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WO2025021943A1 - Quinazolinone, benzoxazinone et dérivés de benzoxazépinone utilisés en tant qu'inhibiteurs de protéine kinase - Google Patents

Quinazolinone, benzoxazinone et dérivés de benzoxazépinone utilisés en tant qu'inhibiteurs de protéine kinase Download PDF

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WO2025021943A1
WO2025021943A1 PCT/EP2024/071181 EP2024071181W WO2025021943A1 WO 2025021943 A1 WO2025021943 A1 WO 2025021943A1 EP 2024071181 W EP2024071181 W EP 2024071181W WO 2025021943 A1 WO2025021943 A1 WO 2025021943A1
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formula
independently
occurrence
compound
hydrogen
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Dominique Surleraux
Rémi GUILLON
Céline LASCHET
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Neuralis
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Neuralis
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention is in the field of medicinal chemistry and pharmaceuticals.
  • Protein phosphorylation is the most common form of reversible post- translational modification, with an estimated 50% of all proteins undergoing phosphorylation.
  • the phosphorylation state of any given protein is controlled by the coordinated action of specific kinases and phosphatases that add and remove phosphate, respectively.
  • protein kinases are a kind of protein phosphotransferases bringing the phosphate of ATP to the specific amino acid residue. They may conventionally be divided into five classes: tyrosine protein kinases, serine/threonine protein kinases, histidine protein kinases, tryptophan protein kinases and aspartyl/glutamoyl protein kinases.
  • tumours the abnormal oncogenic activation of protein kinases derives from multiple types of genetic and epigenetic changes. These alterations result in increased specific activity of the kinase itself, its overexpression, or the loss of negative regulation leading to uncontrolled cellular growth and sustained malignant behaviour.
  • the signalling networks operating in cancer cells can also contribute to innate or acquired resistance to treatment, since they are able to create the most common or rare oncogenic mutations different from tumour to tumour.
  • the search for small-molecule inhibitors targeting the altered protein kinase molecules in tumour cells has become a major research focus in the academia and pharmaceutical companies.
  • Such inhibitors can be products that are derived (isolated) from sources such as plants, animals or microorganisms, or can be small- molecules that are designed (synthetized).
  • WO 2004/022572 discloses classes of biologically active compounds interacting with kinases, and the preparation of these compounds.
  • pexidartinib is utilized to inhibit the colony-stimulating factor-1 receptor (CSF1 R), the KIT proto-oncogene receptor tyrosine kinase (KIT) and the FMS-like tyrosine kinase 3 (FLT3) in, for example, the treatments of patients with symptomatic tenosynovial giant cell tumors (TGCT); edicotinib to inhibit the CSF1 R and currently in phase II for acute myeloid leukemia, cognition disorders or Crohn’s disease; or nintedanib to inhibit the endothelial growth factor receptor (VEGFR), fibroplast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and CSF1 R in, for example, the treatment of idiopathic pulmonary fibrosis.
  • CSF1 R colony-stimulating factor-1 receptor
  • KIT KIT proto-oncogene receptor tyrosine kinase
  • FLT3
  • WO 201 1/090738 A2 discloses compounds that are able to inhibit B-RAF and B-RAF mutations and methods for treating diseases related to B-RAF and B-RAF mutation modulation.
  • US 2009/0325945 describes active compounds, specifically, certain imidazo[4,5-b]pyridin-2-one and oxazolo[4,5-b]pyridin-2-one compounds and analogs inhibiting RAF (e.g., B-RAF) activity in a cell, in vitro or in vivo, inhibiting receptor tyrosine kinase (RTK) activity, such as FGFR, Tie, VEGFR and/or Eph activity, for example, FGFR-1 , FGFR-2, FGFR-3, Tie2, VEGFR-2 and/or EphB2 activity, in a cell, in vitro or in vivo.
  • RAF e.g., B-RAF
  • RTK receptor tyrosine kinase
  • the present invention further relates to a pharmaceutical composition comprising a carrier, and as active ingredient an effective amount of a compound as defined in any one of the embodiments presented herein.
  • the present invention relates to a compound as defined in any one of the embodiments presented herein, for use as a medicament.
  • the present invention relates to a compound as defined in any one of the embodiments presented herein for use in the treatment of a disease selected from cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel diseases, e.g.
  • Crohn’s disease and ulcerative colitis inflammatory pulmonary diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriasis arthritis), neurological disorders (such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren Syndrome, renal allograft rejection, viral induced diseases, circulatory diseases, bone osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathies, age-related macular degeneration and uveitis) chronic and neuropathic pain, and fibro- proliferative diseases.
  • neurological disorders such as Alzheimer’s disease, Parkinson’s disease, multiple
  • the present invention relates to a compound as defined in any one of the embodiments presented herein, for use in the treatment of pain sensitization.
  • the present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal said method comprising the administration to an animal in need thereof, of a kinase-inhibitory effective amount of a compound according to any one of the embodiments presented herein.
  • the present invention further relates to a method of treating a disease selected from cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel diseases, e.g.
  • each of R 1 in compound (C) of formula (I), independently from each other and at each occurrence, is selected from hydrogen or C 1-6 alkyl. More preferably, each of R 1 , independently from each other and at each occurrence, is selected from hydrogen, or C 1-4 alkyl. Even more preferably, each of R 1 , independently from each other and at each occurrence, is C 1-4 alkyl.
  • each of R1, independently from each other and at each occurrence is methyl;
  • each of X in compound (C) of formula (I), independently from each other and at each occurrence is selected from O, S, or NR7, wherein R7 is selected from hydrogen or C1-6 alkyl. More preferably, each of X, independently from each other and at each occurrence is selected from O, S, or NR 7 , wherein R 7 is selected from hydrogen or C 1-4 alkyl. Even more preferably, each of X, independently from each other and at each occurrence is selected from O, S, or NH. Even more preferably, each of X, independently from each other and at each occurrence is O.
  • each of Y in compound (C) of formula (I), independently from each other and at each occurrence is selected from the group consisting of O, S, and NR 7 , wherein R 7 is selected from hydrogen or C 1-6 alkyl. More preferably, each of Y independently from each other and at each occurrence is selected from the group consisting of O, S, and NR 7 , wherein R 7 is selected from hydrogen or C 1-4 alkyl. Even more preferably, each of Y independently from each other and at each occurrence is selected from the group consisting of O, S, and NH. Even more preferably, each of Y independently from each other and at each occurrence is selected from O, or NH.
  • each of R5 and R5’ in compound (C) of formula (I), independently from each other and at each occurrence is selected from hydrogen or C1-6 alkyl. More preferably, each of R5, and R5’, independently from each other and at each occurrence is selected from hydrogen or C1-4 alkyl. Even more preferably, each of R5, and R5’, independently from each other and at each occurrence is selected from hydrogen or methyl.
  • each of n5 in compound (C) of formula (I), independently from each other and at each occurrence is an integer equal to 0 or 1. More preferably, each of n5, independently from each other and at each occurrence, is an integer equal to 0.
  • R6 in compound (C) of formula (I) is selected from the group consisting of halo, NO2, C1-6 alkyl, CF3, CN, OR11, SR11, N(R11)2, COR11, C(O)OR11, CON(R11)2, OC(O)R11, and wherein R11 is independently selected from the group consisting of hydrogen, C1-6 alkyl, and CF3. More preferably, R 6 is selected from the group consisting of halo, NO 2 , C 1-6 alkyl, CF 3 , CN, OR 11 , and N(R 11 ) 2 , and wherein R 11 is independently selected from the group consisting of hydrogen, and C 1-6 alkyl.
  • R 6 is selected from the group consisting of halo, NO 2 , C 1-6 alkyl, CF 3 , CN, OR 11 , and N(R 11 ) 2 , and wherein R 11 is independently selected from the group consisting of hydrogen, and C 1-4 alkyl. Even more preferably, R 6 is halo.
  • each of n 6 in compound (C) of formula (I), independently from each other and at each occurrence is an integer equal to 0 or 1. More preferably, each of n 5 , independently from each other and at each occurrence, is an integer equal to 0.
  • each of Z in compound (C) of formula (I), independently from each other and at each occurrence is selected from the group consisting of O, S, and NR 7 , wherein R 7 is selected from hydrogen or C 1-6 alkyl. More preferably, each of Z independently from each other and at each occurrence is selected from the group consisting of O, S, and NR7, wherein R7 is selected from hydrogen or C1-4 alkyl. Even more preferably, each of Z independently from each other and at each occurrence is NR7, wherein R7 is selected from hydrogen or C1-4 alkyl. Even more preferably, each of Z, independently from each other and at each occurrence, is NR7, wherein R7 is selected from hydrogen or methyl.
  • each of z in compound (C) of formula (I), independently from each other and at each occurrence, is an integer equal to 0, 1, 2 or 3. More preferably, z, independently from each other and at each occurrence, is an integer equal to 0, 1, or 2;
  • each of A in compound (C) of formula (I), independently from each other and at each occurrence, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, NO 2 , C 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocyclyl
  • each of A independently from each other and at each occurrence, is selected from the group consisting of hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, CF3, CN, OR11, N(R11)2, OC(R11)2O, OC(R11)2C(R11)2O, S(O)R12, SO2R12, SO2N(R11)2, COR11, C(O)OR11, CON(R11)2, OC(O)R11, and OCON(R11)2; and wherein each of R11
  • each of A independently from each other and at each occurrence, is selected from the group consisting of hydrogen, C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-6 alkyl, CF 3 , CN, OR 11 , N(R 11 ) 2 , OC(R 11 ) 2 O, SO 2 N(R 11 ) 2 ; and wherein each of R 11 and R 12 , independently from each other and at each occurrence, is selected from the group consisting of hydrogen or C 1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl
  • each of halo is F, Cl, Br, or I
  • each of R is hydrogen or C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl is isobutyl, preferably R is hydrogen, methyl, ethyl, 2-methylpropyl or tert-butyl.
  • the compound (C) according to formula (I), or the N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof preferably is a compound of formulae (I-a-1) [compound (C) of class (I-a) herein-after]: Formula (I-a-1) wherein R 1 , X, Y, R 5 , R 5 ’, R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) according to formula (I), or the N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof preferably is a compound chosen among those of formulae (I-b-1) to (I-b-3) [compound (C) of class (I-b) herein-after]: Formula (I-b-1) Formula (I-b-2) Formula (I-b-3) wherein R1, X, R5, R4, R4’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) according to formula (I), or the N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof preferably is a compound according to formula (I-c-1) [compound (C) of class (I-c) herein-after]: Formula (I-c-1) wherein R 1 , X, Z, R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) according to formula (I), or the N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof preferably is a compound of formulae (I-d-1) [compound (C) of class (I-d) herein-after]: Formula (I-d-1) wherein R1, X, Y, R5, n5, R4, R4’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) according to formula (I), or the N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof preferably is a compound of formulae (I-e-1) [compound (C) of class (I-e) herein-after]: Formula (I-e-1) wherein R1, X, Y, Z, R5, n5, R4, R4’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) according to formula (I), or the N-oxide, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or stereoisomer thereof preferably is a compound of formulae (I-f-1) [compound (C) of class (I-f) herein-after]: Formula (I-f-1) wherein R1, X, Y, Z, R6 and n6 have the same meaning as defined above for formula (I).
  • R1, X, Y, Z, R6 and n6 have the same meaning as defined above for formula (I).
  • X is O
  • Y is O
  • Z is NR7.
  • Preferred compounds (C) of class (I-a) are thus compounds of formula (I-a-1-1) herein below: Formula (I-a-1-1) wherein R 1 , R 5 , R 5 ’, R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I).
  • the compounds (C) of class (I-a) are selected from those of formula (I-a-1-1).
  • Preferred compounds (C) of class (I-b) are thus selected from those of formulae (I-b-1-1) to (I-b-3-1) herein below: Formula (I-b-1-1) Formula (I-b-2-1) Formula (I-b-3-1) wherein R1, R5, R4, R4’, z and A have the same meaning as defined above for formula (I).
  • the compounds (C) of class (I-b) are selected from those of formula (I-b-1-1), (I-b-2-1) or (I-b-3-1).
  • Preferred compounds (C) of class (I-c) are thus compounds of formula (I-c-1-1) herein-below: Formula (I-c-1-1) wherein R 1 , R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I), and wherein R 7 is selected from hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with halogen atom, preferably R 7 is hydrogen or methyl, more preferably R 7 is hydrogen.
  • the compounds (C) of class (I-c) are selected from those of formula (I-c-1-1).
  • Preferred compounds (C) of class (I-d) are thus compounds of formula (I-d-1-1) herein-below: Formula (I-d-1-1) wherein R1, R5, n5, R4, R4’, z and A have the same meaning as defined above for formula (I).
  • the compounds (C) of class (I-d) are selected from those of formula (I-d-1-1).
  • Preferred compounds (C) of class (I-e) are thus compounds of formula (I-e-1-1) herein-below: Formula (I-e-1-1) wherein R 1 , R 5 , n 5 , R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I), and wherein R7 is selected from hydrogen or C1-6 alkyl, wherein said alkyl is optionally substituted with halogen atom, preferably R7 is hydrogen or methyl, more preferably R7 is hydrogen.
  • the compounds (C) of class (I-e) are selected from those of formula (I-e-1-1).
  • Preferred compounds (C) of class (I-f) are thus compounds of formula (I- f-1-1) herein-below: Formula (I-f-1-1) wherein R1, R6, and n6 have the same meaning as defined above for formula (I), and wherein R 7 is selected from hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with halogen atom, preferably R 7 is hydrogen or methyl, more preferably R 7 is hydrogen.
  • the compounds (C) of class (I-f) are selected from those of formula (I-f-1-1).
  • the compound (C) of class (I-a) is selected from those of formula (I-a-1-1-1) herein-below: Formula (I-a-1-1-1) wherein R1, R5, R5’, R4, R4’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) of formula (I-b-1-1) of class (I-b) is selected from those of formula (I-b-1-1-1) to formula (I-b-1-1-3) herein-below: Formula (I-b-1-1-1) Formula (I-b-1-1-2) Formula (I-b-1-1-3) wherein R 1 , R 5 , R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) of formula (I-b-2-1) of class (I-b) is selected from those of formulae (I-b-2-1-1) to (I- b-2-1-3) herein-below: Formula (I-b-2-1-1) Formula (I-b-2-1-2) Formula (I-b-2-1-3) wherein R 1 , R 5 , R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) of formula (I-b-3-1) of class (I-b) is selected from those of formula (I-b-3-1-1) to (I- b-3-1-3) herein-below: Formula (I-b-3-1-1) Formula (I-b-3-1-2) Formula (I-b-3-1-3) wherein R1, R5, R4, R4’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) of class (I-c) is selected from those of formula (I-c-1-1-1) herein-below: Formula (I-c-1-1-1) wherein R1, R4, R4’, z and A have the same meaning as defined above for formula (I), and wherein R7 is selected from hydrogen or C1-6 alkyl, wherein said alkyl is optionally substituted with halogen atom, preferably R7 is hydrogen or methyl, more preferably R7 is hydrogen.
  • the compound (C) of class (I-d) is selected from those of formula (I-d-1-1-1) herein-below: Formula (I-d-1-1-1) wherein R 1 , R 5 , n 5 , R 4 , R 4 ’, z and A have the same meaning as defined above for formula (I).
  • the compound (C) of class (I-f) is selected from those of formula (I-f-1-1-1) herein-below: Formula (I-f-1-1-1) wherein R1, R6 and n6 have the same meaning as defined above for formula (I).
  • the compound (C) of formula (I-a-1-1-1) of class (I-a) according to the present invention is a compound chosen among those of formula (I-a-1-1-1-1) to (I-a-1-1-1-6) herein below: Formula (I-a-1-1-1-1) Formula (I-a-1-1-1-2) Formula (I-a-1-1-1-3) Formula (I-a-1-1-1-4) Formula (I-a-1-1-1-5) Formula (I-a-1-1-1-6) wherein R4, R4’ and z have the same meaning as defined above for formula (I) and wherein: - each of R 8 independently from each other and at each occurrence is selected from the group consisting of hydrogen, halo and CF3.
  • the compound (C) of formula (I-b-1-1-1) of class (I-b) according to the present invention is selected from those of formula (I-b-1-1-1-1) to (I-b-1-1-1-13) herein below: Formula (I-b-1-1-1-1) Formula (I-b-1-1-1-2) Formula (I-b-1-1-1-3) Formula (I-b-1-1-1-4) Formula (I-b-1-1-1-5) Formula (I-b-1-1-1-1-6) Formula (I-b-1-1-1-7) Formula (I-b-1-1-1-1-8) Formula (I-b-1-1-1-9) Formula (I-b-1-1-1-10) Formula (I-b-1-1-1-11) Formula (I-b-1-1-12) Formula (I-b-1-1-13) wherein R4, R4’ and z have the same meaning as defined above for formula
  • the compound (C) of Formula (I-b-1-1-2) of class (I-b) according to the present invention is selected from those of formula (I-b-1-1-2-1) herein below: Formula (I-b-1-1-2-1) wherein R 4 , R 4 ’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-b-1-1-3) of class (I-b-1) according to the present invention is selected from those of formula (I-b-1-1-3-1) herein below: Formula (I-b-1-1-3-1) wherein R4, R4’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-b-2-1-1) of class (I-b-2) according to the present invention is selected from those of formula (I-b-2-1-1-1) herein below: H O R 4 N O Halo N N N N N R 4 ' H 3 C z Formula (I-b-2-1-1-1) wherein R 4 , R 4 ’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-b-2-1-2) of class (I-b-2) according to the present invention is selected from those of formula (I-b-2-1-2-1) herein below: Formula (I-b-2-1-2-1) wherein R 4 , R 4 ’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-b-2-1-3) of class (I-b-2) according to the present invention is selected from those of formula (I-b-2-1-3-1) herein below: Formula (I-b-2-1-3-1) wherein R4, R4’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-b-3-1-1) of class (I-b-3) according to the present invention is selected from those of formula (I-b-3-1-1-1) herein below: Formula (I-b-3-1-1-1) wherein R 4 , R 4 ’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-b-3-1-2) of class (I-b) according to the present invention is selected from those of formula (I-b-3-1-2-1) herein below: Formula (I-b-3-1-2-1) wherein R4, R4’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-b-3-1-3) of class (I-b) according to the present invention is selected from those of formula (I-b-3-1-3-1) herein below: Formula (I-b-3-1-3-1) wherein R 4 , R 4 ’ and z have the same meaning as defined above for formula (I) and wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of Formula (I-c-1-1-1) of class (I-c) according to the present invention is selected from those of formula (I-c-1-1-1) or (I-c-1-1-1-2) herein below:
  • Formula (I-c-1-1-1-1) Formula (I-c-1-1-1-2) wherein R 4 , R 4 ’ and z have the same meaning as defined above for formula (I) and wherein: - each of R 7 ’ , independently from each other and at each occurrence is H or CH 3 ;
  • - each of U is independently C-R 12c or N;
  • - each of R 12c independently from each other and at each occurrence, is hydrogen, halo or OCH 3 ;
  • - n 12c is an integer equal to 0, 1 or 2.
  • the compound (C) of Formula (I-d-1-1-1) of class (I-d) according to the present invention is selected from those of formula (I-d-1-1-1) or (I-d-1-1-1-2) herein below:
  • Formula (I-d-1-1-1-1) Formula (I-d-1-1-1-2) wherein R 4 , R 4 ’ and z have the same meaning as defined above for formula (I) and wherein: - each of U is independently C-R 12d or N; - each of R 12d , independently from each other and at each occurrence, is hydrogen, halo or CF 3 ; - n 12d is an integer equal to 0, 1 or 2.
  • the compound (C) of formula (I-f-1-1-1) of class (I-f) is selected from those of formula (I-f-1-1-1-1) herein-below: Formula (I-f-1-1-1-1) wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of formula (I-a-1-1-1-3) of class (I-a) is preferably selected from those of formula (I-a-1-1- 1-3-0) herein-below: Formula (I-a-1-1-1-3-0) wherein: - each of R 80 independently from each other and at each occurrence is selected from hydrogen or halo; - n 80 is an integer equal to 0 or 1.
  • the compound (C) of formula (I-a-1-1-1-3) of class (I-a) is preferably selected from those of formula (I-a-1-1- 1-3-1) herein-below: Formula (I-a-1-1-1-3-1) wherein: - each of R 5 and R 5 ’, independently from each other and at each occurrence is hydrogen or methyl; - each of R 81 independently from each other and at each occurrence is selected from the group consisting of hydrogen, halo and CF 3 ; - n81 is an integer equal to 0, 1 or 2.
  • the compound (C) of formula (I-a-1-1-1-3) of class (I-a) is preferably selected from those of formula (I-a-1-1- 1-3-2) herein-below: Formula (I-a-1-1-1-3-2) wherein each of R82 independently from each other and at each occurrence is selected from hydrogen or halo.
  • the compound (C) of formula (I-a-1-1-1-6) of class (I-a) is preferably selected from those of formula (I-a-1-1- 1-6-2) herein-below: Formula (I-a-1-1-1-6-2)
  • the compound (C) of formula (I-b-1-1-1-4) of class (I-b) is preferably selected from those of formula (I-a-1-1- 1-4-0) herein-below: Formula (I-b-1-1-1-4-0) wherein each of R 110 , independently from each other and at each occurrence is selected from hydrogen or halo.
  • the compound (C) of formula (I-b-1-1-1-1) of class (I-b) is preferably selected from those of the following formulae herein-below: Formula (I-b-1-1-1-1-2) Formula (I-b-1-1-1-4-2) Formula (I-b-1-1-1-1-4-2a) Formula (I-b-1-1-1-5-2) Formula (I-b-1-1-1-5-2a) Formula (I-b-1-1-1-6-2) Formula (I-b-1-1-1-7-2) wherein: - R 92 is selected from hydrogen, N(CH 3 ) 2 or ethyl; - R 42 is selected from hydrogen or ethyl; - each of R 112 , independently from each other and at each occurrence is selected from the group consisting of hydrogen, halo, and CF 3 ; - each of R 102 , independently from each other and at each occurrence is selected from hydrogen or methyl; - each of n 102 , independently from each other and at each occurrence is an integer
  • the compound (C) of formula (I-b-2-1-1-1) of class (I-b) is preferably selected from those of the following formulae herein-below: Formula (I-b-2-1-1-1-1) wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of formula (I-b-2-1-2-1) of class (I-b) is preferably selected from those of the following formulae herein-below: Formula (I-b-2-1-2-1-1) wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of formula (I-b-2-1-3-1) of class (I-b) is preferably selected from those of the following formulae herein-below: Formula (I-b-2-1-3-1-1) wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of formula (I-b-3-1-1-1) of class (I-b) is preferably selected from those of the following formulae herein-below: Formula (I-b-3-1-1-1-1) wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of formula (I-b-3-1-2-1) of class (I-b) is preferably selected from those of the following formulae herein-below: Formula (I-b-3-1-2-1-1) wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of formula (I-b-3-1-3-1) of class (I-b) is preferably selected from those of the following formulae herein-below: Formula (I-b-3-1-3-1-1) wherein halo is selected from the group consisting of F, Cl, Br and I.
  • the compound (C) of formula (I-c-1-1-1-2) of class (I-c) is preferably selected from those of formulae (I-c-1- 1-2-1) herein-below: Formula (I-c-1-1-1-2-1) wherein: - each of R7’, independently from each other and at each occurrence is H or CH3; - each of U is independently selected from C-R12’ or N; - each of R12c1, independently from each other and at each occurrence, is hydrogen, halo or OCH3; - n12c1 is an integer equal to 0, 1 or 2.
  • the compound (C) of formula (I-d-1-1-1-1) of class (I-d) is preferably selected from those of formulae (I-d-1- 1-1-0) or (I-d-1-1-1-1-0) herein-below: Formula (I-d-1-1-1-1-0) wherein: - each of U is independently C-R 12d0 or N; - each of R 12d0 , independently from each other and at each occurrence, is selected from the group consisting of hydrogen, halo, or CF 3 ; - n 12d0 is an integer equal to 0, 1 or 2; In one embodiment of the present invention, the compound (C) of formula (I-d-1-1-1-1) of class (I-d) is preferably selected from those of formulae (I-d-1-1- 1-1-1) herein-below: Formula (I-d-1-1-1-1-1-1) wherein: - each of U is independently C-R12d1 or N; - each of R12d1, independently from each other and at
  • the compound (C) according to general formula (I-a-1) is a compound chosen among those of formulae (II) to (XXIX) herein below: Formula (I) Formula (II) Formula (III) Formula (IV) Formula (V) Formula (VI) Formula (VII) Formula (VIII) Formula (IX) Formula (X) Formula (XI) Formula (XII) Formula (XIII) Formula (XIV) Formula (XV) Formula (XVI) Formula (XVII) Formula (XVIII) Formula (XIX) Formula (XX) Formula (XXI) Formula (XXII) Formula (XXIII) Formula (XXIV) Formula (XXV) Formula (XXVI) Formula (XVII) Formula (XXVIII) Formula (XXIX) In a preferred embodiment of the present invention, the compound (C) according to general formula (I-b-1) is a compound chosen among those of formulae (XXX) to (CIII) herein below:
  • each of n6, independently from each other and at each occurrence, is an integer equal to 0, 1 or 2;
  • - each of Z independently from each other and at each occurrence is selected from the group consisting of O, S and NR 7 , wherein R 7 is selected from hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with at least one halogen atom;
  • - each of z, independently from each other and at each occurrence is an integer equal to 0, 1, 2, 3 or 4;
  • - each of A independently from each other and at each occurrence, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl
  • halo - alone or in combination means all halogens, that is, chloro (Cl), bromo (Br), fluoro (F), iodo (I).
  • alkyl - alone or in combination means an alkane-derived radical containing from 1 to 15 carbon atoms, unless otherwise specified, for example C F-G alkyl defines a straight or branched alkyl radical having from F to G carbon atoms, e.g.
  • C 1-4 alkyl defines a straight or branched alkyl radical having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1-propyl, 2-propyl, I-butyl, 2-butyl, 2-methyl-1-propyl.
  • An alkyl group may be a straight chain alkyl or branched alkyl.
  • straight or branched alkyl groups containing from 1- 10, more preferably 1 to 8, even more preferably 1-6 and most preferably 1-4, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
  • Alkyl also includes a straight chain or branched alkyl group that contains or is interrupted by a cycloalkyl portion.
  • the straight chain or branched alkyl group is attached at any available point to produce a stable compound. Examples of this include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl- cyclopropylpentyl.
  • alkenyl - alone or in combination means a straight or branched hydrocarbon containing 2-15, more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms, unless otherwise specified and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond.
  • alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like.
  • Alkenyl also includes a straight chain or branched alkenyl group that contains or is interrupted by a cycloalkyl portion. Carbon to carbon double bonds may be either contained within a cycloalkyl portion, with the exception of cyclopropyl, or within a straight chain or branched portion.
  • alkynyl - alone or in combination means a straight or branched hydrocarbon containing 2-15 more preferably 2-10, even more preferably 2-8, most preferably 2-4, carbon atoms containing at least one, preferably one, carbon to carbon triple bond.
  • alkynyl groups include ethynyl, propynyl, butynyl and the like.
  • aryl - alone or in combination means phenyl, naphthyl or anthracenyl optionally carbocyclic fused with a cycloalkyl or heterocyclyl of preferably 5-7, more preferably 5-6, ring members and/or optionally substituted with 1 to 5 groups or substituent.
  • An aryl may be optionally substituted whereby the substituent is attached at one point to the aryl or whereby the substituent is attached at two points to the aryl to form a bicyclic system e.g. benzodioxole, benzodioxan, benzimidazole.
  • heteroaryl - alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing 1-3, heteroatoms independently selected from the group O, S, and N, and optionally substituted with 1 to 5 groups or substituents.
  • Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
  • a carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable aromatic ring is retained.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran, and benzodiazepin-2-one-5-yl, and the like.
  • heterocyclyl - alone or in combination is intended to denote a saturated, partially unsaturated or completely unsaturated monocycle, bicycle, or tricycle having 3 to 12 carbon atoms and containing 1 or 2 heteroatoms each independently selected from O, S, P or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted as in the case of cycloalkyl.
  • Heterocycyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment is at a carbon or nitrogen atom.
  • cycloalkyl refers to a cyclic or polycyclic alkyl group containing 3 to 7 carbon atoms.
  • cycloalkyl groups are monocyclic, bicyclic or tricyclic ring systems of 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like.
  • aralkyl refers to organic compounds containing an aromatic nucleus to which an alkyl radical is bonded.
  • alkyl radicals include methyl, ethyl, propyl, butyl, octyl, etc. radicals.
  • aralkyl is thus seen to include aralkyl hydrocarbons such as the alkyl benzenes, and the various alkyl naphthalenes. From this definition of the term aralkyl compound it is seen that the term includes compounds such as benzyl, the three isomeric xylyls, the two isomeric trimethyl benzenes, ethyl benzene, p-methyl biphenyl, a-methyl naphthalene, etc.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a carrier, and as active ingredient an effective amount of a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (I-a-1), (I-b-1)- (I-b-3), (I-c-1), (I-d-1), (I-e-1), (I-f-1), (I-a- 1-1), (I-b-1-1), (I-b-2-1), (I-b-3-1), (I-c-1-1), (I-d-1-1), (I-e-1-1), (I-f-1), (I-a-1-1- 1), (I-b-1-1-1)- (I-b-1-1-3), (I-b-2-1-1)- (I-b-2-1-3), (I-b-3-1-1)- (I-b-3-1-3), (I-c-1- 1-1), (I-d-1-1), (I-f-1-1), (I-a-1-1-1)- (
  • the present invention relates to a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (I-a-1), (I-b-1)- (I-b-3), (I-c-1), (I-d-1), (I-e-1), (I-f-1), (I-a-1-1), (I-b-1-1), (I-b-2-1), (I-b-3-1), (I-c-1-1), (I-d-1-1), (I-e-1-1), (I-f-1), (I-a-1-1-1), (I-b-1-1-1)- (I-b-1-1-3), (I-b-2-1-1)- (I-b-2-1-3), (I-b-3-1-1)- (I-b-3-1-3), (I-c-1-1), (I-d-1-1), (I-f-1-1), (I-a-1-1-1-1)- (I-a-1-1-1-6), (I-b-1-1-1-1)- (I-b-1-1-1-1-1-1
  • the present invention relates to a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1), (l-b-1)- (l-b-3), (l-c-1), (l-d-1), (l-e-1), (l-f-1), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1), (l-d-1 -1), (l-e-1-1), (l-f-1 -1), (l-a-1-1 -1), (l-b-1-1-1)- (l-b-1-1-3), (l-b-2-1 -1 )- (l-b-2-1 -3), (l-b-3-1 -1 )- (l-b-3-1 -3), (l-c-1 -1 -1 ), (l-d-1 -1 -1 ), (l-f-1 -1 ), (l-a-1-1 -1 ), (l-b-1-1)- (
  • Crohn’s disease and ulcerative colitis inflammatory pulmonary diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriasis arthritis), neurological disorders (such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren Syndrome, renal allograft rejection, viral induced diseases, circulatory diseases, bone osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathies, age-related macular degeneration and uveitis) chronic and neuropathic pain, and fibro- proliferative diseases.
  • neurological disorders such as Alzheimer’s disease, Parkinson’s disease, multiple
  • the present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal said method comprising the administration to an animal in need thereof, of a kinase-inhibitory effective amount of a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- ( l-b-3) , (l-c-1 ), (I- d-1), (l-e-1), (l-f-1 ), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1), (l-d-1-1 ), (I- e-1), (l-f-1 -1 ), (l-a-1 -1 -1 ), (l-b-1 -1 )- (l-b-1 -1 -3), (l-b-2-1 -1 )- (l-b-2-1 -1 )- (l-
  • the present invention further relates to a method of inhibiting protein kinase activity in a warm-blooded animal said method comprising the administration to an animal in need thereof, of a kinase-inhibitory effective amount of a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- (l-b-3), (l-c-1 ), (I- d-1), (l-e-1), (l-f-1), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1), (l-d-1-1), (I- e-1-1), (l-f-1 -1 ), (l-a-1 -1 -1 ), (l-b-1-1-1)- (l-b-1 -1 -3), (l-b-2-1 -1 )- (l-b-2-1 -3), (l-b-3- 1-1)- (
  • the present invention further relates to a method of treating a disease selected from cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel diseases, e.g. Crohn’s disease and ulcerative colitis, inflammatory pulmonary diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriasis arthritis), neurological disorders (such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren Syndrome, renal allograft rejection, viral induced diseases, circulatory diseases, bone osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathies, age-
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • pyridyl includes 2-pyridyl, 3- pyridyl and 4-pyridyl
  • pentyl includes 1 -pentyl, 2-pentyl and 3-pentyl.
  • One embodiment comprises the compounds (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1), (l-b-1)- (l-b-3), (l-c-1), (l-d-1), (l-e-1 ), (l-f-1), (l-a- 1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1), (l-d-1-1), (l-e-1), (l-f-1), (l-a-1 -1 -
  • Another embodiment comprises the compounds (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- (I- b-3), (l-c-1), (l-d-1), (l-e-1), (l-f-1), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1- 1), (l-d-1-1 ), (l-e-1 -1 ), (l-f-1 -1 ), (l-a-1-1 -1), (l-b-1 -1 -1)- (l-b-1 -1 -3), (l-b-2-1 -1 )- (I- b-2-1-3), (l-b-3-1-1)- (l-b-3-1-3), (l-c-1-1), (l-d-1-1), (l-f-1-1), (l-a-1 -1 -1 -1 )- (l-a-1 -1-1-6-
  • stereochemically isomeric forms as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1), (l-b-1 )- (l-b-3), (l-c-1), (l-d-1), (l-e-1), (l-f-1), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1 ), (l-c-1-1 ), (l-d-1 -1), (l-e-1), (l-f-1 -1), (l-a-1-1 -1), (l-b-1-1-1)- (l-b-1-1-3), (l-b-2-1 -1 )- (l-b-2-1 -3), (l-b-3-1 -1 )- (l-b-3-1 -3), (l-b-b-3-1
  • Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or mixed with each other are intended to be embraced within the scope of the present invention.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%.
  • enantiomerically pure and “diastereomerically pure” should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application procedures known in the art.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • a person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
  • the present invention is also intended to include all isotopes of atoms occurring on the present to a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- (l-b-3), (l-c-1), (l-d-1), (l-e-1), (l-f-1 ), (l-a-1 -1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c- 1-1), (l-d-1-1), (l-e-1-1), (l-f-1-1), (l-a-1-1-1 ), (l-b-1 -1 -1 )- (l-b-1-1-3), (l-b-2-1 -1 )- (l-b-2-1-3), (l-b-3-1-1 )- (l-b-3-1-3), (l-c-1-1 -1 ), (l-d-1 -1 -1), (l-f-1 -1), (l
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non- toxic acid and base addition salt forms that the compounds (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1), (l-b-1)- (l-b-3), (l-c-1), (l-d-1), (l-e-1), (l-f-1), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1 ), (l-d-1 -1), (l-e-1-1), (l-f-1 -1), (l-a-1-1 -1), (l-b-1-1-1)- (l-b-1-1-3), (l-b-2-1 -1 )- (l-b-2-1 -3), (l-b-3-1 -1 )- (l-b-3-1 -3), (l-c-1 -1 ), (l-d-1 -1 ), (l-d
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid in an anion form.
  • Appropriate anions comprise, for example, trifluoroacetate, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyiate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, n
  • Appropriate basic salts comprise those formed with organic cations such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, and the like; and those formed with metallic cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like. Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.
  • addition salt as used hereinabove also comprises the solvates which the compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- (l-b-3), (l-c-1 ), (I- d-1), (l-e-1), (l-f-1), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1), (l-d-1-1), (I- e-1), (l-f-1 -1 ), (l-a-1 -1 -1 ), (l-b-1-1-1)- (l-b-1 -1 -3), (l-b-2-1 -1 )- (l-b-2-1 -3), (l-b-3- 1-1)- (l-b-3-1 -3), (l-c-1 -1 -1 ), (l-d-1 -1 -1 ), (l-f-1 -1 ), (l-a-1
  • the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- (l-b-3), (l-c-1), (l-d-1), (l-e-1 ), (l-f-1 ), (l-a- 1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1), (l-d-1-1), (l-e-1), (l-f-1), (l-a-1 -1 -
  • a therapeutically effective amount in this context is an amount sufficient to prophylactically act against, to stabilize or reduce illnesses mediated by protein kinases in ill subjects or subjects being at risk of being ill, in particular a protein kinase selected from the group consisting of CSF1R, FLT3, Kit, PDGFRB (PDGFR beta), PDGFRA (PDGFR alfa), ABL1, ACVR1B (ALK4), AKT1 (PKB alpha), AMPK A1/B1/G1, AURKA (Aurora A), BTK, CDK1/cyclin B, CHEK1 (CHK1), CSNK1G2 (CK1 gamma 2), CSNK2A1 (CK2 alpha 1), DYRK3, EGFR (ErbB1), EPHA2, ERBB2 (HER2), FGFR1, FRAP1 (mTOR), GSK3B (GSK3 beta), IGF1 R, IKBKB (IKK beta), INSR, IRAK4, JAK3, KDR
  • illnesses mediated by protein kinases include in particular of illnesses mediated by protein kinases include in particular cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel diseases, e.g. Crohn’s disease and ulcerative colitis, inflammatory pulmonary diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriasis arthritis), neurological disorders (such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren Syndrome, renal allograft rejection, viral induced diseases, circulatory diseases, bone osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such
  • this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- ( l-b-3) , (l-c-1 ), (I- d-1), (l-e-1), (l-f-1), (l-a-1-1), (l-b-1-1), (l-b-2-1), (l-b-3-1), (l-c-1-1), (l-d-1-1), (I- e-1-1), (l-f-1 -1 ), (l-a-1 -1 -1 ), (l-b-1 -1 -1 )- (l-b-1 -1 -3), (l-b-2-1 -1 )- (l-b-2-1 -3), (l-b-3- 1-1)- (l-b-3-1),
  • compositions usually employed for systemically administering drugs there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound (C) of formula (I), as specified herein, or a compound of any of the subgroups of compounds of formula (l-a-1 ), (l-b-1 )- (l-b-3), (l-c-1 ), (l-d-1 ), (l-e-1 ), (l-f-1 ), (l-a-1 -1 ), (l-b-1 -1 ), (l-b-2-1 ), (l-b-3-1 ), (l-c-1 -1 ), (l-d-1 -1 ), (I- e-1 -1 ), (l-f-1 -1 ), (l-a-1 -1 -1 ), (l-b-1 -1 )- (l-b-1 -1 -3), (l-b-2-1 -1 )- (l-b-2-1 -3), (l-b-3- 1 -1 )- (l-b-3-1 -3), (l-b
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • Illnesses and diseases treatable using the compounds and methods of the present invention include protein kinase mediated diseases like like cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel diseases, e.g. Crohn’s disease and ulcerative colitis, inflammatory pulmonary diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriasis arthritis), neurological disorders (such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Charcot-Marie- Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren Syndrome, renal allograft rejection, viral induced diseases, circulatory diseases, bone osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma,
  • Many of the compounds of this invention may show a favourable pharmacokinetic profile and have attractive properties in terms of bioavailability, including an acceptable half-life, AUC (area under the curve) and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
  • the combinations of the present invention may be used as medicaments.
  • Said use as a medicine or method of treatment comprises the systemic administration to ill subjects of an amount effective to combat the conditions associated with the illnesses. Consequently, the combinations of the present invention can be used in the manufacture of a medicament useful for treating, preventing or combating illness or disease associated with protein kinases including cancer, metabolic disorders (such as diabetes), inflammatory and autoimmune disorders (such as inflammatory bowel diseases, e.g.
  • Crohn’s disease and ulcerative colitis inflammatory pulmonary diseases, rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus and psoriasis and psoriasis arthritis), neurological disorders (such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Charcot-Marie-Tooth neuropathy, amyotrophic lateral sclerosis and epilepsy), atherosclerosis and cardiovascular diseases, Sjogren Syndrome, renal allograft rejection, viral induced diseases, circulatory diseases, bone osteolysis and osteoporosis, osteoarthritis, sarcopenia, Langerhans cell histiocytosis, spinal cord injury, endometriosis, asthma and allergic asthma, eye diseases (such as retinopathies, age-related macular degeneration and uveitis) chronic and neuropathic pain, and fibro- proliferative diseases.
  • neurological disorders such as Alzheimer’s disease, Parkinson’s disease, multiple
  • terapéuticaally effective amount means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought, in the light of the present invention, by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • Example 1 General procedure for the preparation of analogues 4-66 Cs 2 CO 3 , DMF 100°C Method A Pd(PPh 3 ) 4 , Cs 2 CO 3 1M, dioxane, 100°C, 1h Method B 1 2 Vilsmeier reagent, CH 2 Cl 2 , rt, 1h30 Method C RNH 2 , AcOH, MW, 100°C, 20 min Method D 4-66 3 Method A: To a solution of methyl 2-amino-5-hydroxybenzoate (527 mg, 3.15 mmol) in DMF (12 mL) under nitrogen was added solid cesium carbonate (2.569 g, 7.88 mmol) followed by 2-chloro-4-nitropyridine derivative (500 mg, 3.15 mmol).
  • Method B To a stirred solution of intermediate 1 (400 mg, 1.44 mmol) in dioxane (7 mL) were added under nitrogen 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-1H-pyrazole (448 mg, 2.15 mmol), Cs 2 CO 3 1M (4.306 mL, 4.31 mmol) and Pd(PPh 3 ) 4 (166 mg, 0.14 mmol). The reaction mixture was stirred at 100°C for 1h.
  • ESI-MS 440.10 (M+H) + .
  • 5-(aminomethyl)-N-methyl-pyridin-2-amine was prepared by the following procedure: To a mixture 6-(methylamino)nicotinonitrile (251 mg, 1.8 mmol) in ammonia (solution 7N in MeOH, 15 mL) was added Raney nickel (slurry in water, 1g). After stirring overnight under a hydrogen atmosphere, the reaction mixture was filtered through a pad of Celite, rinsed with MeOH, and concentrated under reduced pressure to provide the expected compound which was used without further purification.
  • ESI-MS 138.20 (M+H) + .
  • ESI-MS 442.10 (M+H) + .
  • (1-isopropylimidazol-4-yl)methanamine was prepared by hydrogenation of 1- isopropyl-1H-imidazole-4-carbonitrile (WO 2009/070485) according to example 22.
  • 2-(cis-2,6-dimethylpiperidin-1-yl)ethanamine was prepared by the following procedure: To a solution of cis-2,6-dimethylpiperidine (100 mg, 0.88 mmol) and potassium carbonate (245 mg, 1.77 mmol) in acetonitrile (4.5 mL) was added 2- bromoacetonitrile (74 ⁇ L, 1.06 mmol). The resulting mixture was stirred at 60°C for 2h. The reaction mixture was diluted with DCM and washed with water. Organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • 2-(4,4-difluoro-1-piperidyl)ethanamine was prepared by the following procedure: To a solution of 4,4-difluoropiperidine (200 mg, 1.65 mmol) and potassium carbonate (456 mg, 3.30 mmol) in acetonitrile (5 mL) was added tert-butyl (2- bromoethyl)carbamate (444 mg, 1.98 mmol). The resulting mixture was stirred at 60°C for 4h. The reaction mixture was diluted with DCM and washed with water. Organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.
  • the reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NH 4 Cl.
  • the organic layer was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the crude product was purified by flash column chromatography (DCM/MeOH from 100/0 to 95/5) and reverse phase chromatography (H 2 O/MeOH: 0 to 100%) to give the expected compound.
  • Example 3 General procedure for the preparation of analogues 79-87 3-Chlorobenzylamine, Vilsmeier reagent, AcOH, CH 2 Cl 2 , rt, 1h30 MW, 100°C, 20 min Method C Method D 1 77 78 1) Benzophenone imine, Pd 2 dba 3 , BINAP, t-BuONa, toluene, 90°C Boronic ester, Amine, 2) HCl (4M), dioxane, rt Pd(PPh 3 ) 4 , Cs 2 CO 3 1M, Pd 2 dba 3 , Xantphos, dioxane, 100°C Cs 2 CO 3 , dioxane, 100°C Method H Method B Method G R 2 COOH, EDC.HCl, DMAP, CH 2 Cl 2 , rt Method I 85-87 84 79-83 Preparation of methyl 5-[(2-chloro-4-pyridyl)oxy]-2
  • reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (DCM/MeOH from 100/0 to 97/3) and reverse phase chromatography (H2O/MeOH from 100/0 to 0/100) to give 69 mg of 6-[(2-amino- 4-pyridyl)oxy]-3-[(3-chlorophenyl)methyl]quinazolin-4-one 84 as a white powder in 34% yield.
  • ESI-MS 378.90 (M+H) + .
  • Example 4 General procedure for the preparation of analogues 104-119 NH2 NH2 NH2 O OH NH 4 OH, HOBt, NH2 O NaOH 2N, MeOH, O EDC.HCl, NMM, O 50°C, 2h DMF, rt, 2h O O O Method J
  • Method K N N N N N N N N 2 N 88 N 89 RCOCl, TEA, RCOOH, DMAP, THF, rt, 2h HOBt, EDC.HCl, Method L DMF, rt, Method M O R N R N R NH N NH O Cs 2 CO 3 , MeI, O t-BuOK, t-BuOH, 80°C, 1 NH2 DMF h O , rt O O Method F Method N O N N N N N N N N N 118-119 104-117 N 90-103
  • Method J To a solution of intermediate 2 (582 mg, 1.79 mmol) in MeOH (6 m
  • Method K To a solution of 88 (138 mg, 0.45 mmol) in DMF (4 mL) cooled to 0°C with an ice bath were added HOBt (136 mg, 0.89 mmol), EDC.HCl (171 mg, 0.89 mmol) and N-methylmorpholine (98 ⁇ L, 0.89 mmol). Ammonium hydroxide (30%, 0.77 mmol) was then added dropwise. The ice bath was removed, and the reaction mixture was allowed to stir at room temperature for 2h. The reaction mixture was concentrated under reduced pressure.
  • Example 5 General procedure for the preparation of analogues 145-167 Preparation of methyl 5-[(2-chloro-4-pyridyl)oxy]-2-hydroxy-benzoate (120): Intermediate 120 was synthesized from 2-chloro-4-nitropyridine (3.15 mmol) and methyl 2,5-dihydroxybenzoate (3.15 mmol) as a white powder in 60% yield according to the general method A.
  • Example 7 General procedure for the preparation of analogues 178-194 Method T: To a solution of derivative 169 (250 mg, 0.81 mmol) in DMF (13 mL) under nitrogen was added potassium carbonate (1.113 g, 8.05 mmol) and 1,2- dibromoethane (0.555 mL, 6.45 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed twice with a saturated solution of NH4Cl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Example 8 General procedure for the preparation of analogues 202-205 Cs 2 CO 3 , DMF 100°C Method A Pd(PPh 3 ) 4 , Cs 2 CO 3 1M, dioxane, 100°C, 1h Method B 195 196 NaOH 2N, MeOH, 50°C, 2h Method J RNH 2 , DBU, DMF EDC.HCl, 150°C HOBt, DMF, rt, Method W Method O 202-205 198-201 197 Preparation of methyl 5-[(2-chloro-4-pyridyl)oxy]-2-fluoro-benzoate (195): Intermediate 195 was synthesized from 2-chloro-4-nitropyridine (1.24 mmol) and methyl 2-fluoro-5-hydroxybenzoate (1.24 mmol) as a white powder in 88% yield according to the general method A.
  • Example 9 Cell-based assays: Biological assay measuring cell proliferation in cell lines Compounds were evaluated in different cancer cell lines (Molm-13, M-NFS-60, HL-60 and P815) and in PDGFR ⁇ -BaF3 stable cell line. For each, cell proliferation were measured. The protocols of these assays are described below.
  • MOLM-13 Exponential growing MOLM-13 cells (DSMZ, ACC-554) were seeded at 2.10 ⁇ 4 per 200 ⁇ L of complete medium.20 ⁇ L of test compound dilution were added to each well and the plates were incubated for 72 h at 37 °C, 5% CO2.
  • WST-1 solution Cell Proliferation Reagent WST-1, Roche Applied Science.
  • optical densities were measured at 450 nm and 620 nm for the background on microplate reader (Envision 2105, Perkinelmer).
  • M-NFS-60 Exponential growing M-NFS-60 cells (ATCC, CRL-1838) were seeded at 10 ⁇ 4 per 200 ⁇ L of complete medium with beta-mercaptoethanol and M-CSF (62 ng/mL) or IL34 (500 ng/mL). Twenty ⁇ L of test compound dilution were added to each well and the plates were incubated for 72 h at 37 °C, 5% CO 2 . Untreated cells and positive control (0.5% triton X-100, for the last 15 min) served as reference for maximum and minimum viability.
  • HL-60 Exponential growing HL-60 cells (DSMZ, ACC-3) were seeded at 2.10 ⁇ 4 per 200 ⁇ L of complete RPMI medium.20 ⁇ L of test compound dilution were added to each well and the plates were incubated for 72 h at 37 °C, 5% CO 2 .
  • WST-1 solution Cell Proliferation Reagent WST-1, Roche Applied Science.
  • optical densities were measured at 450 nm and 620 nm for the background on microplate reader (Envision 2105, Perkinelmer). IC50 were measured and some biological results of these assays are presented in the following table.
  • P-815 Exponential growing P-815 cells (DSMZ, ACC-1) were seeded at 2.10 ⁇ 4 per 200 ⁇ L of complete RPMI medium. Twenty ⁇ L of test compound dilution were added to each well and the plates were incubated for 72 h at 37 °C, 5% CO2. Untreated cells and positive control (0,5% triton X-100, for the last 15 min) served as reference for maximum and minimum viability. At the end of incubation 100 ⁇ L of supernatant were removed and replaced by 10 ⁇ L of WST- 1 solution (Cell Proliferation Reagent WST-1, Roche Applied Science).
  • BaF3-PDGFR ⁇ Exponential growing BaF3 cells stably transfected with a plasmid encoding the fusion gene GFP-ETV6-PDGFRA (ABMGood, T3082) were seeded at 5.10 ⁇ 3 per 200 ⁇ L of complete RPMI medium. Twenty ⁇ L of test compound dilution were added to each well and the plates were incubated for 72 h at 37 °C, 5% CO2.
  • WST-1 solution Cell Proliferation Reagent WST-1, Roche Applied Science.
  • optical densities were measured at 450 nm and 620 nm for the background on microplate reader (Envision 2105, Perkinelmer). IC50 were measured and some biological results of these assays are presented in the following table.
  • HEK-CSF1R-STAT5-Luc Exponential growing HEK293T cells (ATCC® CRL- 3216TM), ectopically expressing human CSF1R receptor (Origene) and five copies of a STAT5 response element (STAT5 RE, promega) that drives transcription of the luciferase reporter were seeded at 5.10 ⁇ 3 per 20 ⁇ L of complete DMEM medium.
  • test compound dilution 2 ⁇ L were added to each well and stimulated with 600 ng/ml of M-CSF.
  • the plates were incubated for 24 h at 37 °C, 5% CO2. Unstimulated and stimulated cells served as reference for maximum and minimum induction.
  • 25 ⁇ L of Steady-Glo® Luciferase Assay System (Promega) were added after 5 min of lysis, luminescence was measured on microplate reader (Envision 2105, Perkinelmer).
  • HEK-CSF1R-WST-1 Exponential growing HEK293T cells (ATCC® CRL- 3216TM), were seeded at 5.10 ⁇ 3 per 200 ⁇ L of complete DMEM medium. The next day, twenty ⁇ L of test compound dilution were added to each well and the plates were incubated for 72 h at 37 °C, 5% CO2. Untreated cells and positive control (0,5% triton X-100, for the last 15 min) served as reference for maximum and minimum viability. At the end of incubation 100 ⁇ L of supernatant were removed and replaced by 10 ⁇ L of WST-1 solution (Cell Proliferation Reagent WST-1, Roche Applied Science).

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Abstract

La présente invention concerne un composé approprié pour être utilisé en tant qu'inhibiteur de kinase.
PCT/EP2024/071181 2023-07-26 2024-07-25 Quinazolinone, benzoxazinone et dérivés de benzoxazépinone utilisés en tant qu'inhibiteurs de protéine kinase Pending WO2025021943A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004022572A1 (fr) 2002-09-06 2004-03-18 Alchemia Limited Composes qui interagissent avec des kinases
WO2009070485A1 (fr) 2007-11-29 2009-06-04 Boehringer Ingelheim International Gmbh Dérivés d'amides de l'acide 6,7-dihydro-5h-imidazo[1,2-α]imidazole-3-carboxylique
WO2009089042A1 (fr) * 2008-01-09 2009-07-16 Signal Pharmaceuticals, Llc Composés de pyrazole pyramine amine en tant qu'inhibiteurs de kinase, compositions les contenant et procédé de traitement les employant
US20090325945A1 (en) 2006-04-26 2009-12-31 Dan Niculescu-Duvaz Imidazo[4, 5-b]pyridin-2-one and oxazolo[4, 5-b]pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds
WO2011032277A1 (fr) * 2009-09-18 2011-03-24 Boehringer Ingelheim International Gmbh Dérivés de quinazolinone comme inhibiteurs de polymérase virale
WO2011090738A2 (fr) 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinase raf de type ii
WO2015042077A1 (fr) * 2013-09-22 2015-03-26 Calitor Sciences, Llc Composés substitués d'aminopyrimidine et procédés d'utilisation
US20150182526A1 (en) 2007-12-19 2015-07-02 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-b]pyrazin-8-substituted compounds and their use
WO2021023888A1 (fr) * 2019-08-08 2021-02-11 B.C.I. Pharma Dérivés d'isoquinoline utilisés comme inhibiteurs de protéine kinase

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004022572A1 (fr) 2002-09-06 2004-03-18 Alchemia Limited Composes qui interagissent avec des kinases
US20090325945A1 (en) 2006-04-26 2009-12-31 Dan Niculescu-Duvaz Imidazo[4, 5-b]pyridin-2-one and oxazolo[4, 5-b]pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds
WO2009070485A1 (fr) 2007-11-29 2009-06-04 Boehringer Ingelheim International Gmbh Dérivés d'amides de l'acide 6,7-dihydro-5h-imidazo[1,2-α]imidazole-3-carboxylique
US20150182526A1 (en) 2007-12-19 2015-07-02 Institute Of Cancer Research: Royal Cancer Hospital (The) Pyrido[2,3-b]pyrazin-8-substituted compounds and their use
WO2009089042A1 (fr) * 2008-01-09 2009-07-16 Signal Pharmaceuticals, Llc Composés de pyrazole pyramine amine en tant qu'inhibiteurs de kinase, compositions les contenant et procédé de traitement les employant
WO2011032277A1 (fr) * 2009-09-18 2011-03-24 Boehringer Ingelheim International Gmbh Dérivés de quinazolinone comme inhibiteurs de polymérase virale
WO2011090738A2 (fr) 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinase raf de type ii
WO2015042077A1 (fr) * 2013-09-22 2015-03-26 Calitor Sciences, Llc Composés substitués d'aminopyrimidine et procédés d'utilisation
WO2021023888A1 (fr) * 2019-08-08 2021-02-11 B.C.I. Pharma Dérivés d'isoquinoline utilisés comme inhibiteurs de protéine kinase

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