employed in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compound according to the invention is conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafiuoroethane, a hydrofluoroalkane such as tetrafluoroethane or heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafiuoroethane, a hydrofluoroalkane such as tetrafluoroethane or heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafiuor
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • a therapeutically effective amount of a compound of the present invention will normally depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration.
  • an effective amount of a compound of formula (I) for the treatment of an inflammatory disease for example rheumatoid arthritis (RA) will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a pharmaceutically acceptable salt, prodrug or metabolite thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • the compounds of the formula (I) can be purified by customary purification procedures, for example by distillation, recrystallization or chromatography.
  • the starting compounds for the preparation of the compounds of the formula (I) are commercially available or can be prepared according to or analogously to literature procedures.
  • compounds of the present invention may be prepared by the following method for the preparation of a compound according to formula (I), comprising the step of
  • Analogues compounds of the present invention may be prepared in an analogues way. Further analogues routes are described in WO-A 2008/025821 and/or are known to a practitioner in the art.
  • NMR spectra were obtained on a Brucker dpx400.
  • LCMS was carried out on an Agilent 1100 using a Gemini C18, 3 x 30 mm, 3 micron or Gemini C18, 4.6 x 150 mm, 5 microns column. Column flow was 1.0 or 1.2 mL/min. and solvents used were water and acetonitrile (0.1% formic acid) with an injection volume of 3 or lO ⁇ l. Wavelengths were 254 and 210nm.
  • PI3K lipid kinase activity can be measured using purified or recombinant enzyme in a solution-based assay with phopholipid vesicles.
  • the reaction is terminated by the addition of acidified organic solvents and subsequent phase separation by extraction or thin layer chromatography analysis (Carpenter et al., 1990, J. Biol. Chem. 265, 19704-19711).
  • Another assay described in the art is based on the phosphate transfer from radiolabeled ATP to phosphatidylinositol immobilized on plates.
  • This assay type also uses recombinant PI3K gamma enzyme but can be performed in a high throughput mode (Fuchikami et al., 2002, J. Biomol. Screening 7, 441-450).
  • test compounds as described were tested in the PI3K kinobeads assay as described (EP-A 1 887 359; WO-A 2008/015013). Briefly, test compounds (at various concentrations) and the affinity matrix with the immobilized phenylthiazole ligand 1 were added to cell lysate aliquots and allowed to bind to the proteins in the lysate sample. After the incubation time the beads with captured proteins were separated from the lysate.
  • Bound proteins were then eluted and the presence of PI3K gamma, PDK alpha, PBK beta, PBK delta and DNA-dependent protein kinase (DNA-PK) was detected and quantified using a specific antibody in a dot blot procedure and the Odyssey infrared detection system.
  • DNA-PK DNA-dependent protein kinase

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Abstract

L'invention concerne des composés de formule (I) dans laquelle X1, R et R1 à R4 ont la signification citée dans la description et les revendications. Lesdits composés sont utiles en tant qu'inhibiteurs de protéine kinases, spécialement des inhibiteurs de la Pi3K, pour le traitement ou la prophylaxie de troubles immunologiques, inflammatoires, auto-immuns ou allergiques. L'invention concerne également des compositions pharmaceutiques renfermant lesdits composés, la préparation de tels composés ainsi que leur production et utilisation en tant que médicaments.
PCT/EP2010/051462 2009-02-10 2010-02-08 Dérivés d'urée-triazolo[1,5-a]pyridine en tant qu'inhibiteurs de pi3k WO2010092015A1 (fr)

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US8501936B2 (en) 2009-06-05 2013-08-06 Cephalon, Inc. Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
US8551980B2 (en) 2009-11-30 2013-10-08 Bayer Intellectual Property Gmbh Substituted triazolopyridines
WO2014072937A1 (fr) 2012-11-08 2014-05-15 Rhizen Pharmaceuticals Sa Compositions pharmaceutiques contenant un inhibiteur de pde4 et un inhibiteur de pi3 kinase delta ou un double inhibiteur de pi3 kinase delta et gamma
US9512126B2 (en) 2012-03-14 2016-12-06 Bayer Intellectual Property Gmbh Substituted imidazopyridazines
US9555022B2 (en) 2010-06-16 2017-01-31 Bayer Intellectual Property Gmbh Substituted triazolopyridines
US9586958B2 (en) 2013-06-11 2017-03-07 Bayer Pharma Aktiengesellschaft Prodrug derivatives of substituted triazolopyridines
US9663510B2 (en) 2011-12-12 2017-05-30 Bayer Pharma Aktiengesellschaft Substituted triazolopyridines and their use as TTK inhibitors
US9676766B2 (en) 2009-11-30 2017-06-13 Bayer Intellectual Property Gmbh Triazolopyridines

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501936B2 (en) 2009-06-05 2013-08-06 Cephalon, Inc. Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
US8633173B2 (en) 2009-06-05 2014-01-21 Cephalon, Inc Preparation and uses of 1,2,4-triazolo [1,5a] pyridine derivatives
WO2011064328A1 (fr) * 2009-11-30 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Derives de triazolopyridines
US8551980B2 (en) 2009-11-30 2013-10-08 Bayer Intellectual Property Gmbh Substituted triazolopyridines
US9676766B2 (en) 2009-11-30 2017-06-13 Bayer Intellectual Property Gmbh Triazolopyridines
US9555022B2 (en) 2010-06-16 2017-01-31 Bayer Intellectual Property Gmbh Substituted triazolopyridines
US9663510B2 (en) 2011-12-12 2017-05-30 Bayer Pharma Aktiengesellschaft Substituted triazolopyridines and their use as TTK inhibitors
US9512126B2 (en) 2012-03-14 2016-12-06 Bayer Intellectual Property Gmbh Substituted imidazopyridazines
WO2014072937A1 (fr) 2012-11-08 2014-05-15 Rhizen Pharmaceuticals Sa Compositions pharmaceutiques contenant un inhibiteur de pde4 et un inhibiteur de pi3 kinase delta ou un double inhibiteur de pi3 kinase delta et gamma
US9586958B2 (en) 2013-06-11 2017-03-07 Bayer Pharma Aktiengesellschaft Prodrug derivatives of substituted triazolopyridines

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