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WO2015091531A1 - Dérivés d'imidazopyridmin-2-yl comme inhibiteurs de la jak - Google Patents

Dérivés d'imidazopyridmin-2-yl comme inhibiteurs de la jak Download PDF

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WO2015091531A1
WO2015091531A1 PCT/EP2014/078037 EP2014078037W WO2015091531A1 WO 2015091531 A1 WO2015091531 A1 WO 2015091531A1 EP 2014078037 W EP2014078037 W EP 2014078037W WO 2015091531 A1 WO2015091531 A1 WO 2015091531A1
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group
pyridin
piperidin
fluoroimidazo
fluoro
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Jordi Bach Taña
Daniel Perez Crespo
Oriol Llera Soldevila
Cristina Esteve Trias
Lorena Taboada Martinez
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Almirall SA
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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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • Cytokines have critical functions in regulating many aspects of immunity and inflammation, ranging from the development and differentiation of immune cells to the suppression of immune responses.
  • Type I and type II cytokine receptors lack intrinsic enzymatic activity capable of mediating signal transduction, and thus require association with tyrosine kinases for this purpose.
  • the JAK family of kinases comprises four different members, namely JAK1 , JAK2, JAK3 and TYK2, which bind to type I and type II cytokine receptors for controlling signal transduction (Murray PJ, (2007).
  • the JAK-STAT signalling pathway input and output integration. J Immunol, 178: 2623).
  • Each of the JAK kinases is selective for the receptors of certain cytokines.
  • JAK-deficient cell lines and mice have validated the essential role of each JAK protein in receptor signalling: JAK1 in class II cytokine receptors (I FN and IL-10 family), those sharing the gp130 chain (IL-6 family) and the common gamma chain (IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21 ) (Rodig et al. (1998). Disruption of the JAK1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biological response. Cell, 93:373; Guschin et al. (1995).
  • JAK1 protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.
  • Kinase-negative mutants of JAK1 can sustain intereferon-gamma-inducible gene expression but not an antiviral state.
  • JAK2 is essential for signalling through a variety of cytokine receptors.
  • JAK3 in receptors sharing the common gamma chain (IL-2 family)
  • IL-2 family common gamma chain
  • Park et al. (1995). Developmental defects of lymphoid cells in JAK3 kinase-deficient mice. Immunity, 3:771 ; Thomis et al., (1995). Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking JAK3. Science, 270:794; Russell et al., (1995). Mutation of JAK3 in a partient with SCID: Essential role of JAK3 in lymphoid development.
  • Receptor stimulation leads sequentially to JAK activation by phosphorylation, receptor phosphorylation, STAT protein recruitment and STAT activation and dimerization.
  • the STAT dimer then functions as a transcription factor, translocating to the nucleus and activating the transcription of multiple response genes.
  • STAT1 STAT2
  • STAT3, STAT4 STAT5a
  • STAT5b STAT6
  • Each particular cytokine receptor associates preferentially with a particular STAT protein.
  • Some associations are independent of cell type (ex: IFNg- STAT1 ) while others may be cell type dependent (Murray PJ, (2007).
  • the JAK-STAT signaling pathway input and output integration. J Immunol, 178: 2623).
  • JAK3 associates exclusively with the common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines.
  • JAK3 knock out mice and common gamma chain deficient mice have an identical phenotype (Thomis et al., (1995).
  • JAK3-deficient mice are viable but display abnormal lymphopoiesis which leads to a reduced thymus size (10-100 fold smaller than wild type). JAK3-deficient peripheral T cells are unresponsive and have an activated/memory cell phenotype (Baird et al., (1998). T cell development and activation in JAK3-deficient mice. J. Leuk. Biol. 63: 669).
  • Interleukin (IL)-7 Gene-deleted Mice Identifies IL-7 as a non-redundant Cytokine. J Exp Med, 181 :1519; Peschon et al, (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med, 180: 1955). These mice, like SCID humans, have no NK cells, probably due to the absence of IL-15 signaling, a survival factor for these cells. JAK3 knockout mice, unlike SCID patients, show deficient B cell lymphopoiesis while in human patients, B cells are present in circulation but are not responsive leading to hypoglobulinemia (O'Shea et al., (2004).
  • JAK2 -deficient mice are embrionically lethal, due to the absence of definitive erythropoiesis.
  • Myeloid progenitors fail to respond to Epo, Tpo, IL-3 or GM-CSF, while G-CSF and IL-6 signaling are not affected.
  • JAK2 is not required for the generation, amplification or functional differentiation of lymphoid progenitors (Parganas et al., (1998). JAK2 is essential for signaling through a variety of cytokine receptors. Cell, 93:385).
  • JAK1 -deficient mice die perinatally due to a nursing defect.
  • JAK1 binds exclusively to the gp130 chain shared by the IL-6 cytokine family (i.e. LIF, CNTF, OSM, CT-1 ) and along with JAK3, is an essential component of the receptors sharing the common gamma chain, by binding to the non-shared receptor subunit.
  • JAK1 - deficient mice show similar hematopoiesis defects as JAK3-deficient mice. In addition, they show defective responses to neurotrophic factors and to all interferons (class II cytokine receptors) (Rodig et al., (1998). Disruption of the JAK1 gene demonstrates obligatory and non-redundant roles of the JAKs in cytokine-induced biological response. Cell, 93:373).
  • Tyk2-deficient mice show an impaired response to IL-12 and IL-23 and only partially impaired to IFN-alpha (Karaghiosoff et al., (2000). Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity, 13:549; Shimoda et al., (2000). Tyk2 plays a restricted role in IFNg signaling, although it is required for IL-12-mediated T cell function. Immunity, 13:561 ). However, human Tyk2 deficiency demonstrates that Tyk2 is involved in the signaling from IFN-a, IL-6, IL-10, IL-12 and IL-23 (Minegishi et al., (2006). Human Tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity, 25:745).
  • JAK kinases in transducing the signal from a myriad of cytokines makes them potential targets for the treatment of diseases in which cytokines have a pathogenic role, such as inflammatory diseases, including but not limited to allergies and asthma, chronic obstructive pulmonary disease (COPD), psoriasis, autoimmune diseases such as rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, uveitis, transplant rejection, as well as in solid and hematologic malignancies such as myeloproliferative disorders, leukemia and lymphomas.
  • COPD chronic obstructive pulmonary disease
  • psoriasis psoriasis
  • autoimmune diseases such as rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis
  • uveitis uveitis
  • transplant rejection as well as in solid and hematologic malignancies such as myeloproliferative disorders, le
  • JAK inhibitor CP-690,550 tofacitinib, formerly tasocitinib
  • CP-690,550 has shown efficacy in several animal models of transplantation (heretopic heart transplantation in mice, cardiac allografts implanted in the ear of mice, renal allotransplantation in cynomolgous monkeys, aorta and tracheal transplantation in rats) by prolonging the mean survival time of grafts (West K (2009).
  • CP-690,550 a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr. Op. Invest. Drugs 10: 491 ).
  • IL-6 rheumatoid arthritis
  • RA rheumatoid arthritis
  • IL-6 activates the transcription factor STAT3, through the use of JAK1 binding to the gp130 receptor chain (Heinrich et al., (2003). Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochem J. 374: 1 ).
  • JAK inhibitors for signal transduction, making JAK inhibitors potential pleiotropic drugs in this pathology. Consequently, administration of several JAK inhibitors in animal models of murine collagen-induced arthritis and rat adjuvant- induced arthritis has shown to reduce inflammation, and tissue destruction (Milici et al., (2008). Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arth. Res. 10:R14).
  • IBD Inflammatory bowel disease
  • cytokines including interleukins and interferons
  • Activation of the IL-6/STAT3 cascade in lamina propia T cells has been shown to induce prolonged survival of pathogenic T cells (Atreya et al, (2000).
  • Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn's disease and experimental colitis in vivo. Nature Med. 6:583).
  • STAT3 has been shown to be constitutively active in intestinal T cells of Crohn's disease patients and a JAK inhibitor has been shown to block the constitutive activation of STAT3 in these cells (Lovato et al, (2003). Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease. J Biol Chem. 278:16777).
  • Multiple sclerosis is an autoimmune demyelinating disease characterized by the formation of plaques in the white matter.
  • cytokines include blockade of IFN-g, IL-6, IL-12 and IL-23 (Steinman L. (2008). Nuanced roles of cytokines in three major human brain disorders. J Clin Invest. 1 18:3557), cytokines that signal through the JAK- STAT pathways.
  • Use of tyrphostin, a JAK inhibitor has been shown to inhibit IL-12- induced phosphorylation of STAT3, and to reduce the incidence and severity of active and passive experimental autoimmune encephalitis (EAE) (Bright et al., (1999)
  • Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol. 162:6255).
  • Another multikinase inhibitor, CEP701 has been shown to reduce secretion of TNF- alpha, IL-6 and IL-23 as well as the levels of phospho-STAT1 , STAT3, and STAT5 in peripheral DCs of mice with EAE, significantly improving the clinical course of EAE in mice (Skarica et al, (2009). Signal transduction inhibition of APCs diminishes Th17 and Th1 responses in experimental autoimmune encephalomyelitis. J. Immunol.
  • Psoriasis is a skin inflammatory disease which involves a process of immune cell infiltration and activation that culminates in epithelial remodeling.
  • the current theory behind the cause of psoriasis states the existence of a cytokine network that governs the interaction between immune and epithelial cells (Nickoloff BJ. (2007). Cracking the cytokine code in psoriasis, Nat Med, 13:242).
  • IL-23 produced by dendritic cells is found elevated in psoriatic skin, along with IL-12.
  • IL-23 induces the formation of Th17 cells which in turn produce IL-17 and IL-22, the last one being responsible for epidermis thickening.
  • IL-23 and IL-22 induce the phosphorylation of STAT-3, which is found abundantly in psoriatic skin. JAK inhibitors may thus be therapeutic in this setting.
  • a JAK1/3 inhibitor, R348 has been found to attenuate psoriasiform skin inflammation in a spontaneous T cell-dependent mouse model of psoriasis (Chang et al., (2009). JAK3 inhibition significantly attenuates psoriasiform skin inflammation on CD18 mutant PL/J mice. J Immunol. 183:2183).
  • Th2 cytokine-driven diseases such as allergy and asthma could also be a target of JAK inhibitors.
  • IL-4 promotes Th2 differentiation, regulates B-cell function and
  • immunoglobulin class switching regulates eotaxin production, induces expression of IgE receptor and MHC II on B cells, and stimulates mast cells.
  • Other Th2 cytokines like IL-5 and IL-13 can also contribute to eosinophil recruitment in bronchoalveolar lavage by stimulating eotaxin production.
  • Pharmacological inhibition of JAK has been shown to reduce the expression of IgE receptor and MHCII induced by IL-4 stimulation on B cells (Kudlacz et al., (2008).
  • the JAK3 inhibitor CP-690,550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia. European J. Pharm. 582: 154).
  • JAK3-deficient mice display poor eosinophil recruitment and mucus secretion to the airway lumen upon OVA challenge, as compared to wild type mice (Malaviya et al, (2000). Treatment of allergic asthma by targeting Janus kinase 3- dependent leukotriene synthesis in mast cells with 4-(3', 5'- dibromo-4'- hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97). JP£7295:912.).
  • cytokines play a pathogenetic role in ocular inflammatory disease such as uveitis or dry eye syndrome.
  • JAK inhibition vallochi et al, (2007).
  • drugs or biologicals that interfere with IL-2 signaling such as cyclosporine or anti-IL-2 receptor antibody (daclizumab) have shown efficacy in the treatment of keratoconjuctivitis sicca and refractory uveitis, respectively (Lim et al, (2006). Biologic therapies for inflammatory eye disease. Clin Exp Opht 34:365).
  • allergic conjunctivitis a common allergic eye disease characterized by conjuctival congestion, mast cell activation and eosinophil infiltration, could benefit from JAK inhibition.
  • STAT3 as a target for inducing apoptosis in solid and haematological tumors. Cell Res. 18: 254).
  • Antagonism of STAT3 by means of dominant-negative mutants or antisense oligonucleotides has shown to promote apoptosis of cancer cells, inhibition of angiogenesis and up-regulation of host immunocompetence.
  • Inhibition of constitutively active STAT3 in human tumors by means of JAK inhibitors may provide a therapeutic option to the treatment of this disease.
  • the use of the JAK inhibitor tyrphostin has been shown to induce apoptosis of malignant cells and inhibit cell proliferation in vitro and in vivo (Meydan et al., (1996).
  • JAK-2 inhibitor Inhibition of acute lymphoblastic leukemia by a JAK-2 inhibitor. Nature, 379:645). Hematological malignancies with dysregulated JAK-STAT pathways may benefit from JAK inhibition. Recent studies have implicated dysregulation of JAK2 kinase activity by chromosomal translocations and mutations within the pseudokinase domain (such as the JAK2V617F mutation) in a spectrum of myeloproliferative diseases (Ihle and Gililand, 2007), including polycythemia vera, myelofibrosis and essential
  • JAK inhibitors that tackle JAK2 such as TG-101209 (Pardanani et al., (2007). TG101209, a small molecular JAK2-selective inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations Leukemia. 21 :1658-68), TG101348 (Wernig et al, (2008). Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera.
  • CEP701 is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with
  • JAK inhibitors may be therapeutic in this setting (Tomita et al, (2006). Inhibition of constitutively active JAK-STAT pathway suppresses cell growth of human T-cell leukemia virus type I- infected T cell lines and primary adult T-cell leukemia cells. Retrovirology, 3:22). JAK1 - activating mutations have also been identified in adult acute lymphoblastic leukemia of T cell origin (Flex et al, (2008). Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J. Exp. Med. 205:751 -8) pointing to this kinase as a target for the development of novel antileukemic drugs.
  • Conditions in which targeting of the JAK pathway or modulation of the JAK kinases, particularly JAK1 , JAK2 and JAK3 kinases, are contemplated to be therapeutically useful for the treatment or prevention of diseases include: neoplastic diseases (e.g. leukemia, lymphomas, solid tumors); transplant rejection, bone marrow transplant applications (e.g., graft- versus-host disease); autoimmune diseases (e.g. diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease); respiratory inflammation diseases (e.g. asthma, chronic obstructive pulmonary disease), inflammation-linked ocular diseases or allergic eye diseases (e.g.
  • neoplastic diseases e.g. leukemia, lymphomas, solid tumors
  • transplant rejection e.g., bone marrow transplant applications (e.g., graft- versus-host disease)
  • autoimmune diseases e.g. diabetes, multiple sclerosis, rheumatoid arthritis
  • dry eye dry eye, glaucoma, uveitis, diabetic retinopathy, allergic conjunctivitis or age-related macular degeneration
  • skin inflammatory diseases e.g., atopic dermatitis or psoriasis
  • novel pyrimidin-2-yl derivatives for use in the treatment of conditions in which targeting of the JAK pathway or inhibition of JAK kinases can be therapeutically useful.
  • the compounds described in the present invention are simultaneously potent JAK1 , JAK2 and JAK3 inhibitors, i.e. pan-JAK inhibitors. This property makes them useful for the treatment or prevention of pathological conditions or diseases such as
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia or myelofibrosis), leukemia, lymphomas and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), inflammation-linked ocular diseases or allergic eye diseases (such as dry eye, uveitis, or allergic conjunctivitis), allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), and skin inflammatory diseases (such as atopic dermatitis or psoriasis).
  • rheumatoid arthritis multiple sclerosis
  • inflammatory bowel disease such as ulcerative colitis or Crohn's disease
  • inflammation-linked ocular diseases or allergic eye diseases such as dry eye, uveitis, or allergic conjunctivitis
  • allergic rhinitis asthma,
  • Gi is selected from the group consisting of a linear or branched Ci -4 alkyl group, a monocyclic C 5- 8 aryl group, a monocyclic C 3- 8 cycloalkyi group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a saturated or non-saturated monocyclic 4- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the alkyl, aryl, cycloalkyi, heteroaryl and heterocyclyl groups are unsubstituted or substituted with one or more substituents selected from a halogen atom, a hydroxyl group, -CHO group, a Ci-2 alkyl group, a Ci -2 hydroxyalkyl group, a di (Ci -2 alkyl)amino-Ci -4 alkyl group, a Ci -2 carboxyalkyl group, oxo group, and
  • R 1 is selected from the group consisting of a hydrogen atom, a linear or branched Ci -4 alkyl group optionally substituted with a -NR'R" group or with -OH group, a monocyclic C 5 -8 aryl group, a monocyclic C 3- 8 cycloalkyl group, a mono- or bicyclic 5- to 14- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a mono- or bicyclic 5- to 14- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched Ci -6 alkyl group, a linear or branched Ci -6 hydroxyalkyl group, a linear or branched Ci -4
  • R 2 is selected from the group consisting of a halogen atom and a linear or branched, non-substituted Ci -4 alkyl group and a NH 2 group,
  • R 3 is selected from the group consisting of a hydrogen atom, a Ci -4 alkyl group and a -(CH 2 ) (2-4) NR'R"- group,
  • G 2 is selected from the group consisting of a monocyclic C 5- 8 aryl group, a mono or a bicyclic C3-10 cycloalkyl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N , wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl groups are
  • L 3 represents a direct bond, -CO- group, -S(0) 2 -(CH 2 )(o-i)- group, or a -C(0)0- group, a -N H-CO- group
  • R 4 is selected from the group consisting of a hydroxyl group, a -(CH 2 )(o-i)-CN group, a - CF 3 group, a mono cyclic 3 to 8-membered heterocyclyl group containing at least one heteroatom selected from N , O and S, a monocyclic C 5- 8 aryl group, a linear or branched Ci -4 alkyl group, a linear or branched C1-4 alkoxy group, a linear or branched Ci -4 hydroxyalkyi group, a Ci -2 haloalkyl and a Ci -4 aminoalkyl groupwherein the alkyl and the hydroxyalkyi groups are optionally substituted with one or more methyl groups,
  • R a and R b are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a Ci -4 alkyl group or R a and R b together with the carbon atom to which they are attached form a C 3- 6 cycloalkyl group or a 3- to 5-membered heterocyclic group containing at least one heteroatom selected from N , O and S,
  • R 5 is selected from the group consisting of a hydrogen atom and a linear or branched Ci_4 alkyl group
  • R c is selected from the group consisting of a hydrogen atom, a halogen atom, a Ci -4 alkyl group, a Ci -4 alkoxy group, a C 5- 8 aryl group, a 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a -N R'R" group, wherein the heteroaryl group is optionally substituted with one or more substituents selected form the group consisting of a halogen atom and a Ci -4 alkyl group,
  • R d represents a linear or branched Ci -4 alkyl group optionally substituted with one or more substituents selected from a phenyl group, a methyl group and a-N R'R",
  • R e is selected from the group consisting of a monocyclic C 5 - 8 aryl group and a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N, which cyclic ring are optionally substituted with one or more substituents selected from a hydroxyl group, a linear or branched Ci -4 alkyl group and a -CF 3 group, R' and R" independently represents a hydrogen atom, a Ci -4 alkyl group or a C 3- 6 cycloalkyl group, or R' and R" together with the nitrogen atom to which they are attached form a 4 to 6 membered N-containing heterocyclic group optionally containing one or more additional heteroatom selected from N, S and O, and optionally substituted with a dimethylamino group, n, m and q independently have a value of 0 or 1 , p has a value of 0, 1 or 2, with the proviso that the compound is not any one of the
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically-acceptable diluent or carrier.
  • the invention is also directed to the compounds of the invention as described herein, for use in the treatment of a pathological condition or disease susceptible to
  • JAK Janus Kinases
  • the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune- mediated diseases and inflammatory diseases; more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • COPD chronic obstructive pulmonary disease
  • the invention is also directed to use of the compounds of the invention as described herein, in the manufacture of a medicament for treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases; more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • JAK Janus Kinases
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis; comprising administering a therapeutically effective amount of the compounds of the invention or a pharmaceutical composition of the invention to a subject in need of such treatment.
  • JK Janus Kinases
  • the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome;
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis
  • COPD chronic obstructive pulmonary disease
  • the invention also provides a combination product comprising (i) the compounds of the invention as described herein; and (ii) one or more additional active substances which are known to be useful in the treatment of myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or mielofibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune- mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • myeloproliferative disorders such as polycythemia vera, essential thrombocythemia or mielofibrosis
  • Ci-C 6 alkyl embraces linear or branched radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, isopentyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, n-hexyl, 1 -ethylbutyl, 2- ethylbutyl, 1 ,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl and iso-hexyl radical
  • Ci-C 4 hydroxyalkyi embraces linear or branched alkyl radicals having 1 to 4 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxy methyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
  • C1-2 carboxyalkyl embraces alkyl radicals having 1 or 2 carbon atoms, any one of which may be substituted with one or more carboxy radicals. Examples of such radicals include carboxymethyl and carboxyethyl.
  • (Ci-C 4 )alkylamino embraces radicals containing an optionally substituted, linear or branched alkyl radicals of 1 to 4 carbon atoms attached to a divalent -NH- radical.
  • Preferred (Ci-C 4 )alkylamino radicals include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, sec-butylamino and t- butylamino.
  • di-(Ci-C 2 )alkylamino embraces radicals containing a trivalent nitrogen atoms with two linear or branched alkyl radicals of 1 to 2 carbon atoms in each alkyl radical.
  • Preferred di(Ci-C 2 )alkylamino radicals include dimethylamino
  • C1-C4 alkoxy (or alkyloxy) embraces linear or branched oxy- containing radicals each having alkyl portions of 1 to 4 carbon atoms.
  • Examples of C C 4 alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy or t-butoxy.
  • C 3 -C 8 cycloalkyi embraces saturated monocyclic carbocyclic radicals having from 3 to 8 carbon atoms, preferably from 3 to 7 carbon atoms.
  • An optionally substituted C 3 -C 8 cycloalkyi radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • substituents may be the same or different.
  • substituents on a C 3 -C 8 cycloalkyi group are themselves unsubstituted.
  • Examples of monocyclic cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C 5 -C 8 aryl radical embraces typically a C 5 -C 8 , preferably C 5 -C 6 monocyclic aryl radical such as phenyl.
  • a said optionally substituted C 5 -C 8 aryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • substituents on a C 5 -C 8 aryl group are typically themselves unsubstituted.
  • the term 5- to 14- membered heteroaryl radical embraces typically a 5- to 14- membered ring system, preferably a 5- to 10- membered ring system, more preferably a 5- to 6- membered ring system, comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N.
  • a 5- to 14- membered heteroaryl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom.
  • a said optionally substituted 5- to 14- membered heteroaryl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different.
  • substituents may be the same or different.
  • the substituents on a 5- to 14- membered heteroaryl radical are typically themselves unsubstituted.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2
  • the term 4- to 14-membered heterocyclyl radical embraces typically a non-aromatic, saturated or unsaturated C 4 -Ci 4 carbocyclic ring system, preferably C 5 - Cio carbocyclic ring system, more preferably C 5 -C 6 carbocyclic ring system, in which one or more, for example 1 , 2, 3 or 4 of the carbon atoms preferably 1 or 2 of the carbon atoms are replaced by a heteroatom selected from N, O and S.
  • a heterocyclyl radical may be a single ring or two or more fused rings wherein at least one ring contains a heteroatom. When a 5 to 14-membered heterocyclyl radical carries 2 or more substituents, the substituents may be the same or different.
  • a said optionally substituted 4- to 14-membered heterocyclyl radical is typically unsubstituted or substituted by 1 , 2 or 3 substituents which may be the same or different. Typically, the substituents on a 4 to 14-membered heterocyclyl radical are themselves unsubstituted.
  • Examples of 4- to 14-membered heterocyclyl radicals include azetidinyl, piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, pyrazolinyl, pirazolidinyl, quinuclidinyl, triazolyl, pyrazolyl, tetrazolyl, imidazolidinyl, imidazolyl, oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl, 4,5-dihydro-oxazolyl, 2- benzofuran-1 (3H)-one, 1 ,3-dioxol-2-one, tetrahydrofuranyl, 3-aza-tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl,
  • a 4- to 14-membered heterocyclyl radical carries 2 or more substituents
  • the substituents may be the same or different.
  • atoms, radicals, moieties, chains and cycles present in the general structures of the invention are "optionally substituted".
  • substituents can be either unsubstituted or substituted in any position by one or more, for example 1 , 2, 3 or 4, substituents, whereby the hydrogen atoms bound to the unsubstituted atoms, radicals, moieties, chains and cycles are replaced by chemically acceptable atoms, radicals, moieties, chains and cycles.
  • substituents When two or more substituents are present, each substituent may be the same or different. The substituents are typically themselves unsubstituted.
  • halogen atom embraces chlorine, fluorine, bromine and iodine atoms.
  • a halogen atom is typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine.
  • halo when used as a prefix has the same meaning.
  • Compounds containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, in the form of racemic mixtures and in the form of mixtures enriched in one or more stereoisomer.
  • the scope of the invention as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers, diastereomers, and stereoisomer-enriched mixtures.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • the resulting diastereomehc mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomer conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by Ernest L. Eliel (Wiley, New York, 1994).
  • the term pharmaceutically acceptable salt refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal.
  • Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
  • Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid; and organic acids, for example citric, fumaric, gluconic, glutamic, lactic, maleic, malic, mandelic, mucic, ascorbic, oxalic, pantothenic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, p-toluenesulphonic acid, xinafoic (1 -hydroxy-2-naphthoic acid), napadisilic (1 ,5-naphthalenedisulfonic acid) and the like.
  • inorganic acids for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid
  • organic acids for example citric, fumaric,
  • Salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, methanesulfonic, xinafoic, and tartaric acids are particularly preferred.
  • Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including alkyl amines, arylalkyl amines, heterocyclyl amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the
  • X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate
  • organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate.
  • X " is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X " is chloride, bromide, trifluoroacetate or methanesulphonate.
  • an N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules.
  • hydrate is employed when said solvent is water.
  • solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
  • more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate.
  • less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non- solvate form of the compounds.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon- 14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • Preferred isotopically-labeled compounds include deuterated derivatives of the compounds of the invention.
  • deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium.
  • Deuterium (D or 2 H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.
  • Hydrogen deuterium exchange is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. Said exchange (incorporation) reaction can be total or partial.
  • a deuterated derivative of a compound of the invention has an isotopic enrichment factor (ratio between the isotopic abundance and the natural abundance of that isotope, i.e. the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen) for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation).
  • the isotopic enrichment factor is at least 5000 (75% deuterium). In a more preferred embodiment, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In a most preferred embodiment, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent from the other deuteration sites.
  • the isotopic enrichment factor can be determined using conventional analytical methods known too en ordinary skilled in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).
  • Prodrugs of the compounds described herein are also within the scope of the invention.
  • certain derivatives of the compounds of the present invention which derivatives may have little or no pharmacological activity themselves, when administered into or onto the body may be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of the present invention with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • R c is selected from the group consisting of a hydrogen atom, a halogen atom and a methyl group, preferably, a hydrogen atom or a fluorine atom.
  • d is selected from the group consisting of a monocyclic C 5- 8 aryl group, a monocyclic 5- to 8- membered heteroaryl group containing at least one heteroatom selected from O, S and N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, a hydroxyl group, a Ci -4 alkyl group and a Ci-2 hydroxyalkyl group.
  • d is selected from the group consisting of a phenyl group, a pyridyl group and a monocyclic 6- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, pyridyl and heterocyclyl groups are unsubstituted or substituted by one or two substituents selected from a halogen atom, and a Ci -2 alkyl group. More preferably, d is selected from the group consisting of a phenyl group, a pyridyl group, a morpholinyl and a piperazinyl group.
  • U is selected from the group consisting of a -(CH 2 )(o-i)-, -NR x -(CH 2 )(i)- group, wherein R x is selected from the group consisting of a hydrogen atom and a Ci -2 alkyl group optionally substituted with -(CH 2 ) (0 - 2 )NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group, preferably, L-i is selected from the group consisting of direct bond and -NR X -(CH 2 ) (1) - group, wherein R x is selected from the group consisting of a hydrogen atom and a methyl group.
  • L-i represents a direct bond
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, -(CH 2 ) ( o-i ) -C(0)-(CH 2 ) ( o- i ) -0-(CH 2 )(o-i)-, and -NR- group, wherein R represents a hydrogen atom or a methyl group, wherein p has a value of 0 or 1 , preferably, L 2 is selected from the group consisting of a -(CH 2 ) P -, -N(CH 3 )-, -(CH 2 )-C(0)-0-(CH 2 )-, and -(CH 2 )-C(0)-0-, wherein p has a value of 0 or 1. More preferably, L 2 is selected from the group consisting of -(CH 2 ) P -, wherein p has a value of 0 or 1
  • R 1 is selected from the group consisting of a hydrogen atom, a linear or branched Ci -4 alkyl group, a monocyclic C 5- 8 aryl group, a mono- or bicyclic 5- to 14- membered heteroaryl group containing at least one heteroatom selected from N and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from N, wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a linear or branched Ci -5 alkyl group, a linear Ci -2 alkoxy group, and -(0) ( o-i ) (CH 2 ) ( o-3 ) -NR'R" group, wherein R' and R" independently represents a hydrogen atom or a methyl group, and q has a value of 0 or 1.
  • R 1 is selected from the group consisting of a hydrogen atom, a branched C 3- 4 alkyl group a monocyclic C 5- 8 aryl group and a monocyclic 5- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the aryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a a linear or branched Ci -5 alkyl group, a -(0)(CH 2 )2-NR'R" group and a -NR'R"- group, wherein R' and R" independently represents a hydrogen atom or a methyl group, and q has a value of 0 or 1.
  • R 1 is selected from the group consisting of a hydrogen atom, a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and
  • heterocyclyl groups are substituted by one substituent selected from the group consisting of a methyl group, -(0)(CH 2 )2-NR'R" group and a -NR'R"- group, wherein both R' and R" represents a methyl group, and q has a value of 0 or 1.
  • R 2 is selected from the group consisting of a halogen atom and a Ci -2 alkyl group, preferably a fluorine atom and a methyl group, more preferably, a fluorine atom.
  • R 3 is selected from the group consisting of a hydrogen atom, a Ci -2 alkyl group and -(CH 2 ) (2-4) NR'R"- group, wherein R' and R" are as defined in claim 1 , preferably, R 3 is selected from a hydrogen atom and a -(CH 2 ) (2) NR'R"- group, wherein both R' and R" represent a methyl group.
  • R 5 is selected from the group consisting of a hydrogen atom and a methyl group, and n has a value of 0 or 1 , preferably n has a value of 0.
  • G 2 is selected from the group consisting of a monocyclic N-containing 6- to 8- membered heteroaryl group and a monocyclic 5- to 8- membered heterocyclyl group containing at least one heteroatom selected from O, S and N, wherein the heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a methyl group and a group of formula
  • L 3 represents -CO- group, or a -C(0)0- group
  • R 4 is selected from the group consisting of a cyano group, a -CF 3 group, a methyl group,
  • R a and R b are independently selected from the group consisting of a hydrogen atom, a hydroxyl, a methyl group and,
  • m has a value of 0 or 1.
  • G 2 represents a monocyclic N-containing 6- membered heterocyclyl group which is substituted by a group of formula (a):
  • L 3 represents -CO- group
  • both R a and R b represent a hydrogen atom
  • m has a value of 1
  • R 4 represents a ciano group.
  • R c represents a hydrogen atom or a fluorine atom
  • Gi is selected from the group consisting of a phenyl group, a pyridyl group, a morpholinyl group and a piperazinyl group,
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, wherein p has a value of 0 or 1
  • R 1 is selected from the group consisting of a hydrogen atom, a phenyl group and a monocyclic 6- to 7- membered heterocyclyl group containing one or two nitrogen atom as heteroatom, wherein the phenyl and heterocyclyl groups are substituted by one substituent selected from the group consisting of a methyl group, -(0)(CH 2 )2-NR'R" group and a -NR'R"- group, wherein both R' and R" represents a methyl group, and q has a value of 0 or 1 ,
  • R 2 is a fluorine atom
  • R 3 is selected from a hydrogen atom and a -(CH 2 )(2 ) NR'R"- group, wherein both R' and R" represent a methyl group,
  • R 5 represents a hydrogen atom and n has a value of 1 .
  • G 2 represents a monocyclic N-containing 6- membered heterocyclyl group which is substituted by a group of formula
  • L 3 represents -CO- group
  • both R a and R b represent a hydrogen atom, m has a value of 1 , and
  • R 4 represents a cyano group.
  • compounds of the present invention having formula (I) wherein R c is selected from the group consisting of a hydrogen atom and a fluorine group,
  • Gi is selected from the group consisting of a phenyl group, a monocyclic N-containing 6- membered heteroaryl group and a monocyclic 4-8- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one substituent selected from a fluorine atom, a hydroxyl group, a methyl group, a hydroxymethyl group, a carboxymethyl group, an oxo group, and a hydroxyethyl group, L-i is selected from the group consisting of a direct bond and -NH- group,
  • L 2 is selected from the group consisting of a -(CH 2 ) P -, -O-(CH 2 ) (0 - 2) ,-C(O)-O-(CH 2 )-, - (CH 2 )-C(0)-0-(CH 2 )-, -C(0)-(CH 2 )-0-(CH 2 )-, -(CH 2 )-C(0)-0-, -C(O)- and -N(CH 3 )- group, wherein p has a value of 0 or 1 .
  • R 1 is selected from the group consisting of a hydrogen atom, a t-butyl group, a hydroxymethyl group, a phenyl group, a mono- or bicyclic 5- to 9- membered heteroaryl group containing at least one N as heteroatom and a monocyclic 5-7- membered heterocyclyl group containing at least one heteroatom selected from O and N, wherein the phenyl, heteroaryl and heterocyclyl groups are unsubstituted or substituted by one or more substituents selected from the group consisting of a fluroine atom, a hydroxyl group, a methyl group, a dihydroxypropyl group, a methoxy group, a dimethylamino group, -(0)-(CH 2 )2-N(CH 3 )2 group; R 2 is selected from the group consisting of a fluorine atom and a methyl group,
  • R 3 is selected from the group consisting of a hydrogen atom and a -(CH 2 ) (2-3) NR'R"- group
  • G 2 is selected from the group consisting of a pyridyl group substituted with a fluorine atom, and a piperidinyl substituted with a group of formula (a):
  • L 3 represents a direct bond, -CO- group, or a -C(0)0- group
  • R 4 is selected from the group consisting of a phenyl group, hydroxyl group, -
  • Both R a and R b are a hydrogen atom
  • R 5 is selected from the group consisting of a hydrogen atom and a methyl group
  • R' and R" independently represents a hydrogen atom or a methyl group, or R' and R" together with the nitrogen atom to which they are attached form a 5 to 6 membered N- containing heterocyclic group optionally containing one or more additional heteroatom selected from N, and O, and optionally substituted with a methyl group or a dimethylamino group, n, m and q independently have a value of 0 or 1. p has a value of 0, 1 or 2.
  • Particular individual compounds of the invention include:
  • the compounds of the invention can be prepared using the methods and procedures described herein or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • compounds of general formula (I) may be prepared by the following synthetic route as illustrated in Scheme 1 :
  • compounds of formula (I) may be obtained from chloropyrimidines of formula (IV) by reaction with compounds of formula (V), where Y is a boronic acid or a boronate ester, under Suzuki-Miyaura reaction conditions (Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457).
  • Such reactions may be catalysed by a suitable palladium catalyst such as [1 , 1 '-bis(diphenyl phosphino)ferrocene]dichloropalladium(l l) complex with dichloromethane or tetrakis (triphenylphosphine)palladium(O) in a solvent such as toluene, methanol, 1 ,4-dioxane or 1 ,2-dimethoxyethane in the presence of a base such as cesium carbonate or sodium carbonate at temperatures ranging from 80 °C to 1 10 °C with or without the use of microwave irradiation.
  • a suitable palladium catalyst such as [1 , 1 '-bis(diphenyl phosphino)ferrocene]dichloropalladium(l l) complex with dichloromethane or tetrakis (triphenylphosphine)palladium(O) in a solvent such as to
  • Boronic acids or boronates of formula (V) where L-i is a direct bond, Gi is an aryl or heteroaryl ring and Y is a boronic acid or boronate ester may be commercially available or may be prepared from the corresponding bromoderivatives of formula (V), where Y is a bromine atom, by treatment with an appropriate boron reagent such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi-1 ,3,2-dioxaborolane with a palladium catalyst such as [1 ,1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride dichloromethane complex, in a solvent such as 1 ,4-dioxane, in the presence of a base such as potassium acetate at temperatures ranging from 80-120 °C.
  • a palladium catalyst such as [1 ,1 - bis(diphenylphos
  • compounds of formula (I) may be prepared by reaction of chloroderivatives of formula (IV) with heterocyclic amines of formula (V), where Y is an hydrogen atom, in the presence of a base such as sodium hydrogencarbonate or /V-ethyl-/V-isopropylpropan-2-amine without the use of a solvent or in a solvent such as ⁇ /,/V-dimethylacetamide or 1 -methyl-2-pyrrolidine at temperatures ranging from 80-130 °C with or without the use of microvawe irradiation.
  • a base such as sodium hydrogencarbonate or /V-ethyl-/V-isopropylpropan-2-amine
  • compounds of formula (I) can be also prepared by reaction of chloropyrimidines of formula (VI) with amines of formula (III) using a suitable catalyst such as tris(dibencylideneacetone)dipalladium(0), in the presence of a ligand such as 2-dicyclohexylphosphino-2'-(/V,/V-dimethylamino)-biphenyl, and a base, for example sodium ie f-butoxide, in a solvent such as toluene at a temperature ranging from 80 °C to reflux.
  • a suitable catalyst such as tris(dibencylideneacetone)dipalladium(0)
  • a ligand such as 2-dicyclohexylphosphino-2'-(/V,/V-dimethylamino)-biphenyl
  • a base for example sodium ie f-butoxide
  • Bicyclic nitriles of formula (VIII) may be prepared by treatment of 2-aminopyridines of formula (VII) with 3-methoxyacrylonitrile in the presence of /V-bromosuccinimide in a suitable solvent such a dioxane/water mixture at temperatures ranging from ambient temperature to reflux.
  • Nitriles of formula (VIII) may be converted to the corresponding amidines of formula (IX) by first formation of the corresponding imidate by reaction with alkoxy derivatives such as sodium methoxide or sodium ethoxide in a suitable alcoholic solvent at temperatures ranging from 0 °C to reflux followed by addition of ammonium chloride or ammonium hydroxide.
  • Amidines of formula (IX) may be reacted with malonate esters of formula (X) to give dihydroxypirimidines of formula (XI). Such reactions may be carried out in the presence of a suitable base such as sodium methoxide in a solvent such as methanol at temperatures ranging from 0 °C to ambient temperature. Dihydroxypirimidines of formula (XI) may be converted to dichloropyrimidines of formula (II) by treatment with a suitable chlorinating agent, for example phosphorus(V) oxychloride, at temperatures ranging from 25 °C to reflux.
  • a suitable chlorinating agent for example phosphorus(V) oxychloride
  • Such reactions may be catalysed by a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as 1 ,2-dimethoxyethane in the presence of a base such as sodium carbonate at 80 °C.
  • a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a solvent such as 1 ,2-dimethoxyethane in the presence of a base such as sodium carbonate at 80 °C.
  • Reaction of chloropyrimidines of formula (XIV) with imidazopyridines of formula (XV) in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base such as potassium acetate in a solvent such as ⁇ /,/V-dimethylacetamide at 150 °C provides compounds of formula (I).
  • compounds of formula (I), where R 3 is an hydrogen atom may undergo further reaction with a suitable base, such as sodium hydride, in a solvent such as ⁇ /, ⁇ /'-dimethylformamide, followed by the addition of an alkylating agent, such as (2-chloroethyl)dimethylamine hydrochloride or related haloalkyl derivatives containing one or more tertiary amines at temperatures ranging from ambient temperature to 80 °C, to furnish compounds of formula (I), where R 3 is now an alkyl group containing one or more tertiary amine groups.
  • a suitable base such as sodium hydride
  • a solvent such as ⁇ /, ⁇ /'-dimethylformamide
  • an alkylating agent such as (2-chloroethyl)dimethylamine hydrochloride or related haloalkyl derivatives containing one or more tertiary amines at temperatures ranging from ambient temperature to 80 °C
  • compounds of formula (I), in which the residue at G-i, G 2 or R 1 contains an alcohol, phenol or carboxylic acid moiety functionalized with an appropriate protecting group such as benzyl (Bn) or methoxy (OMe), may be deprotected at the alcohol, phenol or carboxylic acid moiety under standard conditions ⁇ Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540).
  • an appropriate protecting group such as benzyl (Bn) or methoxy (OMe
  • the free alcohol may then be oxidized under standard conditions to give the corresponding aldehyde.
  • compounds of formula (I) and compounds of formula (XIV) in which the residue at d contains an aldehyde moiety may be further reacted with a primary or secondary amine in the presence of a reductive agent, such as sodium triacetoxyborohydride, in a solvent such as dichloromethane at ambient temperature to give compounds of formula (I) and compounds of formula (XIV) in which the residue at Gi is now a secondary or tertiary amine.
  • a reductive agent such as sodium triacetoxyborohydride
  • compounds of formula (I), in which the residue at Gi, G 2 or R 1 contains an amine moiety functionalized with an appropriate protecting group such as ie f-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), may be deprotected at the amine moiety under standard conditions (Greene's Protective Groups in Organic Synthesis, ISBN: 0471697540).
  • BOC ie f-butoxycarbonyl
  • CBZ benzyloxycarbonyl
  • 6-Fluoroimidazo[1 ,2-a]pyridine-3-carboximidamide (Preparation 1 b, 2.0 g, 8.39 mmol,) was added portionwise to a stirred solution of sodium (0.46 g, 20.21 mmol) in methanol (35 mL) at 0 °C. Diethyl 2-fluoromalonate (2.65 mL, 16.8 mmol) was then added and the reaction mixture was stirred from 0 °C to room temperature overnight. The solvent was evaporated to dryness and the resulting crude was dissolved in water (90 mL). After stirring for 30 min, a 2N solution of hydrochloric acid was added until acid pH. The solid formed was filtered and dried to yield the title compound (0.95 g, 43%) as a brown solid that was used in the next synthetic step without further purification.
  • Trifluoroacetic acid (0.507 mL, 6.58 mmol) was added to a solution of (R)-ieri-butyl 3- ((5-fluoro-2-(6-fluoroimidazo[1 ,2-a]pyridin-3-yl)-6-(3-hydroxyazetidin-1 -yl)pyrimidin-4-yl) amino)piperidine-1 -carboxylate (Preparation 10, 0.22 g, 0.44 mmol) in dichloromethane (2 mL) and the mixture was stirred at ambient temperature for 8h. Solvent was evaporated and the residue was treated with diethyl ether, filtered and dried in vacuo to yield the title compound (0.258 g, 59%) as a trifluoroacetate salt.
  • Triethylamine (0.065 ml_, 0.47 mmol) and 3-[(2,5-dioxopyrrolidin-1 -yl)oxy]-3- oxopropanenitrile (prepared as described in BE875054(A1 )), 0.032 g, 0.18 mmol) were added to a solution of (R)-6-(4-(benzyloxy)phenyl)-5-fluoro-2-(6-fluoroimidazo[1 ,2- a]pyridin-3-yl)-/V-(piperidin-3-yl) pyrimidin-4-amine (Preparation 18, 0.06 g, 0.12 mmol) in dichloromethane (3 mL) and the resulting mixture was stirred at ambient temperature for 30 min. Additional dichloromethane was added and the mixture was washed with water and brine. The organic layer was separated by Phase separator and the solvent was evaporated to dryness to yield the title compound (66 mg, 97%).
  • the Schlenk tube was subjected to three cycles of evacuation- backfilling with argon and then [1 ,1 -bis (diphenylphosphino)ferrocene]palladium(ll) dichloride (0.10 g, 0.12 mmol) was added. After three further cycles of evacuation- backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C for 4h. The mixture was cooled, filtered through diatomaceous earth (Celite ® ) and the solvent was concentrated to dryness. The residue was treated with petroleum ether, filtered and the solvent was evaporated to dryness to yield the title compound (0.5 g, 86%) as a yellow oil.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (0.017 g, 0.02 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °C. The solvent was removed and the residue was purified by reverse phase chromatography (water to methanol) to yield the title compound (53 mg, 23%) as a solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis (triphenylphosphine)palladium(O) (80 mg, 0.07 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 80 °C overnight. The solvent was removed and the residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) to yield the title compound (0.14 g, 40%) as a solid.
  • Aqueous hydrogen chloride solution (0.5 ml_, 16.3 mmol) was added to (2,2- dimethoxy ethyl)dimethylamine (0.25 g, 1 .90 mmol) in a sealed tube and the mixture was stirred at 100 °C for 1 h. The solution was cooled to 0 °C and 6N aqueous sodium hydroxide solution was added until a basic pH was reached. A solution of ie f-butyl (3R)-3-aminopiperidine-1 -carboxylate (0.19 g, 0.95 mmol) in 1 ,2-dichloroethane (10 mL) was added and the reaction mixture was stirred at ambient temperature for 15 min.
  • a Schlenk tube was charged with 1 -bromo-3-iodobenzene (0.70 ml_, 5.49 mmol), 1 - methyl piperazine (0.61 ml_, 5.50 mmol), sodium ie f-butoxide (1 .48 g, 15.40 mmol) and toluene (8 ml_).
  • the Schlenk tube was subjected to three cycles of evacuation- backfilling with argon and then tris(dibenzylideneacetone)dipalladium(0) (0.20 g, 0.22 mmol) and 2, 2'-bis(diphenylphosphino)-1 ,1 '-binaphthalene (0.27 g, 0.43 mmol) were added.
  • Triethylamine (0.32 ml_, 0.85 mmol) was added to a solution of (R)-3-(3-((6-chloro-5- fluoro-2-(6-fluoroimidazo[1 ,2-a]pyridin-3-yl)pyrimidin-4-yl)amino)piperidin-1 -yl)-3- oxopropanenitrile (Preparation 23a, 0.28 g, 0.65 mmol) in ⁇ /, ⁇ /'-dimethylformamide (1.5 mL) and the reaction mixture was stirred at room temperature for 30 minutes.
  • Lithium hydroxide monohydrate (0.01 g, 0.24 mmol) was added to a mixture of benzyl ⁇ 4-[6- ⁇ [(3R)-1 -(cyanoacetyl)piperidin-3-yl]amino ⁇ -5-fluoro-2-(6-fluoroimidazo[1 ,2-a] pyridin-3-yl)pyrimidin-4-yl]piperazin-1 -yl ⁇ acetate (Example 3, 0.14 g, 0.22 mmol), tetrahydrofuran (4 mL) and water (4 mL) and the reaction mixture was stirred overnight at ambient temperature.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then [1 ,1 '-bis(diphenylphosphino)ferrocene] palladium(ll) dichloride (0.01 g, 0.01 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 80 °C. The mixture was partitioned between 4% aqueous solution of sodium hydrogencarbonate and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulphate and the solvent was evaporated to dryness. The residue was purified by flash chromatography (dichloromethane to dichloromethane/methanol 95:5) to give the title compound (19 mg, 28%) as a light brown solid.
  • the Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.02 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated at 90 °C overnight. The solvent was removed and the residue was purified by reverse phase chromatography (water to methanol) to yield the title compound (42 mg, 28%) as a yellow solid.
  • JAK1 The catalytic domains of human JAK1 (aa 850-1 154), JAK2 (aa 826-1 132), JAK3 (aa 795-1 124) and Tyk2 (aa 871 -1 187) were expressed as N-terminal GST-fusion proteins using a baculovirus expression system and were purchased from Carna Biosciences.
  • the enzymatic activity was assayed using as substrate a biotinylated peptide, poly (GT)-Biotin (CisBio).
  • the peptide concentration in the reactions was 60 nM for JAK1 , 20 nM for JAK2, 140 nM for JAK3 and 50 nM for Tyk2.
  • TR-FRET time-resolved fluorescence energy transfer
  • IC 50 s of compounds were measured for each kinase in a reaction mixture containing the enzyme, ATP and the peptide in 8 mM MOPS (pH 7.0), 10 mM MgCI 2 , 0.05% ⁇ - mercaptoethanol, 0.45 mg/ml BSA.
  • the ATP concentration in the reactions was 3 ⁇ for JAK1 , 0.2 ⁇ for JAK2, 0.6 ⁇ for JAK3 and 1.8 ⁇ for Tyk2.
  • the enzymatic reactions took place for 30 minutes at room temperature.
  • BSA bovine serum albumin
  • EDTA ethylenediaminetetraacetic acid
  • SA-XL665 Streptavidin (biotin-binding tetrameric protein isolated from Streptomyces avidinii) XL665
  • Table 1 depicts IC 50 values for certain exemplary compounds described in the invention.
  • “A” represents an IC 50 value of less than 0.1 ⁇ (100 nM)
  • “B” represents an IC 50 value in the range of 0.1 ⁇ (100 nM) to 1 ⁇ (1000 nM)
  • C represents an IC 50 value higher than 1 ⁇ (1000 nM).
  • compounds of formula (I) are potent inhibitors of JAK1 , JAK2 and JAK3 kinases.
  • Preferred compounds of the invention possess an IC 50 value for the inhibition of JAK1 , JAK2 and JAK3 kinases (determined as defined above) of less than 1 ⁇ (1000 nM), preferably of less than 0.5 ⁇ (500 nM), more preferably of less than 0.2 ⁇ (200 nM) for each Janus Kinase
  • the invention is also directed to a compound of the invention as described herein for use in the treatment of the human or animal body by therapy.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds of the present invention may also be combined with other active compounds in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Janus Kinases.
  • the combinations of the invention can optionally comprise one or more additional active substances which are known to be useful in the treatment of myeloproliferative disorders (such as polycythemia vera, essential thrombocythemia or mielofibrosis), leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory , more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis, such as (a) Dyhydrofolate reductase inhibitors, such as Methotrexate or CH- 1504; (b) Dihydroorotate dehydrogenase (DHODH) inhibitors such as leflunomide, teriflunomide, or the
  • WO2008/077639 and WO2009/021696 Immunomodulators such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod;
  • Immunomodulators such as Glatiramer acetate (Copaxone), Laquinimod or Imiquimod;
  • Inhibitors of DNA synthesis and repair such as Mitoxantrone or Cladribine;
  • Immunosuppressants such as Imuran (azathioprine) or Purinethol (6-mercaptopurine or 6-MP);
  • Anti-alpha 4 integrin antibodies such as Natalizumab (Tysabri);
  • Alpha 4 integrin antagonists such as R- 1295 , TBC-4746, CDP-323, ELND-002, Firategrast or TMC-2003;
  • Corticoids and glucocorticoids such as prednisone or methylprednisolone, fluticasone, mometasone, budeson
  • IL-6R Anti-lnterleukin 6 Receptor
  • IL-12R Anti- Interleukin 12 Receptor
  • IL-23R Interleukin 23 Receptor
  • Sphingosine-1 (S1 P) liase inhibitors such as LX2931 ;
  • PKC Protein Kinase Inhibitors
  • (cc) Anti-cholinergic agents such as tiotropium or aclidinium;
  • (dd) Beta adrenergic agonists such as formoterol, indacaterol or abediterol (LAS100977);
  • MABAs Muscarinic Antagonist-Beta2 Agonist activity
  • (ff) Histamine 1 (H 1 ) receptor antagonists such as azelastine or ebastine;
  • corticoids and glucocorticoids that can be combined with the JAK inhibitors of the present invention are prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate,
  • methylprednisolone aceponate dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclometasone dipropionate, halometasone,
  • methylprednisolone suleptanate mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RPR-106541 , deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone,
  • the specific examples of suitable corticoids and glucocorticoids that can be combined with the JAK inhibitors of the present invention are prednisolone, methylprednisolone, dexamethasone,
  • Syk kinase inhibitors that can be combined with the JAK inhibitors of the present invention are fosfamatinib (from Rigel), R-348 (from Rigel), R- 343 (from Rigel), R-1 12 (from Rigel), piceatannol, 2-(2-Aminoethylamino)-4-[3- (trifluoromethyl)phenylamino] pyrimidine-5-carboxamide, R-091 (from Rigel), 6-[5- Fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino]-2,2-dimethyl-3,4-dihydro- 2H-pyrido[3,2-b][1 ,4]oxazin-3-one benzenesulfonate (R-406 from Rigel), 1 -(2,4,
  • M3 antagonists anticholinergics
  • suitable M3 antagonists include tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, zamifenacin, revatropate, espatropate, darotropium bromide, CI-923, NPC-14695, BEA-2108, 3-[2- Hydroxy-2,2-bis(2-thienyl)acetoxy]-1 -(3-phenoxypropyl)-1 -azoniabicyclo[2.2.2]octane salts (in particular aclidinium salts, more preferably aclidinium bromide), 1 -(2- Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1 -azoniabicyclo[2.2.2]octane salts, 2-oxo- 1 ,2,3,4-te
  • salts chlorides, bromides, iodides and methanesulphonates are preferred.
  • beta adrenergic agonists that can be combined with the JAK inhibitors of the present invention are are terbutaline sulphate, eformoterol fumarate, formoterol fumarate, bambuterol, ibuterol, isoprenaline hydrochloride, dopexamine, metaprotenerol, tulobuterol, procaterol hydrochloride, sibenadet hydrochloride, mabuterol hydrochloride, albuterol sulphate, salbutamol sulphate, salmefamol, salmeterol xinafoate, carmoterol hydrochloride, (R)-albuterol hydrochloride, Levalbuterol hydrochloride; Levosalbutamol hydrochloride; (-)- Salbutamol hydrochloride, formoterol, (R,R)-Formoterol tartrate; Arformoterol tartrate, s
  • Phosphosdiesterase IV (PDE IV) inhibitors that can be combined with the JAK inhibitors of the present invention are benafentrine dimaleate, etazolate, denbufylline, rolipram, cipamfylline, zardaverine, arofylline, filaminast, tipelukast, tofimilast, piclamilast, tolafentrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, filaminast, (R)-(+)-4- [2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), N-(3,5- Dichloro-4-pyridinyl)-2-[1 -(4-
  • Phosphoinositide 3-Kinases examples include 2-Methyl-2-[4-[3-methyl- 2-oxo-8-(3-quinolinyl)-2,3-dihydro-1 H-imidazo[4,5-c]quinolin-1 -yl]phenyl]propanenitrile (BEZ-235 from Novartis), CAL-101 (from Calistoga Pharmaceuticals) and N-Ethyl-N'-[3- (3,4,5-trimethoxyphenylamino)pyrido[2,3-b]pyrazin-6-yl]thiourea (AEZS-126 from Aeterna Zentaris).
  • PI3Ks Phosphoinositide 3-Kinases
  • the compounds of formula (I) and the combinations of the invention may be used in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, wherein the use of a JAK inhibitor is expected to have a beneficial effect, for example rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (such as ulcerative colitis or Crohn's disease), dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • rheumatoid arthritis multiple sclerosis
  • inflammatory bowel disease such as ulcerative colitis or Crohn's disease
  • COPD chronic obstructive pulmonary disease
  • the active compounds in the combination product may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • all active agents would be administered at the same time, or very close in time.
  • one or two actives could be administered in the morning and the other (s) later in the day.
  • one or two actives could be administered twice daily and the other (s) once daily, either at the same time as one of the twice-a-day dosing occurred, or separately.
  • at least two, and more preferably all, of the actives would be administered together at the same time.
  • at least two, and more preferably all actives would be administered as an admixture.
  • the invention is also directed to a combination product of the compounds of the invention together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • JAK Janus Kinases
  • the pathological condition or disease is selected from respiratory diseases; allergic diseases; inflammatory or autoimmune- mediated; function disorders and neurological disorders; cardiovascular diseases; viral infection; metabolism/endocrine function disorders; neurological disorders and pain; bone marrow and organ transplant rejection; myelo-dysplastic syndrome;
  • MPDs myeloproliferative disorders
  • the pathological condition or disease is selected from leukemia, lymphomas and solid tumors, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosis, autoimmune hemolytic anemia, type I diabetes, cutaneous vasculitis, cutaneous lupus erythematosus, dermatomyositis, blistering diseases including but not limited to pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, cough, idiopathic pulmonary fibrosis, sarcoidosis, allergic rhinitis, atopic dermatitis, contact dermatitis, eczema, psoriasis, basal cell carcinoma, squamous cell carcinoma and
  • COPD chronic
  • the invention also encompasses the use of a combination of the compounds of the invention together with one or more other therapeutic agents for the manufacture of a formulation or medicament for treating these diseases.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis; comprising administering a therapeutically effective amount of a combination of the compounds of the invention together with one or more other therapeutic agents.
  • JK Janus Kinases
  • the active compounds in the combinations of the invention may be administered by any suitable route, depending on the nature of the disorder to be treated, e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc).
  • suitable route e.g. orally (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc); topically (as creams, ointments, lotions, nasal sprays or aerosols, etc); by injection (subcutaneous, intradermic, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion,
  • the pyridin-2(1 H)-one derivatives of the invention, and the other optional active compounds may be administered together in the same pharmaceutical composition or in different compositions intended for separate, simultaneous, concomitant or sequential administration by the same or a different route.
  • One execution of the present invention consists of a kit of parts comprising a pyridin- 2(1 H)-one derivative of the invention together with instructions for simultaneous, concurrent, separate or sequential use in combination with another active compound useful in the treatment of myeloproliferative disorders, leukemia, lymphoid
  • rheumatoid arthritis multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • COPD chronic obstructive pulmonary disease
  • Another execution of the present invention consists of a package comprising a pyridin- 2(1 H)-one derivative of the invention and another active compound useful in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular useful in the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • Pharmaceutical Compositions comprising a pyridin- 2(1 H)-one derivative of the invention and another active compound useful in the treatment of myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular useful in the treatment of
  • compositions according to the present invention comprise the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier.
  • pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, N-oxides, stereoisomers, deuterated derivatives thereof or prodrugs thereof, with other chemical components, such as
  • compositions are physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a physiologically/pharmaceutically acceptable diluent or carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • the invention further provides pharmaceutical compositions comprising the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier together with one or more other therapeutic agents for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), such as the ones previously described.
  • JK Janus Kinases
  • the invention is also directed to pharmaceutical compositions of the invention for use in the treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory , more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis.
  • COPD chronic obstructive pulmonary disease
  • the invention also encompasses the use of a pharmaceutical composition of the invention for the manufacture of a medicament for treating these diseases.
  • the invention also provides a method of treatment of a pathological condition or disease susceptible to amelioration by inhibiton of Janus Kinases (JAK), in particular wherein the pathological condition or disease is selected from myeloproliferative disorders, leukemia, lymphoid malignancies and solid tumors; bone marrow and organ transplant rejection; immune-mediated diseases and inflammatory diseases, more in particular wherein the pathological condition or disease is selected from rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, dry eye, uveitis, allergic conjunctivitis, allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis and psoriasis, comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention.
  • JAK Janus Kinases
  • compositions which comprise, as an active ingredient, at least a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent.
  • the active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01 % to 90% by weight, of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.
  • the compositions are made up in a form suitable for oral, inhalation, topical, nasal, rectal, percutaneous or injectable administration.
  • Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001 .
  • compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additional suitable carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001 . i) Oral Administration
  • compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules, inhalation aerosols, inhalation solutions, dry powder inhalation, or liquid preparations, such as mixtures, solutions, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • composition is in the form of a tablet
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • examples of such carriers include magnesium stearate, talc, gelatine, acacia, stearic acid, starch, lactose and sucrose.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium
  • the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablet
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste- masking agents.
  • Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatine capsule.
  • composition is in the form of a soft gelatine capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatine capsule.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1 -14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol,
  • methylcellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • the solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup.
  • the suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. ii) Oral mucosal administration
  • the compounds of the invention can also be administered via the oral mucosal.
  • delivery of drugs is classified into three categories: (a) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (b) buccal delivery, which is drug
  • Pharmaceutical products to be administered via the oral mucosal can be designed using mucoadhesive, quick dissolve tablets and solid lozenge formulations, which are formulated with one or more mucoadhesive (bioadhesive) polymers (such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, polyisobutylene or polyisoprene); and oral mucosal permeation enhancers (such as butanol, butyric acid, propranolol, sodium lauryl sulphate and others) iii) Inhaled administration
  • mucoadhesive polymers such as hydroxy propyl cellulose, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, polyvinyl alcohol, polyisobutylene or poly
  • the compounds of the invention can also be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
  • Formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred.
  • a suitable powder base such as lactose or starch.
  • lactose is preferred.
  • Each capsule or cartridge may generally contain between 0.001 -50 mg, more preferably 0.01 -5 mg of active ingredient or the equivalent amount of a pharmaceutically acceptable salt thereof.
  • the active ingredient (s) may be presented without excipients.
  • Packaging of the formulation may be suitable for unit dose or multi-dose delivery.
  • the formulation can be pre-metered or metered in use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multiple unit dose and (c) multi dose devices.
  • inhalers of the first type single doses have been weighed by the manufacturer into small containers, which are mostly hard gelatine capsules.
  • a capsule has to be taken from a separate box or container and inserted into a receptacle area of the inhaler.
  • the capsule has to be opened or perforated with pins or cutting blades in order to allow part of the inspiratory air stream to pass through the capsule for powder entrainment or to discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation.
  • the emptied capsule has to be removed from the inhaler again.
  • disassembling of the inhaler is necessary for inserting and removing the capsule, which is an operation that can be difficult and burdensome for some patients.
  • Some capsule inhalers have a magazine from which individual capsules can be transferred to a receiving chamber, in which perforation and emptying takes place, as described in WO 92/03175.
  • Other capsule inhalers have revolving magazines with capsule chambers that can be brought in line with the air conduit for dose discharge (e. g. WO91/02558 and GB 2242134). They comprise the type of multiple unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disk or on a strip. Blister inhalers provide better moisture protection of the medicament than capsule inhalers. Access to the powder is obtained by perforating the cover as well as the blister foil, or by peeling off the cover foil.
  • Multi-dose inhalers do not contain pre-measured quantities of the powder formulation. They consist of a relatively large container and a dose measuring principle that has to be operated by the patient. The container bears multiple doses that are isolated individually from the bulk of powder by volumetric displacement.
  • Reproducible dose measuring is one of the major concerns for multi dose inhaler devices.
  • the powder formulation has to exhibit good and stable flow properties, because filling of the dose measuring cups or cavities is mostly under the influence of the force of gravity.
  • Multi dose inhalers can contain a much higher number of doses, whereas the number of handlings to prime a dose is generally lower.
  • the inspiratory air stream in multi-dose devices is often straight across the dose measuring cavity, and because the massive and rigid dose measuring systems of multi dose inhalers can not be agitated by this inspiratory air stream, the powder mass is simply entrained from the cavity and little de-agglomeration is obtained during discharge. Consequently, separate disintegration means are necessary. However in practice, they are not always part of the inhaler design. Because of the high number of doses in multi- dose devices, powder adhesion onto the inner walls of the air conduits and the de- agglomeration means must be minimized and/or regular cleaning of these parts must be possible, without affecting the residual doses in the device. Some multi dose inhalers have disposable drug containers that can be replaced after the prescribed number of doses has been taken (Ex. WO 97/000703). For such semi-permanent multi dose inhalers with disposable drug containers, the requirements to prevent drug accumulation are even stricter.

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Abstract

La présente invention concerne de nouveaux dérivés d'imidazopyridmin-2-yl ainsi que leur procédé de préparation, des compositions pharmaceutiques les comprenant et leur utilisation comme inhibiteurs des Janus Kinases (JAK) pour le traitement de troubles myéloprolifératifs, la leucémie, les tumeurs malignes lymphoïdes et les tumeurs solides ; rejet de greffe de moelle osseuse et d'organe ; les maladies à médiation immunitaires et les maladies inflammatoires.
PCT/EP2014/078037 2013-12-19 2014-12-16 Dérivés d'imidazopyridmin-2-yl comme inhibiteurs de la jak Ceased WO2015091531A1 (fr)

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CN111867581A (zh) * 2018-01-29 2020-10-30 默克专利股份有限公司 Gcn2抑制剂及其用途
WO2021096304A1 (fr) * 2019-11-15 2021-05-20 Ildong Pharmaceutical Co., Ltd. Agoniste du récepteur glp-1 et son utilisation
WO2021112538A1 (fr) * 2019-12-02 2021-06-10 Hyundai Pharm Co., Ltd. Agoniste du récepteur glp-1
CN113316569A (zh) * 2019-02-11 2021-08-27 庄信万丰股份有限公司 比美替尼与dmso的结晶溶剂化物以及比美替尼与柠檬酸的共结晶形式
EP4041241A1 (fr) 2019-09-27 2022-08-17 Disc Medicine, Inc. Procédés de traitement de la myélofibrose et d'affections associées
US11629124B2 (en) * 2017-03-09 2023-04-18 Novartis Ag Solid forms comprising an oxime ether compound, compositions and methods of use thereof
JP2023518774A (ja) * 2020-03-16 2023-05-08 上海海雁医薬科技有限公司 置換ピリミジンまたはピリジルアミン誘導体、その組成物及び医薬的使用
WO2025063737A1 (fr) * 2023-09-21 2025-03-27 Yunovia Co., Ltd. Procédé de préparation d'un dérivé d'imidazole condensé substitué
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis

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WO2011076419A1 (fr) * 2009-12-24 2011-06-30 Almirall, S.A. Dérivés de l'imidazopyridine en tant qu'inhibiteurs de jak

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US11629124B2 (en) * 2017-03-09 2023-04-18 Novartis Ag Solid forms comprising an oxime ether compound, compositions and methods of use thereof
AU2019212969B2 (en) * 2018-01-29 2025-01-23 Merck Patent Gmbh GCN2 inhibitors and uses thereof
US12084438B2 (en) 2018-01-29 2024-09-10 Merck Patent Gmbh GCN2 inhibitors and uses thereof
EP3746071A4 (fr) * 2018-01-29 2021-09-01 Merck Patent GmbH Inhibiteurs de gcn2 et leurs utilisations
CN111867581A (zh) * 2018-01-29 2020-10-30 默克专利股份有限公司 Gcn2抑制剂及其用途
CN111867581B (zh) * 2018-01-29 2023-12-26 默克专利股份有限公司 Gcn2抑制剂及其用途
CN113316569A (zh) * 2019-02-11 2021-08-27 庄信万丰股份有限公司 比美替尼与dmso的结晶溶剂化物以及比美替尼与柠檬酸的共结晶形式
EP4041241A1 (fr) 2019-09-27 2022-08-17 Disc Medicine, Inc. Procédés de traitement de la myélofibrose et d'affections associées
CN114728939A (zh) * 2019-11-15 2022-07-08 日东制药株式会社 Glp-1受体激动剂及其用途
US11643403B2 (en) 2019-11-15 2023-05-09 Ildong Pharmaceutical Co., Ltd. GLP-1 receptor agonist and use thereof
CN114728939B (zh) * 2019-11-15 2023-12-08 日东制药株式会社 Glp-1受体激动剂及其用途
US11932618B2 (en) 2019-11-15 2024-03-19 Ildong Pharmaceutical Co., Ltd. GLP-1 receptor agonist and use thereof
WO2021096304A1 (fr) * 2019-11-15 2021-05-20 Ildong Pharmaceutical Co., Ltd. Agoniste du récepteur glp-1 et son utilisation
CN114761395A (zh) * 2019-12-02 2022-07-15 现代药品株式会社 Glp-1受体激动剂
WO2021112538A1 (fr) * 2019-12-02 2021-06-10 Hyundai Pharm Co., Ltd. Agoniste du récepteur glp-1
US12421205B2 (en) 2019-12-02 2025-09-23 Hyundai Pharm Co., Ltd. GLP-1 receptor agonist
JP2023518774A (ja) * 2020-03-16 2023-05-08 上海海雁医薬科技有限公司 置換ピリミジンまたはピリジルアミン誘導体、その組成物及び医薬的使用
JP7654008B2 (ja) 2020-03-16 2025-03-31 上海海雁医薬科技有限公司 置換ピリミジンまたはピリジルアミン誘導体、その組成物及び医薬的使用
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis
WO2025063737A1 (fr) * 2023-09-21 2025-03-27 Yunovia Co., Ltd. Procédé de préparation d'un dérivé d'imidazole condensé substitué

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