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WO2010072823A1 - Dérivés de pyrazole[1,5a]pyridine - Google Patents

Dérivés de pyrazole[1,5a]pyridine Download PDF

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Publication number
WO2010072823A1
WO2010072823A1 PCT/EP2009/067883 EP2009067883W WO2010072823A1 WO 2010072823 A1 WO2010072823 A1 WO 2010072823A1 EP 2009067883 W EP2009067883 W EP 2009067883W WO 2010072823 A1 WO2010072823 A1 WO 2010072823A1
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alkyl
formula
compound according
optionally substituted
compound
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Jorge Salas Solana
Carmen Almansa Rosales
Josep Comelles Espuga
Montserrat Fontes Ustrell
Robert Soliva Soliva
José Javier PASTOR PORRAS
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Palau Pharma SA
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Palau Pharma 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a new series of pyrazolo[1 ,5-a]pyhdine derivatives, as well as to processes for their preparation, to pharmaceutical compositions comprising them and to their use in therapy.
  • JAKs The Janus kinases
  • STAT transcription
  • JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as transplant rejection and autoimmune diseases, as well as in solid and hematologic malignancies such as leukemias and lymphomas and in myeloproliferative disorders, and has thus emerged as an interesting target for drug invention.
  • JAK3 is mainly found in hematopoietic cells. JAK3 is associated in a non-covalent manner with the ⁇ c subunit of the receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL- 15. These cytokines play an important role in the proliferation and differentiation of T lymphocytes. JAK3-deficient mouse T cells do not respond to IL-2. This cytokine is fundamental in the regulation of T lymphocytes. In this regard, it is known that antibodies directed against the IL-2 receptor are able to prevent transplant rejection.
  • JAK3 has also been shown to play an important role in mast cells, because antigen-induced degranulation and mediator release have been found to be substantially reduced in mast cells from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation nor IgE receptor expression levels. On the other hand, JAK3-/- and JAK3+/+ mast cells contain the same intracellular mediators. Therefore, JAK3 appears to be essential in the IgE-induced release of mediators in mast cells and its inhibition would be, thus, an effective treatment for allergic reactions.
  • JAK3 kinase inhibitors have been recognised as a new class of effective immunosuppresive agents useful for transplant rejection prevention and in the treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, systemic lupus erythematosus, type I diabetes and complications from diabetes, allergic reactions and leukemia (see e.g. O'Shea J.J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrlje
  • novel compounds that are capable of inhibiting JAK/STAT signaling pathways, and in particular which are capable of inhibiting JAK3 activity, and which are good drug candidates.
  • Compounds should exhibit good activity in in vitro and in in vivo pharmacological assays, good oral absorption when administered by the oral route, as well as be metabolically stable and exhibit a favourable pharmacokinetic profile. Moreover, compounds should not be toxic and exhibit few side effects.
  • One aspect of the invention relates to a compound of formula I
  • Ri represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, R 7 -Ci -4 alkyl, halogen, -CN, -CONR 4 R 4 , -COR 5 , -CO 2 R 5 , -OR 4 , -SO 2 R 5 , -SO 2 NR 4 R 4 , -NR 4 R 4 , -NR 6 COR 4, -NR 6 CONR 4 R 4 , -NR 6 CO 2 R 5 , -NR 6 SO 2 R 5 or Cy-i, wherein Cyi is optionally substituted with one or more R 8 ;
  • R 2 represents hydrogen, C-i- 4 alkyl haloC-i- 4 alkyl, hydroxyCi -4 alkyl, R 7 -C-i -4 alkyl or Cy 2 , wherein Cy 2 is optionally substituted with one or more R 8 ;
  • R 3 represents C-
  • each R 4 independently represents hydrogen or R 5 ; each R 5 independently represents Ci -4 alkyl, haloCi -4 alkyl, Ci -4 alkoxyCi- 4 alkyl, hydroxyCi -4 alkyl, cyanoCi -4 alkyl, Cyi-Ci -4 alkyl or Cy-i, wherein Cyi is optionally substituted with one or more R 8 ; R 6 represents hydrogen or Ci -4 alkyl; R 7 represents -CN, -CONR 4 R 4 , -COR 5 , -CO 2 R 5 , -OR 4
  • each R 8 independently represents Ci -4 alkyl, haloCi -4 alkyl, Ci -4 alkoxyCi- 4 alkyl, hydroxyCi -4 alkyl, cyanoCi -4 alkyl, halogen or hydroxyl; each R 9 independently represents hydrogen or Ri 0 ; each R 10 independently represents Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, Rn -C-i -4 alkyl or Cy 5 , wherein Cy 5 is optionally substituted with one or more Ri 3 ;
  • R 11 represents halogen, -CN, -CONR 14 R 14 , -COR 15 , -CO 2 R 15 , -OR 14 , -OCONR 14 R 14 , -SO 2 R 15 , -SO 2 NR 14 R 14 , -NR 14 R 14 , -NR 6 COR 14 , -NR 6 CONR 14 R 14 , -NR 6 CO 2 R 15 , -NR 6 SO 2 R 15 or Cy 5 , wherein Cy 5 is optionally substituted with one or more R 13 ; each R 12 independently represents C 1-4 alkyl, haloC 1-4 alkyl, hyd HDXyC 1 -4 alkyl, R 11 -C 1-4 alkyl, or R 12 represents any of the meanings described for R 11 ; each R 13 independently represents C 1-4 alkyl, haloC 1-4 alkyl, C 1 ⁇ aIkOXyC 1- 4 alkyl, hyd HDXyC 1 -4 alkyl
  • Cy 1 represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups;
  • Cy 2 represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups;
  • Cy 3 represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially uns
  • Cy 4 represents a 3- to 7-membered monocyclic heterocyclic ring that is saturated or partially unsaturated, which is optionally fused to a 5- or 6-membered carbocyclic or heterocyclic ring that is saturated, partially unsaturated or aromatic, wherein Cy 4 optionally contains from 1 to 4 heteroatoms in total independently selected from N, S and O; and wherein one or more C or S atoms of Cy 4 are optionally oxidized forming CO, SO or SO 2 groups; and
  • Cy 5 represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups.
  • the present invention also relates to the salts and solvates of the compounds of formula I.
  • Some compounds of formula I can have chiral centers that can give rise to various stereoisomers.
  • the present invention relates to each of these stereoisomers and also mixtures thereof.
  • the compounds of formula I are JAK, particularly JAK3, kinase inhibitors and therefore can be useful for the treatment or prevention of any disease mediated by this kinase.
  • Ri represents hydrogen, d- 4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, R 7 -C 1-4 alkyl, halogen, -CN, -CONR 4 R 4 , -COR 5 , -CO 2 R 5 , -OR 4 , -SO 2 R 5 , -SO 2 NR 4 R 4 , -NR 4 R 4 , -NR 6 COR 4, -NR 6 CONR 4 R 4 , -NR 6 CO 2 R 5 , -NR 6 SO 2 R 5 or Cy-i, wherein Cyi is optionally substituted with one or more R 8 ;
  • R 2 represents hydrogen, C-i- 4 alkyl haloC-i- 4 alkyl, hydroxyCi -4 alkyl,
  • R 3 represents C-i- 4 alkyl, haloC-i- 4 alkyl, hydroxyCi -4 alkyl, Rn-Ci -4 alkyl, -CONR 9 R 9 , -COR10, -CO 2 Ri 0 , -SO 2 Ri 0 , -SO 2 NR 9 R 9 or Cy 3 , wherein Cy 3 is optionally substituted with one or more Ri 2 ; or R 2 and R 3 can be bonded completing, together with the N atom, a Cy 4 group, wherein Cy 4 is optionally substituted with one or more Ri 2 ; each R 4 independently represents hydrogen or R 5 ; each R 5 independently represents Ci -4 alkyl, haloCi -4 alkyl, Ci -4 alkoxyCi- 4 alkyl, hydroxyCi -4 alkyl, cyanoCi -4 alkyl, Cyi-Ci -4 alkyl or Cyi, wherein Cyi is optionally substituted with one or more R 8 ; R 6
  • R 7 represents -CN, -CONR 4 R 4 , -COR 5 , -CO 2 R 5 , -OR 4 , -SO 2 R 5 , -SO 2 NR 4 R 4 , -NR 4 R 4 , -NR 6 COR 4, -NR 6 CONR 4 R 4 , -NR 6 CO 2 R 5 , -NR 6 SO 2 R 5 or Cy-i, wherein Cyi is optionally substituted with one or more R 8 ; each R 8 independently represents Ci -4 alkyl, haloCi -4 alkyl, Ci -4 alkoxyCi-
  • each R 9 independently represents hydrogen or Ri 0 ; each Ri 0 independently represents Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, Rn-Ci- 4 alkyl or Cy 5 , wherein Cy 5 is optionally substituted with one or more Ri 3 ; Rn represents halogen, -CN, -CONRi 4 Ri 4 , -CORi 5 , -CO 2 Ri 5 , -ORi 4 ,
  • each Ri 2 independently represents Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, Rn-Ci- 4 alkyl, or Ri 2 represents any of the meanings described for Rn ; each Ri 3 independently represents Ci -4 alkyl, haloCi -4 alkyl, Ci -4 alkoxyCi- 4 alkyl, hydroxyCi -4 alkyl, cyanoCi -4 alkyl, halogen, -CN, -CONRi 6 Ri 6 , -CORi 7 , - CO 2 Ri 7 , -ORi
  • Cy 1 represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups;
  • Cy 2 represents a 3- to 7-membered monocyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 3 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups;
  • Cy 3 represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially uns
  • Cy 4 represents a 3- to 7-membered monocyclic heterocyclic ring that is saturated or partially unsaturated, which is optionally fused to a 5- or 6-membered carbocyclic or heterocyclic ring that is saturated, partially unsaturated or aromatic, wherein Cy 4 optionally contains from 1 to 4 heteroatoms in total independently selected from N, S and O; and wherein one or more C or S atoms of Cy 4 are optionally oxidized forming CO, SO or SO 2 groups; and
  • Cy 5 represents a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic ring that is saturated, partially unsaturated or aromatic, and which optionally contains from 1 to 4 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups; for use in therapy.
  • Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAKs, particularly JAK3.
  • the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAKs, particularly JAK3.
  • the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by JAKs, particularly JAK3.
  • the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.
  • Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAKs, particularly JAK3, in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the disease mediated by JAKs, particularly JAK3 is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.
  • the disease mediated by JAKs, particularly JAK3 is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to a method of treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases.
  • Another aspect of the present invention relates to a method of treating or preventing a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, leukemias, lymphomas, and thromboembolic and allergic complications associated
  • Another aspect of the present invention relates to a process for the preparation of a compound of formula I as defined above, which comprises:
  • C 1-4 alkyl as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • a C 1-4 alkoxy group as a group or part of a group, means a group of formula -OC 1-4 alkyl, wherein the C 1-4 alkyl moiety has the same meaning as previously described. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and fe/t-butoxy.
  • Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.
  • a C 1-4 alkoxyC 1 - 4 alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C 1-4 alkyl group with one or more C 1-4 alkoxy groups as defined above, which can be the same or different.
  • Examples include, among others, the groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert- butoxymethyl, dimethoxymethyl, 1 -methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1 ,2-diethoxyethyl, 1 -butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2- butoxypropyl, 1 -methoxy-2-ethoxypropyl, 3-tert-butoxypropyl and 4-methoxybutyl.
  • a haloCi -4 alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci -4 alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different.
  • halogen atoms i.e. fluoro, chloro, bromo or iodo
  • Examples include, among others, the groups trifluoromethyl, fluoromethyl, 1 -chloroethyl, 2- chloroethyl, 1 -fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3- tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl and nonafluorobutyl.
  • a hydroxyCi -4 alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci -4 alkyl group with one or more hydroxy groups. Examples include, among others, the groups hydroxymethyl, 1 - hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyl, 1 -hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3- hydroxybutyl, 2-hydroxybutyl and 1 -hydroxybutyl.
  • a cyanoCi -4 alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci -4 alkyl group with one or more cyano groups. Examples include, among others, the groups cyanomethyl, dicyanomethyl,
  • a CyrCi- 4 alkyl group means a group resulting from the replacement of one hydrogen atom from a Ci -4 alkyl group with one Cyi group.
  • Examples include, among others, the groups (morpholin-4-yl)methyl, 2-(morpholin-4-yl)ethyl, 3- (morpholin-4-yl)propyl, 4-(morpholin-4-yl)butyl, (piperazin-i -yl)methyl, (4- methylpiperazin-1 -yl)methyl, 2-(4-methylpiperazin-1 -yl)ethyl, 3-(4-methylpiperazin- 1 -yl)propyl, 4-(4-methylpiperazin-1 -yl)butyl, (4-ethylpiperazin-1 -yl)methyl, (4- propylpiperazin-1 -yl)methyl, (4-butylpiperazin-1 -yl)methyl, (1 ,1 -dioxothiomorpholin- 4-yl)
  • a Cy 5 -Ci- 4 alkyl group means a group resulting from the replacement of one hydrogen atom from a Ci -4 alkyl group with one Cy 5 group.
  • Examples include, among others, the groups (morpholin-4-yl)methyl, 2-(morpholin-4-yl)ethyl, 3- (morpholin-4-yl)propyl, 4-(morpholin-4-yl)butyl, (indolinyl-1 -yl)methyl, 2-(indolinyl- 1 -yl)ethyl, 3-(indolinyl-1 -yl)propyl, 4-(indolinyl-1 -yl)butyl, (pyridin-1 -yl)methyl, (4- methylpyridin-1 -yl)methyl, 2-(4-methylpyhdin-1 -yl)ethyl, 3-(4-methylpyhdin-1 - yl)propyl, 4-(4-methylpyridin-1 -yl)butyl
  • a R 7 -Ci -4 alkyl group means a group resulting from the replacement of one hydrogen atom from a Ci -4 alkyl group with one R 7 group.
  • a RirCi- 4 alkyl group means a group resulting from the replacement of one hydrogen atom from a C-
  • a Cyi group refers to a 3- to 7-membered monocyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 3 heteroatoms independently selected from N, S and O. Cyi is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C or N atom. When Cyi is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO 2 groups.
  • Cyi is optionally substituted as disclosed above in the definition of a compound of formula I, said substituents can be the same or different and can be placed on any available position of the ring system.
  • Examples of Cyi group include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 - dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homo
  • a Cy 2 group refers to a 3- to 7-membered monocyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 3 heteroatoms independently selected from N, S and O. Cy 2 is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C atom. When Cy 2 is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO 2 groups. Cy 2 is optionally substituted as disclosed above in the definition of a compound of formula I, said substituents can be the same or different and can be placed on any available position of the ring system.
  • Cy 2 group examples include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 - dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopipehdinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imid
  • a Cy 3 group refers to a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic rings may be formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they can be formed by two rings bonded through a single common C atom forming a spiro ring. Cy 3 is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C atom.
  • Cy 3 one or more C or S atoms of a saturated or partially unsaturated ring are optionally oxidized forming CO, SO or SO 2 groups. Cy 3 is optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, said substituents can be the same or different and can be placed on any available position of the ring system.
  • Cy 3 examples include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopipehdinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imid
  • a Cy 4 group refers to a 3- to 7-membered monocyclic heterocyclic ring, which is saturated or partially unsaturated. Cy 4 is optionally fused to a 5- or 6- membered carbocyclic or heterocyclic ring that is saturated, partially unsaturated or aromatic. Cy 4 contains from 1 to 4 heteroatoms in total independently selected from N, S and O. In Cy 4 one or more C or S atoms of a saturated or partially unsaturated ring are optionally oxidized forming CO, SO or SO 2 groups. Cy 4 is optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, said substituents can be the same or different and can be placed on any available position of the ring system.
  • Cy 4 examples include, among others, azepanyl, aziridinyl, azetidinyl, 1 ,4-diazepanyl, pyrrolidinyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolinyl, pyrrolinyl, pyrazolinyl, piperidinyl, homopipehdinyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxothiomorpholinyl, piperazinyl, homopiperazinyl, 2-oxo-azepanyl, 2-oxo-azetidinyl, 2-oxo-1 ,4-diazepanyl, 2-oxo- pyrrolidinyl, 2-oxo-piperazinyl, 2-oxo-pipe
  • a Cy 5 group refers to a 3- to 7-membered monocyclic or 8- to 12-membered bicyclic carbocyclic or heterocyclic ring. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and O. Bicyclic rings may be formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they can be formed by two rings bonded through a single common C atom forming a spiro ring. Cy 5 is saturated, partially unsaturated or aromatic, and is bonded to the rest of the molecule through any available C or N atoms.
  • Cy 5 one or more C or S atoms of a saturated or partially unsaturated ring are optionally oxidized forming CO, SO or SO 2 groups. Cy 5 is optionally substituted as disclosed above in the definition of a compound of formula I; if substituted, said substituents can be the same or different and can be placed on any available position of the ring system.
  • Cy 5 examples include, among others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxothiomorpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopipehdinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imid
  • the term pyrazolopyridinyl can include groups such as 1 H- pyrazolo[3,4-£>]pyridinyl, 1 H-pyrazolo[1 ,5-a]pyridinyl, 1 H-pyrazolo[3,4-c]pyridinyl, 1 H-pyrazolo[4,3-c]pyridinyl and 1 H-pyrazolo[4,3-£>]pyridinyl
  • the term imidazopyrazinyl can include groups such as 1 H-imidazo[4,5-£>]pyrazinyl, imidazo[1 ,2-a]pyrazinyl and imidazo[1 ,5-a]pyrazinyl
  • the term pyrazolopyrimidinyl can include groups such as 1 H-pyrazolo[3,4-c/]p
  • cyclic groups refer to a radical of a ring in general terms, for example pyridyl, thienyl or indolyl, all the available bonding positions are included, unless a limitation is indicated in the corresponding definition for said cyclic group, for example that the ring is bonded through a C atom in Cy 2 and Cy 3 , in which case such limitation applies.
  • piperidinyl includes 1 -piperidinyl, 2-pipehdinyl, 3-piperidinyl and 4-pipehdinyl
  • pyrrolidinyl includes 1 -pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.
  • a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, more preferably with 1 , 2 or 3 substituents, and still more preferably with 1 or 2 substituents, provided that said group has enough positions susceptible of being substituted.
  • the substituents can be the same or different and can be placed on any available position.
  • a non-aromatic ring When a non-aromatic ring is present as a substituent of a non-aromatic ring, it can replace one hydrogen atom, or it can replace two hydrogen atoms on the same C atom thus forming a spiro ring.
  • a non-aromatic ring when a non-aromatic ring is present as a substituent of an alkyl group, it can either replace one hydrogen atom, or it can replace two hydrogen atoms and share one C atom of said alkylgroup, forming groups such as the ones shown below:
  • treatment is meant eliminating, reducing or ameliorating the cause or the effects of a disease.
  • treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).
  • prevention refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also preventing the recurrence of a disease in a subject that has previously suffered said disease.
  • the invention thus relates to the compounds of formula I as defined above.
  • the invention relates to the compounds of formula I wherein Ri represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, R 7 -C 1-4 alkyl, halogen, -CN, -CONR 4 R 4 , -CO 2 R 5 , -OR 4 or -NR 6 COR 4 .
  • the invention relates to the compounds of formula I wherein Ri represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, R 7 -C- ⁇ - 4 alkyl, halogen or -CN.
  • the invention relates to the compounds of formula I wherein Ri represents hydrogen or -CN. In another embodiment, the invention relates to the compounds of formula I wherein Ri represents hydrogen.
  • the invention relates to the compounds of formula I wherein Ri represents-CN.
  • the invention relates to the compounds of formula I wherein R 7 in Ri represents -CN, -CONR 4 R 4 , -CO 2 Rs, -OR 4 or -NR 6 COR 4 .
  • the invention relates to the compounds of formula I wherein:
  • R 2 represents hydrogen, C-i- 4 alkyl, haloC-i- 4 alkyl, hydroxyCi -4 alkyl, R 7 -C-i -4 alkyl or Cy 2 , wherein Cy 2 is optionally substituted with one or more R 8 ; and R 3 represents C-
  • the invention relates to the compounds of formula I wherein R 2 represents hydrogen, Ci -4 alkyl, haloC-
  • the invention relates to the compounds of formula I wherein R 2 represents hydrogen, Ci -4 alkyl, haloC-i- 4 alkyl or hydroxyCi -4 alkyl. In another embodiment, the invention relates to the compounds of formula I wherein R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein R 3 represents hydroxyCi -4 alkyl, Rn-Ci -4 alkyl or Cy 3 , wherein Cy 3 is optionally substituted with one or more Ri 2 . In another embodiment, the invention relates to the compounds of formula I wherein R 3 represents Cy 3 , wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents a 3- to 7-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • Cy 3 represents a 3- to 7-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • Cy 3 represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents cyclohexyl, 2-pipehdinyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents cyclohexyl or 3-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents cyclohexyl, which is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents 3-piperidinyl, which is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein Cy 3 represents 4-piperidinyl, which is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ; and Cy 3 represents a group of formula Cy 3a or Cy 3b :
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3 I 3 ; wherein Ri 2a represents wherein additionally Cy 3a and Cy 3b are independently optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci -4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3 I 3 ; wherein Ri 2a represents wherein additionally Cy 3a and Cy 3 b are independently optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci -4 alkyl; Ri 4 represents hydrogen; and
  • Ri5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3 I 3 ; wherein Ri 2a represents -
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3b ; wherein Ri 2a represents
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ; Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; and wherein additionally Cy 3a is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein: R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3 I 3 ; and wherein additionally Cy 3 I 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents -CORi 5 .
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3 b.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R- ⁇ 2a represents -CORi 5 ; and
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl or hydroxyCi -4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl or hydroxyCi -4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl.
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN; and
  • R 3 represents Cy 3 , wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein: Ri represents -CN ;
  • R 3 represents Cy 3 , wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 , wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 - Ci -4 alkyl; and R 3 represents Cy 3 , wherein Cy 3 is optionally substituted with one or more
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 , wherein Cy 3 is optionally substituted with one or more
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 , wherein Cy 3 is optionally substituted with one or more
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3
  • Cy 3 represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ; and
  • Cy 3 represents a 5- or 6-membered saturated monocyclic carbocyclic ring, which optionally contains 1 or 2 heteroatoms independently selected from N, S and O, wherein said ring is bonded to the rest of the molecule through any available C atom, wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 groups, and wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents cyclohexyl, 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 - Ci -4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents cyclohexyl, optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 - C 1-4 alkyl ;
  • R 3 represents Cy 3 ;
  • Cy 3 represents cyclohexyl, optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents cyclohexyl, optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl; R 3 represents Cy 3 ; and Cy 3 represents cyclohexyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -
  • R 3 represents Cy 3 ;
  • Cy 3 represents 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ; and
  • Cy 3 represents 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ;
  • Cy 3 represents 3-piperidinyl or 4-pipehdinyl, wherein Cy 3 is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, or R 7 - Ci -4 alkyl;
  • R 3 represents Cy 3 ; and Cy 3 represents 3-piperidinyl, optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents 3-piperidinyl, optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ;
  • Cy 3 represents 3-piperidinyl, optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents 3-piperidinyl, optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN, preferably -CN
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3 I 3 ; wherein Ri 2a represents -CONRi 4 Ri 4 , -CORi5, -CO 2 Ri 5 , -SO 2 Ri 5 , -SO 2 NRi 4 Ri 4 or Cy 5 , wherein Cy 5 is optionally substituted with one or more Ri 3 ; and wherein additionally Cy 3a and Cy 3b are independently optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN, preferably -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3b ; wherein Ri 2a represents wherein additionally Cy 3a and Cy 3b are independently optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3b ; wherein Ri 2a represents wherein additionally Cy 3a and Cy 3b are independently optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci -4 alkyl.
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3b ; wherein Ri 2a represents
  • Cy 3a and Cy 3b are independently optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci -4 alkyl; Ri 4 represents hydrogen; and
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3 I 3 ;
  • Ri 2a represents
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3 I 3 ; wherein Ri 2a represents
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ; Cy 3 represents a group of formula Cy 3a or Cy 3 b; wherein R 12a represents -COR 15 ;
  • R- 15 represents C-i- 4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a or Cy 3b ; wherein R 12a represents
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ; Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CONRi 4 Ri 4 , -CORi 5 , -CO 2 Ri 5 , -SO 2 Ri 5 , -SO 2 NRi 4 Ri 4 or Cy 5 , wherein Cy 5 is optionally substituted with one or more Ri 3 ; and wherein additionally Cy 3a is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents
  • the invention relates to the compounds of formula I wherein:
  • R 1 represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, or R 7 -C 1- 4 alkyl;
  • R 3 represents Cy 3 ; Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents
  • Cy 5 is optionally substituted with one or more R 13 ; and wherein additionally Cy 3a is optionally substituted with one or more R 12 groups independently selected from C 1-4 alkyl, haloC 1-4 alkyl, hyd TOXyC 1 -4 alkyl and R 11 -C 1- 4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • R 1 represents hydrogen or -CN
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents -CONR 14 R 14 , -COR 15 , -CO 2 R 15 , -SO 2 R 15 , -SO 2 NR 14 R 14 or Cy 5 , wherein Cy 5 is optionally substituted with one or more R 13 ; and wherein additionally Cy 3a is optionally substituted with one or more R 12 groups independently selected from C 1-4 alkyl, haloC 1-4 alkyl, hyd TOXyC 1 -4 alkyl and R 11 -C 1- 4 alkyl.
  • the invention relates to the compounds of formula I wherein: Ri represents -CN;
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CONR 14 R 14 , -COR 15 , -CO 2 R 15 , -SO 2 R 15 , -SO 2 NR 14 R 14 or Cy 5 , wherein Cy 5 is optionally substituted with one or more R 13 ; and wherein additionally Cy 3a is optionally substituted with one or more R 12 groups independently selected from C 1-4 alkyl, haloC 1-4 alkyl, hyd TOXyC 1 -4 alkyl and R 11 -C 1- 4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • R 1 represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl or R 7 -C 1- 4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents -COR 15 ; and wherein additionally Cy 3a is optionally substituted with one or more R 12 .
  • the invention relates to the compounds of formula I wherein:
  • R 1 represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, or R 7 -C 1- 4 alkyl;
  • R 3 represents Cy 3 ; Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents -COR 15 ; and wherein additionally Cy 3a is optionally substituted with one or more R 12 groups independently selected from C 1-4 alkyl, haloC 1-4 alkyl, hyd TOXyC 1 -4 alkyl and R 11 -C 1- 4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • R 1 represents hydrogen or -CN
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents -CORi 5 ; and wherein additionally Cy 3a is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; and wherein additionally Cy 3a is optionally substituted with one or more Ri 2 .
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; and wherein additionally Cy 3a is optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci- 4 alkyl.
  • the invention relates to the compounds of formula I wherein: Ri represents -CN;
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; and wherein additionally Cy 3a is optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci- 4 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents -CORi 5 ; wherein additionally Cy 3a is optionally substituted with one or more Ri 2 ; and Ri5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN, preferably -CN;
  • R 2 represents hydrogen, Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl, or R 7 -Ci- 4 alkyl;
  • R 3 represents Cy 3 ; Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; wherein additionally Cy 3a is optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci- 4 alkyl; and
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3
  • Cy 3 represents a group of formula Cy 3a
  • Ri 2a represents -CORi 5
  • Cy 3a is optionally substituted with one or more Ri 2
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein: Ri represents -CN;
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; wherein additionally Cy 3a is optionally substituted with one or more Ri 2 ; and R- 15 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R- ⁇ 2a represents -CORi 5 ; wherein additionally Cy 3a is optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rn-Ci- 4 alkyl; and
  • Ri5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein: Ri represents -CN;
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; wherein additionally Cy 3a is optionally substituted with one or more Ri 2 groups independently selected from Ci -4 alkyl, haloCi -4 alkyl, hydroxyCi -4 alkyl and Rii-Ci- 4 alkyl; and
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen or C 1-4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ; and Cy 3 represents a group of formula Cy 3a ; wherein R 12a represents -CORi 5 .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein R- ⁇ 2a represents -CORi 5 ; and
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3a ; wherein Ri 2a represents -CORi 5 ; and
  • Ri 5 represents Ci -4 alkyl or cyanoCi -4 alkyl, preferably cyanomethyl.
  • the invention relates to the compounds of formula I wherein: Ri represents hydrogen or -CN;
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl; R 3 represents Cy 3 ; and Cy 3 represents a group of formula Cy 3b .
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl; R 3 represents Cy 3 ; and Cy 3 represents a group of formula Cy 3 b.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents hydrogen or -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3b ; and Ri 4 represents hydrogen.
  • the invention relates to the compounds of formula I wherein:
  • Ri represents -CN
  • R 2 represents hydrogen or Ci -4 alkyl, preferably hydrogen, methyl or ethyl;
  • R 3 represents Cy 3 ;
  • Cy 3 represents a group of formula Cy 3b ; and Ri 4 represents hydrogen.
  • the invention relates to a compound of formula I or a salt thereof selected from the list of compounds described in the examples 1 to 16.
  • the invention relates to a compound of formula I selected from:
  • the invention relates to a compound of formula I selected from: ⁇ ans-5-cyano-3-[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl]pyrazolo[1 ,5- a]pyridine,
  • the invention relates to a compound of formula I, which provides more than 50% inhibition of JAK3 activity at 10 ⁇ M, more preferably at 1 ⁇ M and still more preferably at 0.1 ⁇ M, in a JAK3 assay such as the one described in example 17.
  • the invention relates to a compound of formula I, which provides more than 50% inhibition of JAK2 activity at 10 ⁇ M, more preferably at 1 ⁇ M, and still more preferably at 0.5 ⁇ M, in a JAK2 assay such as the one described in example 18.
  • the compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids.
  • salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, thfluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid
  • organic acids such as methanesulfonic acid, thfluoromethanesulfonic acid, ethanesul
  • Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases.
  • these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, ⁇ /-methylglucamine, procaine and the like.
  • salts there is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when they are used for therapeutic purposes.
  • pharmaceutically acceptable salt represents those salts which are, according to medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.
  • the salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I with a sufficient amount of the desired acid or base to give the salt in the conventional manner.
  • the salts of the compounds of formula I can be converted into other salts of the compounds of formula I by ion exchange using ionic exchange resins.
  • the compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates.
  • solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent.
  • solvents include pharmaceutically acceptable solvents such as water, ethanol and the like.
  • a complex with water is known as a hydrate.
  • Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention.
  • the compounds of formula I may exist in different physical forms, i.e. amorphous and crystalline forms.
  • the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism.
  • Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I, including all polymorphic forms (“polymorphs”) thereof, are included within the scope of the invention.
  • Some of the compounds of the present invention may exist as several diastereoisomers and/or several optical isomers.
  • Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on products of formula I.
  • Optically pure isomers can also be individually obtained using enantiospecific synthesis.
  • the present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.
  • the compounds of formula I can be obtained by following the processes described below.
  • Step a may be carried out by the reaction of a compound of formula Il with aminosulfonic acid in the presence of a HI aqueous solution; and of a base such as K 2 CO 3 , NaOH or KOH; in a solvent such as dichloromethane, tetrahydrofurane, water, ethanol, methanol, isopropanol or acetonithle; and heating preferably at reflux to obtain a compound of formula III.
  • a base such as K 2 CO 3 , NaOH or KOH
  • a solvent such as dichloromethane, tetrahydrofurane, water, ethanol, methanol, isopropanol or acetonithle
  • step a may be carried out by the reaction of a compound of formula Il with 2,4-dinitrophenylhydroxylamine, o-(p-toluensulfonyl)hydroxylamine, or o-(mesitylsulfonyl)hydroxylamine (obtained in situ from methyl N- mesitylsulfonyloxyacetimidate in the presence of a 70% HCIO 4 aqueous solution; in a solvent such as dioxane; and cooling preferably at -5 5 C); in the presence of a solvent such as dichloromethane; and heating preferably from O 5 C to room temperature to obtain a compound of formula III.
  • step b the reaction of a compound of formula III with ethyl propiolate may be carried out under O 2 atmposphere; in the presence of a base such as K 2 CO 3 ,
  • Step c may be carried out by the reaction of a compound of formula IV with an acid such as H 2 SO 4 , polyphosphohc acid, HCI, HBr, or HI and water in 1 :1 proportion, heating preferably between 120 5 C and 50 5 C to obtain a compound of formula V.
  • Step d may be carried out by the reaction of a compound of formula V with an acid such as H 2 SO 4 , polyphosphohc acid, HCI, HBr, or HI and water in 1 :1 proportion, heating preferably between 120 5 C and 50 5 C to obtain a compound of formula V.
  • Step d may be carried out by the reaction of a compound of formula V with
  • N-bromosuccinimide N-bromosuccinimide (NBS) in the presence of benzoyl peroxide or azobisisobutyronitrile (AIBN); and of a solvent such as dichloromethane or carbon tetrachloride; and at room temperature to obtain a compound of formula Vl.
  • AIBN azobisisobutyronitrile
  • step e the reaction between a compound of formula Vl with a compound of formula VII may be carried out using the conditions described in the literature for Suzuki's coupling reactions.
  • the reaction may be carried out in the presence of a Pd catalyst such as Pd(PPh 3 ) 4 ; in the presence of a base such as K 2 CO 3 ; in a mixture of solvents such as a dimethoxyethane and water; and heating preferably at 85 5 C to obtain a compound of formula VIII.
  • a Pd catalyst such as Pd(PPh 3 ) 4
  • a base such as K 2 CO 3
  • solvents such as a dimethoxyethane and water
  • step f may be carried out by the reaction of a compound of formula VIII with an amine of formula IX in the presence of a base such as diisopropylethylamine, thethylamine or K 2 CO 3 , in a solvent such as N- methylpyrrolidone, N,N-dimethylformamide, dimethylsulfoxide, dimethylamide or pyridine, and heating preferably at 190 5 C to obtain a compound of formula I.
  • step f may be carried out by the reaction of a compound of formula VIII with an amine of formula IX using the conditions described in the literature for Buchwald's coupling reactions.
  • the reaction may be carried out in the presence of a Pd catalyst such as Pd 2 (dba) 3 , and of a phosphine such as 2-dicyclohexylphosphino-2',4',6'- thisopropyl-biphenyl (X-Phos ® ), in the presence of a base such as K 2 CO 3 , in a solvent such as fe/t-butanol, and heating preferably at 100 5 C to obtain a compound of formula I.
  • a compound of formula VIII can be obtained by the method described in Scheme 2:
  • step a of scheme 2 the reaction of a compound of formula X with thmethylsilylacetilene may be carried out using the conditions described in the literature for Sonogashira's coupling reactions.
  • the reaction may be carried out in the presence of a Pd catalyst such as Pd(PPh 3 ) 4 , of CuI, and of a base such as isopropylamine, and at room temperature to obtain a compound of formula Xl after the thmethylsilyl group deprotection in the conditions described in the literature for deprotection reactions of silyl groups.
  • step b the reaction of a compound of formula Xl with a compound of formula III may be carried out in the presence of a base such as 1 ,8- diazabicyclo[5.4.0]undec-7-ene, K 2 CO 3 , diisopropylethylamine, thethylamine, KOH, Cs 2 CO 3 , potassium tert-butoxide in a solvent such as acetonithle, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, ethanol or dimethylsulfoxide, at room temperature or heating preferably between 40 5 C and 80 5 C to obtain a compound of formula VIII.
  • a base such as 1 ,8- diazabicyclo[5.4.0]undec-7-ene
  • K 2 CO 3 diisopropylethylamine
  • thethylamine KOH, Cs 2 CO 3
  • potassium tert-butoxide in a solvent such as acetonith
  • R 1 , R 2 and R 3 have the meaning previously described in relation with a compound of formula I; and X represents halogen.
  • step a of scheme 3 the reaction of a compound of formula VIII with diphenylmethanimine may be carried out using the conditions described in the literature for Buchwald's coupling reactions.
  • the reaction may be carried out in the presence of a Pd catalyst such Pd 2 (dba) 3 ; of a phosphine such as 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP); and of a base such as sodium fe/t-butoxide; in a solvent such as toluene; and heating preferably at reflux to obtain, after an acidic hydrolysis step in the presence of an acid such as HCI, an amine of formula XII.
  • a Pd catalyst such Pd 2 (dba) 3
  • a phosphine such as 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP)
  • BINAP 2,2'
  • step b an amine of formula XII is converted into a compound of formula I in one or several steps using conversion reactions of amino groups well- known in organic chemistry under the standard experimental conditions.
  • step b should be carried out two times. Said transformations include, for example: the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e.
  • some compounds of the present invention can also be obtained from other compounds of formula I by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the standard experimental conditions.
  • Said transformations can be carried out upon R-i, R 2 or R 3 groups and include, for example: the reduction of a nitro group to give an amino group, for example by treatment with hydrogen, hydrazine or formic acid in the presence of a suitable catalyst such as Pd/C; or by treatment with sodium borohydride in the presence of NiCI 2 , Or SnCI 2 ; the substitution of a primary or secondary amine by treatment with an alkylating agent under standard conditions, or by reductive amination, i.e.
  • any of the aromatic rings of the compounds of the present invention can undergo electrophilic aromatic substitution reactions or nucleophilic aromatic substitution reactions, widely described in the literature. Some of these interconversion reactions are explained in greater detail in the examples.
  • the compounds of formula Il and X are commercially available or can be prepared by well-known methods described in the literature starting from commercially available compounds using interconversion reactions such those described above for a compound of formula I, and can be protected with suitable protecting groups.
  • the compounds of the present invention act by inhibiting JAK/STAT signaling pathways, particularly by inhibiting JAK3 activity.
  • the compounds of the invention are expected to be useful to treat or prevent diseases in which JAKs, particularly JAK3, play a role in mammals, including human beings.
  • diseases include, but are not limited to, transplant rejection; immune, autoimmune and inflammatory diseases; neurodegenerative diseases; and proliferative disorders (see e.g. O'Shea J.J. et al, Nat. Rev. Drug.
  • Acute or chronic transplant rejection reactions that can be treated or prevented with the compounds of the present invention include any kind of cell, tissue or organ xenotransplants or allografts, such as of heart, lung, liver, kidney, pancreas, uterus, joints, pancreatic islets, bone marrow, limbs, cornea, skin, hepatocytes, pancreatic beta cells, pluhpotential cells, neuronal cells and myocardial cells, as well as graft-versus-host reactions (see e.g. Rousvoal G. et al, Transpl. Int. 2006, 19(12):1014-21 ; Borie DC. et al, Transplantation 2005,
  • Immune, autoimmune and inflammatory diseases that can be treated or prevented with the compounds of the present invention include among others, rheumatic diseases (e.g. rheumatoid arthritis and psoriatic arthritis), autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis and inflammatory bowel diseases (e.g.
  • ulcerative colitis and Crohn's disease scleroderma, type I diabetes and complications from diabetes, type B hepatitis, type C hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, suppression of HIV replication, infertility of autoimmune origin, autoimmune thyroid disease (Grave's disease), interstitial cystitis, and mast cell- mediated allergic reactions such as asthma, angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis (see e.g.
  • Neurodegenerative diseases that can be treated or prevented with the compounds of the present invention include, among others, amyotrophic lateral sclerosis and Alzheimer's disease (see e.g. Trieu VN. et al, Biochem. Biophys. Res. Commun. 2000, 267(1 ):22-5).
  • Proliferative disorders that can be treated or prevented with the compounds of the present invention include, among others, leukemias, lymphomas, glioblastoma multiforme, colon carcinoma, as well as thromboembolic and allergic complications associated with these diseases (see e.g. Sudbeck EA. et al, Clin. Cancer Res. 1999, 5(6):1569-82; Narla RK. et al, Clin. Cancer Res.
  • JAK2-mediated diseases are myeloproliferative disorders, including polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome (see e.g.
  • JAK2 inhibitors include compounds of examples 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15. These compoundsthus can also be particularly useful, in addition to treating or preventing all the diseases mentioned in the preceding paragraphs, for the treatment or prevention of myeloproliferative disorders (MPD).
  • MPD myeloproliferative disorders
  • another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1v, 2p, 9b, 1 1 , 13, 14 and 15, for use in the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2 is a myeloproliferative disorder.
  • Another aspect of the present invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15, for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2 is a myeloproliferative disorder.
  • Another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15, for use in the treatment or prevention of a myeloproliferative disorder.
  • the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome.
  • Another aspect of the invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, and particularly compounds of examples 1 u, 1 v, 2p, 9b, 11 , 13, 14 and 15, for the manufacture of a medicament for the treatment or prevention of a myeloproliferative disorder.
  • the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome.
  • Biological assays that can be used to determine the ability of a compound to inhibit JAKs, particularly JAK3 and JAK2, are well known in the art.
  • a compound to be tested can be incubated in the presence of JAK3 or JAK2 to determine whether inhibition of JAK3 or JAK2 enzymatic activity occurs, as described in the assays of examples 17 and 18, respectively.
  • Other in vitro useful assays that can be used to measure JAK3-inhibitory activity include cellular assays, for example IL-2-induced proliferation of human T lymphocytes.
  • the immunosuppressive activity of the compounds of the invention can be tested using standard in vivo animal models for immune and autoimmune diseases, which are well known in the art.
  • DTH delayed- type hypersensitivity
  • rheumatoid arthritis models such as collagen-induced arthritis
  • EAE experimental autoimmune encephalomyelitis
  • testing at 10 ⁇ M must result in an activity of more than 50% inhibition of JAK3 activity in the test provided in example 17. More preferably, when tested in this assay compounds should exhibit more than 50% inhibition at 1 ⁇ M, and still more preferably, they should exhibit more than 50% inhibition at 0.1 ⁇ M.
  • testing at 10 ⁇ M must result in an activity of more than 50% inhibition of JAK2 activity in the test provided in example
  • the present invention also relates to a pharmaceutical composition that comprises a compound of the present invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients.
  • excipients must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration.
  • Any route of administration may be used, for example oral, parenteral, nasal, ocular, rectal and topical administration.
  • Solid compositions for oral administration include tablets, granulates and capsules.
  • the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients.
  • excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc.
  • Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability.
  • the active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents.
  • Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.
  • Powders and granulates for the preparation of oral suspensions by the addition of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives. Other excipients can also be added, for example sweetening, flavoring and colouring agents.
  • Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as purified water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, flavoring agents, preservatives and buffers.
  • Injectable preparations for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils.
  • aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils.
  • These compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions, which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process.
  • the active compound can be preferably formulated as a suppository on an oily base, such as for example vegetable oils or solid semisynthetic glycehdes, or on a hydrophilic base such as polyethylene glycols (macrogol).
  • an oily base such as for example vegetable oils or solid semisynthetic glycehdes
  • a hydrophilic base such as polyethylene glycols (macrogol).
  • the compounds of the invention can also be formulated for their topical application for the treatment or prevention of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract.
  • Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.
  • the compound for the nasal administration or for inhalation, can be formulated as an aerosol and it can be conveniently released using suitable propellants.
  • the dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors.
  • a representative example of a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.
  • BINAP 2,2'-bis(diphenylfosfine)-1 ,1 '-binaphthyl
  • TBAF tetrabutylammonium fluoride
  • TEA triethylamine
  • THF tetrahydrofuran
  • TMSI 1 -(trimethylsylyl)imidazole .
  • R retention time
  • X-Phos 2-dicyclohexylphosphino-2',4',6'-thisopropyl-biphenyl
  • Method 1 Waters Acquity UPLC BEH C18 Column (1.7 ⁇ m, 2.1 x 50 mm), temperature 40 5 C, flow rate: 0.5 mL/min, eluent: AcN(A) / Ammonium bicarbonate 10 mM (B), gradient: 0 min 10% A - 3.75 min 90% A.
  • JAK3 kinase activity was determined in 384-well assay microplates using the Z'-Lyte ® Kinase Assay kit-Tyr 6 Peptide, supplied by Invitrogen (Ref: PV4122), following manufacturer instructions.
  • the reaction was started by adding 4 ⁇ M of ATP; after a 1 hour incubation period at 25 Q C, 5 ⁇ L of development reagent were added to Z'-Lyte ® Tyr 6 and it was incubated for 1 hour at 25 Q C. Phosphorylation was then quantified in each well using a Safire2 ® fluorescence meter by Tecan.
  • the compounds of all examples showed more than 50% inhibition of JAK3 activity at 10 ⁇ M in this trial.
  • the compounds 1 c, 1 f, 1 m, 1 o, 1 u, 1 v, 2p, 9b, 13, 14 and 15 showed more than 50% inhibition of JAK3 activity at 0.1 ⁇ M in this assay.
  • JAK2 kinase activity was determined in 384-well assay microplates using the Z'-Lyte ® Kinase Assay kit-Tyr 6 Peptide kit, supplied by Invitrogen (Ref: PV4122), following the manufacturer's instructions.
  • the reaction was started by the addition of said 16 ⁇ M ATP; after incubation for 1 hour at 25 Q C, 5 ⁇ l_ of A Z'-Lyte ® Tyr 6 development reagent was added and the mixture was incubated for 1 hour at 25 Q C. Phosphorylation was then quantified in each well using a Safire2 ® fluorescence microplate reader from Tecan.
  • the compounds 1 u, 1 v, 2p, 9b, 1 1 , 13, 14 and 15 showed more than 50% inhibition of JAK2 activity at 0.5 ⁇ M in this assay.

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Abstract

Dérivés de pyrazolo[1,5-a]pyridine de formule I, où la valeur de R1, R2 et R3 est celle donnée dans la description. Ces composés peuvent être employés en tant qu'inhibiteurs de kinase JAK3.
PCT/EP2009/067883 2008-12-24 2009-12-23 Dérivés de pyrazole[1,5a]pyridine Ceased WO2010072823A1 (fr)

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WO2011136264A1 (fr) * 2010-04-28 2011-11-03 第一三共株式会社 Composé [5,6] hétérocyclique
US9034311B2 (en) 2011-08-01 2015-05-19 Almirall, S.A. Pyridin-2(1 H)-one derivatives as JAK inhibitors
WO2015089218A1 (fr) * 2013-12-10 2015-06-18 David Wustrow Composés monocycliques pyrimidine/pyridine comme inhibiteurs du complexe p97
US9133200B2 (en) 2010-11-26 2015-09-15 Almirall, S.A. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine derivatives as JAK inhibitors
KR20160110506A (ko) * 2014-01-20 2016-09-21 클리브 바이오사이언스 인코포레이티드 (클리브) p97 복합체의 저해제로서 융합된 피리미딘
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
WO2020092015A1 (fr) 2018-11-02 2020-05-07 University Of Rochester Atténuation thérapeutique d'une infection épithéliale
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
EP4041241A1 (fr) 2019-09-27 2022-08-17 Disc Medicine, Inc. Procédés de traitement de la myélofibrose et d'affections associées
US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
WO2025029897A1 (fr) * 2023-08-03 2025-02-06 Neuro3 Therapeutics, Inc. Pyrazolopyridines substituées
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis

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Cited By (23)

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US9206183B2 (en) * 2010-02-18 2015-12-08 Almirall, S.A. Substituted pyrazolo[1,5-a]pyridines as JAK inhibitors
JP2013519696A (ja) * 2010-02-18 2013-05-30 アルミラル・ソシエダッド・アノニマ Ｊａｋ阻害剤としてのピラゾール誘導体
WO2011101161A1 (fr) 2010-02-18 2011-08-25 Almirall, S.A. Dérivés pyrazole comme inhibiteurs jak
AU2011217489B2 (en) * 2010-02-18 2015-09-03 Almirall, S.A. Pyrazole derivatives as JAK inhibitors
WO2011136264A1 (fr) * 2010-04-28 2011-11-03 第一三共株式会社 Composé [5,6] hétérocyclique
US9133200B2 (en) 2010-11-26 2015-09-15 Almirall, S.A. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine derivatives as JAK inhibitors
US9034311B2 (en) 2011-08-01 2015-05-19 Almirall, S.A. Pyridin-2(1 H)-one derivatives as JAK inhibitors
US9868722B2 (en) 2013-12-10 2018-01-16 Cleave Biosciences, Inc. Monocyclic pyrimidine/pyridine compounds as inhibitors of P97 complex
WO2015089218A1 (fr) * 2013-12-10 2015-06-18 David Wustrow Composés monocycliques pyrimidine/pyridine comme inhibiteurs du complexe p97
US9828363B2 (en) 2014-01-20 2017-11-28 Cleave Biosciences, Inc. Fused pyrimidines as inhibitors of P97 complex
KR20160110506A (ko) * 2014-01-20 2016-09-21 클리브 바이오사이언스 인코포레이티드 (클리브) p97 복합체의 저해제로서 융합된 피리미딘
KR101922317B1 (ko) 2014-01-20 2018-11-26 클리브 바이오사이언스 인코포레이티드 (클리브) p97 복합체의 저해제로서 융합된 피리미딘
US10174005B2 (en) 2014-01-20 2019-01-08 Cleave Biosciences, Inc. Fused pyrimidines as inhibitors of p97 complex
US10774064B2 (en) 2016-06-02 2020-09-15 Cadent Therapeutics, Inc. Potassium channel modulators
US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US10717728B2 (en) 2017-01-23 2020-07-21 Cadent Therapeutics, Inc. Potassium channel modulators
US10351553B2 (en) 2017-01-23 2019-07-16 Cadent Therapeutics, Inc. Potassium channel modulators
US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
WO2020092015A1 (fr) 2018-11-02 2020-05-07 University Of Rochester Atténuation thérapeutique d'une infection épithéliale
EP4041241A1 (fr) 2019-09-27 2022-08-17 Disc Medicine, Inc. Procédés de traitement de la myélofibrose et d'affections associées
US12365729B2 (en) 2020-05-13 2025-07-22 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis
US12497452B2 (en) 2020-05-13 2025-12-16 Disc Medicine, Inc. Anti-hemojuvelin (HJV) antibodies for treating myelofibrosis
WO2025029897A1 (fr) * 2023-08-03 2025-02-06 Neuro3 Therapeutics, Inc. Pyrazolopyridines substituées

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