WO2013017479A1 - Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak - Google Patents

Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak Download PDF

Info

Publication number
WO2013017479A1
WO2013017479A1 PCT/EP2012/064510 EP2012064510W WO2013017479A1 WO 2013017479 A1 WO2013017479 A1 WO 2013017479A1 EP 2012064510 W EP2012064510 W EP 2012064510W WO 2013017479 A1 WO2013017479 A1 WO 2013017479A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyridin
pyrazolo
pyrazol
amino
methyl
Prior art date
Application number
PCT/EP2012/064510
Other languages
English (en)
Inventor
Sally Oxenford
Andrew Hobson
Kathryn Oliver
Andrew Ratcliffe
Nigel Ramsden
Original Assignee
Cellzome Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cellzome Limited filed Critical Cellzome Limited
Publication of WO2013017479A1 publication Critical patent/WO2013017479A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a novel class of kinase inhibitors, including pharmaceutically acceptable salts, prodrugs and metabolites thereof, which are useful for modulating protein kinase activity for modulating cellular activities such as signal transduction, proliferation, and cytokine secretion. More specifically the invention provides compounds which inhibit, regulate and/or modulate kinase activity, in particular JAK3 activity, and signal transduction pathways relating to cellular activities as mentioned above. Furthermore, the present invention relates to pharmaceutical compositions comprising said compounds, for example for the treatment or prevention of an immunological, inflammatory, autoimmune, or allergic disorder or disease or a transplant rejection or a Graft-versus host disease and processes for preparing said compounds.
  • Protein kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play key roles in all aspects of eukaryotic cell physiology. Especially, protein kinases and lipid kinases participate in the signaling events which control the activation, growth, differentiation and survival of cells in response to extracellular mediators or stimuli such as growth factors, cytokines or chemokines. In general, protein kinases are classified in two groups, those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor (EGFR) and cytosolic non-receptor kinases such as Janus kinases (JAK).
  • EGFR epidermal growth factor receptor
  • JAK Janus kinases
  • Inappropriately high protein kinase activity is involved in many diseases including cancer, metabolic diseases, autoimmune or inflammatory disorders. This effect can be caused either directly or indirectly by the failure of control mechanisms due to mutation, overexpression or inappropriate activation of the enzyme. In all of these instances, selective inhibition of the kinase is expected to have a beneficial effect.
  • JAK Janus kinase
  • JAK3 Tyrosine kinase 2
  • TYK2 Tyrosine kinase 2
  • Each protein has a kinase domain and a catalytically inactive pseudo-kinase domain.
  • the JAK proteins bind to cytokine receptors through their amino -terminal FERM (Band-4.1, ezrin, radixin, moesin) domains.
  • JA s are activated and phosphorylate the receptors, thereby creating docking sites for signalling molecules, especially for members of the signal transducer and activator of transcription (Stat) family (Yamaoka et al, 2004. The Janus kinases (Jaks). Genome Biology 5(12): 253).
  • JAK1 , JAK2 and TYK2 are ubiquitously expressed.
  • JAK3 is predominantly in hematopoietic cells and it is highly regulated with cell development and activation (Musso et al, 1995. 181(4): 1425-31).
  • JAK1 knockout mice display a perinatal lethal phenotype, probably related to the neurological effects that prevent them from sucking (Rodig et al, 1998. Cell 93(3):373-83).
  • Deletion of the JAK2 gene results in embryonic lethality at embryonic day 12.5 as a result of a defect in erythropoiesis (Neubauer et al, 1998. Cell 93(3):397-409).
  • JAK3 deficiency was first identified in humans with autosomal recessive severe combined immunodeficiency (SCID) (Macchi et al, 1995. Nature 377(6544):65-68). JAK3 knockout mice too exhibit SCID but do not display non-immune defects, suggesting that an inhibitor of JAK3 as an immunosuppressant would have restricted effects in vivo and therefore presents a promising drug for immunosuppression (Papageorgiou and Wikman 2004, Trends in Pharmacological Sciences 25(11):558-62).
  • SCID autosomal recessive severe combined immunodeficiency
  • JAK3 Activating mutations for JAK3 have been observed in acute megakaryoblastic leukemia (AMKL) patients (Walters et al, 2006. Cancer Cell 10(l):65-75). These mutated forms of JAK3 can transform Ba/F3 cells to factor-independent growth and induce features of megakaryoblastic leukemia in a mouse model.
  • JAK3 inhibitors have been reported in the literature which may be useful in the medical field (O'Shea et al, 2004. Nat. Rev. Drug Discov. 3(7):555-64).
  • a potent JAK3 inhibitor (CP-690,550) was reported to show efficacy in an animal model of organ transplantation (Changelian et al, 2003, Science 302(5646):875-888) and clinical trials (reviewed in: Pesu et al, 2008. Immunol. Rev. 223, 132-142).
  • the CP-690,550 inhibitor is not selective for the JAK3 kinase and inhibits JAK2 kinase with almost equipotency (Jiang et al, 2008, J. Med. Chem.
  • JAK3 inhibitor that inhibits JAK3 with greater potency than JAK2 may have advantageous therapeutic properties, because inhibition of JAK2 can cause anemia (Ghoreschi et al, 2009. Nature Immunol. 4, 356-360).
  • Pyrimidine derivatives exhibiting JAK3 and JAK2 kinase inhibiting activities are described in WO-A 2008/009458.
  • Pyrimidine compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3 are described in WO-A 2008/118822 and WO-A 2008/118823.
  • Fluoro substituted pyrimidine compounds as JAK3 inhibitors are described in WO-A 2010/118986.
  • JAK inhibitors are known in the art there is a need for providing additional JAK inhibitors having at least partially more effective pharmaceutically relevant properties, like activity, selectivity especially over JAK2 kinase, and ADME properties.
  • an object of the present invention is to provide a new class of compounds as JAK inhibitors which preferably show selectivity over JAK2 and may be effective in the treatment or prophylaxis of disorders associated with JAK. Accordingly, the present invention provides compounds of formula (I)
  • R is H or F
  • Ring A is a 5 membered aromatic heterocycle in which Z 1 , Z 2 , Z 3 and Z 4 are independently selected from the group consisting of C(R 1 ), N, N(R 1 ), O and S, provided that at least one of
  • Each R 1 is independently H, halogen; CN; C(0)OR 2 ; OR 2 ; C(0)R 2 ; C(0)N(R 2 R 2a ); S(0) 2 N(R 2 R 2a ); S(0)N(R 2 R 2a ); S(0) 2 R 2 ; S(0)R 2 ; N(R 2 )S(0) 2 N(R 2a R 2b ); N(R 2 )S(0)N(R 2a R 2b ); SR 2 ; N(R 2 R 2a ); N0 2 ; OC(0)R 2 ; N(R 2 )C(0)R 2a ; N(R 2 )S(0) 2 R 2a ; N(R 2 )S(0)R 2a ; N(R 2 )C(0)N(R 2a R 2b ); N(R 2 )C(0)OR 2a ; OC(0)N(R 2 R 2a ); T 1 ; or Ci_ 6 alkyl, wherein Ci_ 6 alkyl is optionally substituted with one or more R 3
  • R 2 , R 2a , R 2b are independently selected from the group consisting of H; T 1 ; and Ci_ 6 alkyl, wherein Ci_ 6 alkyl is optionally substituted with one or more R 3 , which are the same or different;
  • R 3 is halogen; CN; C(0)OR 4 ; OR 4 ; C(0)R 4 ; C(0)N(R 4 R 4a ); S(0) 2 N(R 4 R 4a ); S(0)N(R 4 R 4a ); S(0) 2 R 4 ; S(0)R 4 ; N(R 4 )S(0) 2 N(R 4a R 4b ); N(R 4 )S(0)N(R 4a R 4b ); SR 4 ; N(R 4 R 4a ); N0 2 ; OC(0)R 4 ; N(R 4 )C(0)R 4a ; N(R 4 )S(0) 2 R 4a ; N(R 4 )S(0)R 4a ; N(R 4 )C(0)N(R 4a R 4b ); N(R 4 )C(0)OR 4a ; OC(0)N(R 4 R 4a ); or T 1 ; R 4 , R 4a , R 4b are independently selected from the group consisting of H; T 1 ; and Ci_
  • Y is (C(R 5 R 5a )) n ; n is 0, 1 , 2, 3 or 4;
  • R 5 , R 5a are joined to form an unsubstituted C3-7 cycloalkyl
  • X 1 is C(R 6 ) or N
  • X 2 is C(R 6a ) or N
  • X 3 is C(R 6b ) or N
  • X 4 is C(R 6c ) or N
  • X 5 is C(R 6d ) or N, provided that at most two of X 1 , X 2 , X 3 , X 4 , X 5 are N;
  • R 6 , R 6a , R 6b , R 6c , R 6d are independently selected from the group consisting of H; halogen; CN; C(0)OR 7 ; OR 7 ; C(0)R 7 ; C(0)N(R 7 R 7a ); S(0) 2 N(R 7 R 7a ); S(0)N(R 7 R 7a ); S(0) 2 R 7 ; S(0)R 7 ; N(R 7 )S(0) 2 N(R 7a R 7b ); N(R 7 )S(0)N(R 7a R 7b ); SR 7 ; N(R 7 R 7a ); N0 2 ; OC(0)R 7 ; N(R 7 )C(0)R 7a ; N(R 7 )S(0) 2 R 7a ; N(R 7 )S(0)R 7a ; N(R 7 )C(0)N(R 7a R 7b ); N(R 7 )C(0)OR 7a ; OC(0)N(R 7 R 7a ); T 2 ; and
  • R 7 , R 7a , R 7b are independently selected from the group consisting of H; T 2 ; and Ci_ 6 alkyl, wherein Ci_ 6 alkyl is optionally substituted with one or more R 8 , which are the same or different; R 8 is halogen; CN; C(0)OR 9 ; OR 9 ; C(0)R 9 ; C(0)N(R 9 R 9a ); S(0) 2 N(R 9 R 9a ); S(0)N(R 9 R 9a ); S(0) 2 R 9 ; S(0)R 9 ; N(R 9 )S(0) 2 N(R 9a R 9b ); N(R 9 )S(0)N(R 9a R 9b ); SR 9 ; N(R 9 R 9a ); N0 2 ; OC(0)R 9 ; N(R 9 )C(0)R 9a ; N(R 9 )S(0)
  • Ci_ 6 alkyl N(R 13 )C(0)OR 13a ; OC(0)N(R 13 R 13a ); or Ci_ 6 alkyl, wherein Ci_ 6 alkyl is optionally substituted with one or more R 14 , which are the same or different;
  • R 13 , R 13a , R 13b are independently selected from the group consisting of H; and Ci_ 6 alkyl, wherein Ci_ 6 alkyl is optionally substituted with one or more R 14 , which are the same or different;
  • R 11 , R 12 are independently selected from the group consisting of halogen; CN; C(0)OR ; OR 15 ; C(0)R 15 ; C(0)N(R 15 R 15a ); S(0) 2 N(R 15 R 15a ); S(0)N(R 15 R 15a ); S(0) 2 R 15 ; S(0)R 15 ; N(R 15 )S(0) 2 N(R 15a R 15b ); N(R 15 )S(0)N(R 15a R 15b ); SR 15 ; N(R 15 R 15a ); N0 2 ; OC(0)R 15 ; N(R 15 )C(0)R 15a ; N(R 15 )S(0) 2 R 15a ; N(R 15 )S(0)R 15a ; N(R 15 )C(0)N(R 15a R 15b ); N(R 15 )C(0)OR 15a ; OC(0)N(R 15 R 15a ); and T 2 ;
  • R 15 , R 15a , R 15b are independently selected from the group consisting of H; T 2 ; and Ci_ 6 alkyl, wherein Ci_ 6 alkyl is optionally substituted with one or more halogen, which are the same or different;
  • R 14 is halogen; CN; C(0)OR 16 ; OR 16 ; C(0)R 16 ; C(0)N(R 16 R 16a ); S(0) 2 N(R 16 R 16a ); S(0)N(R 16 R 16a ); S(0) 2 R 16 ; S(0)R 16 ; N(R 16 )S(0) 2 N(R 16a R 16b ); N(R 16 )S(0)N(R 16a R 16b ); SR 16 ; N(R 16 R 16a ); N0 2 ; OC(0)R 16 ; N(R 16 )C(0)R 16a ; N(R 16 )S(0) 2 R 16a ; N(R 16 )S(0)R 16a ; N(R 16 )C(0)N(R 16a R 16b ); N(R 16 )C(0)OR 16a ; or OC(0)N(R 16 R 16a ); R 16 , R 16a , R 16b are independently selected from the group consisting of H; and Ci_ 6 alkyl, wherein Ci
  • T 2 is phenyl; naphthyl; indenyl; indanyl; C3-7 cycloalkyl; 4 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T 2 is optionally substituted with one or more R 17 , which are the same or different;
  • T 3 is phenyl; C3_ 7 cycloalkyl; or 4 to 7 membered heterocyclyl, wherein T 3 is optionally substituted with one or more R 18 , which are the same or different;
  • R 19 , R 19a , R 19b are independently selected from the group consisting of H; and Ci_ 6 alkyl, wherein Ci_ 6 alkyl is optionally substituted with one or more R 20 , which are the same or different; R 20 is halogen; CN; C(0)OR 21 ; OR 21 ; C(0)R 21 ; C(0)N(R 21 R 21a ); S(0) 2 N(R 21 R 21a ); S(0)N(R 21 R 21a ); S(0) 2 R 21 ; S(0)R 21 ; N(R 21 )S(0) 2 N(R 21a R 21b ); N(R 21 )S(0)N(R 21a R 21b ); SR 21 ; N(R 21 R 21a ); N0 2 ; OC(0)R 21 ; N(R 21 )C(0)R 21a ; N(R 21 )S(0) 2 R 21a ; N(R 21 )S(0)R 21a ; N(R 21 )C(0)N(R 21a R 21b ); N
  • substituents means one, two or three, preferably one or two and more preferably one substituents. Generally these substituents can be the same or different.
  • Alkyl means a straight-chain or branched hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified herein.
  • Ci_4 alkyl means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. - CH 2 -, -CH2-CH2-, -CH(CH 3 )-, -CH2-CH2-CH2-, -CH(C 2 H 5 )-, -C(CH 3 ) 2 -, when two moieties of a molecule are linked by the alkyl group.
  • Ci_ 4 alkyl Each hydrogen of a Ci_ 4 alkyl carbon may be replaced by a substituent as further specified herein.
  • Ci_6 alkyl means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_ 4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, or e.g.
  • Ci_6 alkyl carbon when two moieties of a molecule are linked by the alkyl group.
  • Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified herein.
  • C 3 _7 cycloalkyl or "C 3 _ 7 cycloalkyl ring” means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl.
  • cyloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein.
  • the term “C 3 _ 5 cycloalkyl” or "C 3 _ 5 cycloalkyl ring” is defined accordingly.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • Examples for a 4 to 7 membered heterocycles are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydro furan, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyr
  • “Saturated 4 to 7 membered heterocyclyl” or “saturated 4 to 7 membered heterocycle” means fully saturated “4 to 7 membered heterocyclyl” or "4 to 7 membered heterocycle”.
  • heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole.
  • Examples for a 7 to 1 1 membered heterobicycle are indole, indoline, benzo furan, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
  • 7 to 11 membered heterobicycle also includes spiro structures of two rings like 6-oxa-2-azaspiro[3,4]octane, 2- oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8- diazabicyclo[3.2.1 Joctane.
  • “Saturated 7 to 1 1 membered heterobicyclyl” or “saturated 7 to 11 membered heterobicycle” means fully saturated “7 to 11 membered heterobicyclyl" or "7 to 11 membered heterobicycle”.
  • Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention.
  • the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.
  • the substituents mentioned below independently have the following meaning. Hence, one or more of these substituents can have the preferred or more preferred meanings given below.
  • R is H.
  • ring A is a pyrazole, an oxazole, an isoxazole or a triazole. More preferably, ring A is a pyrazolyl ring; even more preferred a ring selected from the group consisting of:
  • ring A is preferably unsubstituted or substituted with one or two (more preferably one) R 1 , which are different from H and the same or different.
  • R 1 is Ci_ 4 alkyl, which is optionally substituted with 1 or 2 R 3 , which are the same or different. Accordingly, R 1 is preferably unsubstituted Ci_ 4 alkyl; or Ci_ 4 alkyl, substituted with one or two R 3 . More preferably, R 1 is CH 3 ; CH 2 CH 2 OH; CH 2 C(0)N(R 4 R 4a ); CH 2 CH 2 CN; CH 2 CHF 2 or CH 2 C(0)T 1 .
  • R 3 is halogen; CN; OR 4 ; C(0)N(R 4 R 4a ); S(0) 2 R 4 ; or C(0)T More preferably, R 3 is halogen; CN; OR 4 ; C(0)N(R 4 R 4a ); or C(O)! 1 .
  • R 4a is H; or unsubstituted Ci_ 4 alkyl.
  • R 4 is H; or unsubstituted Ci_ 4 alkyl.
  • T 1 is morpholin-4-yl; piperazin-l-yl; pyrrolidin-l-yl; tetrahydro-lH-furo[3,4- c]pyrrol-5(3H)-yl; 2,5-diazabicyclo[2.2.2]octan-2-yl; 2-tert.-butyloxocarbonyl-2,5- diazabicyclo[2.2.2]octan-5-yl; l-tert.butyloxy-piperazin-4-yl; 2-oxa-6-azaspiro[3.3]heptan-6- yl; or 2,6-diazaspiro[3.3]heptan-6-yl.
  • n 0, 1 or 2. More preferably, n is 1.
  • R 5 , R 5a are H.
  • none or one of X 1 , X 2 , X 3 , X 4 , X 5 is N. More preferably, none of X 1 , X 2 , X 3 , X 4 , X 5 is N.
  • R 6 , R 6a , R 6b , R 6c , R 6d are H. Also preferably, at least one (more preferably one, two or three; even more preferably one or two) of R 6 , R 6a , R 6b , R 6c , R 6d is other than H.
  • R 6 , R 6a , R 6b , R 6c , R 6d are independently selected from the group consisting of H; halogen; CN; C(0)N(R 7 R 7a ); N(R 7 R 7a ); T 2 , provided that 1 or 2 or 3 (more preferably 1 or 2) of R 6 , R 6a , R 6b , R 6c , R 6d are other than H.
  • R 6 , R 6a , R 6b , R 6c , R 6d are independently selected from the group consisting of H; halogen; CN; C(0)N(R 7 R 7a ); T 2 , provided that 1 or 2 of R 6 , R 6a , R 6b , R 6c , R 6d are other than H. More preferably, R 6 , R 6a , R 6b , R 6c , R 6d are independently selected from the group consisting of H; F; CN; C(0)NH 2 ; or morpholin-3-on-4-yl.
  • T 2 is unsubstituted morpholine; substituted morpholine; unsubstituted pyrazole; or substituted pyrazole, wherein substituted morpholine and substituted pyrazole are independently substituted with one or more R 17 , which are the same or different.
  • T 2 is unsubstituted morpholine; or morpholine, substituted with one or more (preferably, one) R 17 , which are the same or different. Even more preferably, T 2 is morpholin- 3-on-4-yl.
  • T 2 is unsubstituted pyrazole; or morpholine, substituted with one or more (preferably, one) R 17 , which are the same or different. Even more preferably, T 2 is 1-methyl- lH-pyrazol-4-yl.
  • Compounds of formula (I) in which some or all of the above-mentioned groups have the preferred meanings are also an object of the present invention.
  • tautomerism e.g. keto-enol tautomerism
  • the individual forms e.g. the keto and enol form
  • stereoisomers e.g. enantiomers, cis/trans isomers, conformers and the like.
  • Isotopic labeled compounds ("isotopic derivatives") of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. The same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
  • the compounds of formula (I) may exist in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included within the scope of the present invention. Polymorphic forms of compounds of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XPvPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).
  • XPvPD X-ray powder diffraction
  • IR infrared
  • Raman spectra Raman spectra
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid state nuclear magnetic resonance
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the term "pharmaceutically acceptable” means that the corresponding compound, carrier or molecule is suitable for administration to humans.
  • this term means approved by a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably in humans.
  • the present invention furthermore includes all solvates of the compounds according to the invention.
  • JAK comprises all members of the JAK family (e.g. JAK1, JAK2, JAK3, and TYK2).
  • the expression “JAK1” or “JAK1 kinase” means “Janus kinase 1".
  • the human gene encoding JAK1 is located on chromosome lp31.3.
  • JAK2 or "JAK2 kinase” means "Janus kinase 2".
  • the human gene encoding JAK2 is located on chromosome 9p24.
  • JAK3 or "JAK3 kinase” means "Janus kinase 3".
  • the gene encoding JAK3 is located on human chromosome 19p 13.1 and it is predominantly in hematopoietic cells.
  • JAK3 is a cytoplasmic protein tyrosine kinase that associates with the gamma-chain of the interleukin 2 (IL-2) receptor. This chain also serves as a component for the receptors of several lymphotropic cytokines, including interleukins IL-4, IL-7, IL-9, IL-15 and IL-21 (Schindler et al, 2007. J. Biol. Chem. 282(28):20059-63).
  • JAK3 plays a key role in the response of immune cells to cytokines, especially in mast cells, lymphocytes and macrophages. Inhibition of JAK3 has shown beneficial effects in the prevention of transplant rejection (Changelian et al, 2003, Science 302(5646):875-888).
  • the expression "JAK3" or "JAK3 kinase” includes mutant forms of JAK3, preferably JAK3 mutants found in acute megakaryoblastic leukemia (AMKL) patients. More preferred, these mutants are single amino acid mutations. Activating JAK3 mutations were observed in acute megakaryoblastic leukemia (AMKL) patients (Walters et al, 2006.
  • the expression "JAK” also includes a JAK3 protein having a V7221 or P132T mutation.
  • the expression “TYK2" or “TYK2 kinase” means “Protein-Tyrosine kinase 2".
  • the JAK3 and TYK2 genes are clustered on chromosome 19p 13.1 and 19pl3.2, respectively.
  • the compounds of the present invention are considered to be useful for the prevention or treatment of diseases and disorders associated with JAK, for example immunological, inflammatory, autoimmune, or allergic disorders, transplant rejection, Graft- versus-Host-Disease or proliferative diseases such as cancer.
  • diseases and disorders associated with JAK for example immunological, inflammatory, autoimmune, or allergic disorders, transplant rejection, Graft- versus-Host-Disease or proliferative diseases such as cancer.
  • the compounds of the present invention are selective JAK3 inhibitors.
  • the compounds of the present invention may be further characterized by determining whether they have an effect on JAK3, for example on its kinase activity (Changelian et al, 2003, Science 302(5646):875-888 and online supplement; Yang et al, 2007. Bioorg. Med. Chem. Letters 17(2): 326-331).
  • JAK3 kinase activity can be measured using a recombinant GST-JAK3 fusion protein comprising the catalytic domain (JH1 catalytic domain).
  • JAK3 kinase activity is measured by ELISA as follows: Plates are coated overnight with a random L-glutamic acid and tyrosine co-polymer (4: 1; 100 ⁇ g/ml) as a substrate. The plates are washed and recombinant JAK3 JH1 :GST protein (100 ng/well) with or without inhibitors is incubated at room temperature for 30 minutes.
  • HPR-conjugated PY20 anti-phosphotyrosine antibody (ICN) is added and developed by TMB (3,3',5,5'-tetramethylbenzidine) (Changelian et al, 2003, Science 302(5646):875-888 and online supplement).
  • TF-1 cell proliferation was described to assess the inhibitory activity of small molecule drugs toward JAK2 or JAK3-dependent signal transduction (Chen et al, 2006. Bioorg. Med. Chem. Letters 16(21): 5633-5638).
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained- release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other JAK inhibitors.
  • Further bioactive compounds may be steroids, leukotriene antagonists, cyclosporine or rapamycin.
  • the compounds of the present invention or pharmaceutically acceptable salt(s) thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur separately or sequentially in any order.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
  • they When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) is administered in combination with another drug or pharmaceutically active agent and/or that the pharmaceutical composition of the invention further comprises such a drug or pharmaceutically active agent.
  • drug or pharmaceutically active agent includes a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • Combined or “in combination” or “combination” should be understood as a functional coadministration, wherein some or all compounds may be administered separately, in different formulations, different modes of administration (for example subcutaneous, intravenous or oral) and different times of administration. The individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical compositions.
  • Suitable examples of pharmaceutically active agents which may be employed in combination with the compounds of the present invention and their salts for rheumatoid arthritis therapy include: immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone; anti-TNFa agents such as etanercept, infliximab, Adalimumab, Anakinra, Abatacept, Rituximab; tyrosine kinase inhibitors such as leflunomide; kallikrein antagonists such as subreum; interleukin 11 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interleukin 1 receptor antagonists such as anakinra; CD8 antagonists such as amiprilose hydrochloride; beta amyloid
  • the treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy.
  • the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment proliferative diseases such as cancer. Suitable agents to be used in combination include:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as f uoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and tax
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3 - methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -yl)ethoxy] -5 -tetrahydropyran- 4-yloxy- quinazoline (AZD0530) and N-(2-chloro-6-methylphenyl)-2- ⁇ 6-[4-(2- hydroxyethyl)piperazin-l-yl] -2-methylpyrimidin- 4-ylamino ⁇ thiazo le-5 -carboxamide
  • dasatinib (dasatinib, BMS-354825), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3- chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), A/-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-A/-(3-chloro-4-fluorophenyl)-7-(3-)
  • vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Application WO 99/02166;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense agent;
  • gene therapy approaches including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapeutic approaches, including ex- vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapeutic approaches including ex- viv
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • a therapeutically effective amount of a compound of the present invention will normally depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration.
  • an effective amount of a compound of formula (I) for the treatment of an inflammatory disease for example rheumatoid arthritis (RA)
  • RA rheumatoid arthritis
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a pharmaceutically acceptable salt, prodrug or metabolite thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • Another aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.
  • Another aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a disease or disorder associated with JAK.
  • a disease or disorder associated with JAK is defined as a disease or disorder where JAK is involved.
  • the diseases or disorder is associated with JAK is an immunological, inflammatory, autoimmune, or allergic disorder or disease of a transplant rejection or a Graft-versus host disease.
  • another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing an immunological, inflammatory, autoimmune, or allergic disorder or disease of a transplant rejection or a Graft-versus host disease.
  • Inflammation of tissues and organs occurs in a wide range of disorders and diseases and in certain variations, results from activation of the cytokine family of receptors.
  • Exemplary inflammatory disorders associated with activation of JAK include, in a non-limiting manner, skin inflammation due radiation exposure, asthma, allergic inflammation and chronic inflammation.
  • an autoimmune disease is a disease which is at least partially provoked by an immune reaction of the body against own components, for example proteins, lipids or DNA.
  • organ-specific autoimmune disorders are insulin- dependent diabetes (Type I) which affects the pancreas, Hashimoto's thyroiditis and Graves' disease which affect the thyroid gland, pernicious anemia which affects the stomach, Cushing's disease and Addison's disease which affect the adrenal glands, chronic active hepatitis which affects the liver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD) and ankylosing spondylitis.
  • non-organ- specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis, systemic lupus and myasthenia gravis.
  • Type I diabetes ensues from the selective aggression of autoreactive T-cells against insulin secreting beta-cells of the islets of Langerhans.
  • Targeting JAK3 in this disease is based on the observation that multiple cytokines that signal through the JAK pathway are known to participate in the T-cell mediated autoimmune destruction of beta-cells.
  • a JAK3 inhibitor, JANEX-1 was shown to prevent spontaneous autoimmune diabetes development in the NOD mouse model of type I diabetes.
  • the autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), psoriasis, systemic lupus erythematosus (SLE), and multiple sclerosis (MS).
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • IBD Inflammatory bowel disease
  • Crohn's disease involves most frequently the terminal ileum and colon, is transmural and discontinuous.
  • ulcerative colitis the inflammation is continuous and limited to rectal and colonic mucosal layers.
  • definitive classification of Crohn's disease or ulcerative colitis cannot be made and are designated 'indeterminate colitis.
  • Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Neutrophil-induced injuries may be prevented by the use of neutrophils migration inhibitors (Asakura et al., 2007, World J Gastroenterol. 13(15):2145-9).
  • Psoriasis is a chronic inflammatory dermatosis that affects approximately 2% of the population. It is characterized by red, scaly skin patches that are usually found on the scalp, elbows, and knees, and may be associated with severe arthritis. The lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis (Schon et al, 2005, New Engl. J. Med. 352: 1899-1912).
  • SLE Systemic lupus erythematosus
  • T cell- mediated B-cell activation results in glomerulonephritis and renal failure.
  • Human SLE is characterized at early stages by the expansion of long-lasting autoreactive CD4+ memory cells (D'Cruz et al, 2007, Lancet 369(9561):587-596).
  • MS Multiple sclerosis
  • JAK3 was shown to be a valid target in the treatment of mast cell mediated allergic reaction.
  • Allergic disorders associated with mast cell activation include Type I immediate hypersensitivity reactions such as allergic rhinitis (hay fever), allergic urticaria (hives), angioedema, allergic asthma and anaphylaxis, for example anaphylatic shock. These disorders may be treated or prevented by inhibition of JAK3 activity, for example, by administration of a JAK3 inhibitor according to the present invention.
  • Transplant rejection includes, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea. It is known that T cells play a central role in the specific immune response of allograft rejection. Hyperacute, acute and chronic organ transplant rejection may be treated. Hyperacute rejection occurs within minutes of transplantation. Acute rejection generally occurs within six to twelve months of the transplant. Hyperacute and acute rejections are typically reversible where treated with immunosuppressant agents. Chronic rejection, characterized by gradual loss of organ function, is an ongoing concern for transplant recipients because it can occur anytime after transplantation.
  • GVDH graft-versus-host disease
  • BMT bone marrow transplantation
  • JAK3 plays a key role in the induction of GVHD and treatment with a JAK3 inhibitor, JANEX-1, was shown to attenuate the severity of GVHD (reviewed in Cetkovic- Cvrlje and Ucken, 2004).
  • the inflammatory disease is an eye disease.
  • Dry eye syndrome (DES, also known as keratoconjunctivitis sicca) is one of the most common problems treated by eye physicians. Sometimes DES is referred to as dysfunctional tear syndrome (Jackson, 2009. Canadian Journal Ophthalmology 44(4), 385-394). DES affects up to 10% of the population between the ages of 20 to 45 years, with this percentage increasing with age. Although a wide variety of artificial tear products are available, these products provide only transitory relief of symptoms. As such, there is a need for agents, compositions and therapeutic methods to treat dry eye.
  • dry eye disorder is intended to encompass the disease states summarized in a recent official report of the Dry Eye Workshop (DEWS), which defined dry eye as "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolality of the tear film and inflammation of the ocular surface.” (Lemp, 2007. "The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop", The Ocular Surface, 5(2), 75-92). Dry eye is also sometimes referred to as keratoconjunctivitis sicca.
  • the treatment of the dry eye disorder involves ameliorating a particular symptom of dry eye disorder, such as eye discomfort, visual disturbance, tear film instability, tear hyperosmolarity, and inflammation of the ocular surface.
  • Uveitis is the most common form of intraocular inflammation and remains a significant cause of visual loss.
  • Current treatments for uveitis employs systemic medications that have severe side effects and are globally immunosuppressive.
  • Clinically chronic progressive or relapsing forms of non-infectious uveitis are treated with topical and/or systemic corticosteroids.
  • macro lides such as cyclosporine and rapamycin are used, and in some cases cytotoxic agents such as cyclophosphamide and chlorambucil, and antimetabolites such as azathioprine, methotrexate, and leflunomide (Srivastava et al, 2010.
  • Uveitis Mechanisms and recent advances in therapy. Clinica Chimica Acta, doi: 10.1016/j .cca.2010.04.017).
  • the disease or disorder associated with JAK is a proliferative disease, especially cancer.
  • Another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing a proliferative disease, especially cancer.
  • Cancer comprises a group of diseases characterized by uncontrolled growth and spread of abnormal cells. All types of cancers generally involve some abnormality in the control of cell growth, division and survival, resulting in the malignant growth of cells. Key factors contributing to said malignant growth of cells are independence from growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, and genome instability (Hanahan and Weinberg, 2000. The Hallmarks of Cancer. Cell 100, 57-70).
  • cancers are classified as hematological cancers (for example leukemias and lymphomas) and solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • hematological cancers for example leukemias and lymphomas
  • solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • the JAK inhibitors of the present invention may also useful in treating certain malignancies, including skin cancer and hematological malignancy such as lymphomas and leukemias.
  • cancers in which the JAK-STAT signal transduction pathway is activated are expected to respond to treatment with JAK3 inhibitors.
  • JAK3 inhibitors include acute megakaryoblastic leukemia (AMKL) (Walters et al, 2006. Cancer Cell 10(l):65-75) and breast cancer (Jeong et al, 2008. Clin. Cancer Res. 14, 3716-3721).
  • Proliferative diseases or disorders comprise a group of diseases characterized by increased cell multiplication as observed in myeloprolifetative disorders (MPD) such as polycythemia vera (PV).
  • MPD myeloprolifetative disorders
  • PV polycythemia vera
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, especially cancer.
  • diseases and disorders associated with JA are as defined above.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of diseases and disorders associated with JAK, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of an immunological, inflammatory, autoimmune, or allergic disorder or disease or a transplant rejection or a Graft-versus host disease, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof a proliferative disease, especially cancer, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • diseases and disorders associated with JAK are as defined above.
  • treating or “treatment” is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • compounds of the present invention may be prepared according to a method comprising the steps of reacting a compound of formula (II)
  • X 1 to X 5 and Y have the meaning as indicated above and C is suitable reactive group (like bromo), or first with a compound of formula (IV) followed by reaction with compound (III) to yield a compound of formula (I).
  • test compounds at various concentrations
  • affinity matrix with the immobilized aminopyrido-pyrimidine ligand 24 were added to cell lysate aliquots and allowed to bind to the proteins in the lysate sample.
  • beads with captured proteins were separated from the lysate. Bound proteins were then eluted and the presence of JAK2 and JAK3 was detected and quantified using specific antibodies in a dot blot procedure and the Odyssey infrared detection system.
  • the affinity matrix was washed two times with 15mL of lx DP buffer containing 0.2% NP40 (IGEPAL® CA-630, Sigma, #13021) and then resuspended in lxDP buffer containing 0.2% NP40 (3% beads slurry).
  • 5xDP buffer 250mM Tris-HCl pH 7.4, 25% Glycerol, 7.5mM MgCl 2 , 750mM NaCl, 5mM
  • the 5xDP buffer is diluted with H 2 0 to lxDP buffer containing lmM DTT and 25mM NaF.
  • test compounds were prepared in DMSO.
  • solution of diluted test compounds at 5mM in DMSO were prepared. Starting with this solution a 1 :3 dilution series (9 steps) was prepared.
  • a buffer containing 2% DMSO was used for control experiments (no test compound) for control experiments (no test compound).
  • Molt4 cells (ATCC catalogue number CRL-1582) and Ramos cells (ATCC catalogue number CRL-1596) were grown in 1L Spinner flasks (Integra Biosciences, #182101) in suspension in RPMI 1640 medium (Invitrogen, #21875-034) supplemented with 10% Fetal Bovine Serum (Invitrogen) at a density between 0.15 x 10 6 and 1.2 x 10 6 cells/mL. Cells were harvested by centrifugation, washed once with 1 x PBS buffer (Invitrogen, #14190-094) and cell pellets were frozen in liquid nitrogen and subsequently stored at -80°C.
  • the supernatant was transferred to an ultracentrifuge (UZ)-polycarbonate tube (Beckmann, 355654) and spun for lhour at lOO.OOOg at 4°C (33.500 rpm in ⁇ 50.2, precooled). The supernatant was transferred again to a fresh 50mL falcon tube, the protein concentration was determined by a Bradford assay (BioRad) and samples containing 50mg of protein per aliquot were prepared. The samples were immediately used for experiments or frozen in liquid nitrogen and stored frozen at -80°C.
  • Cell lysate (approximately 50mg protein per plate) was thawed in a water bath at room temperature and then stored on ice. To the thawed cell lysate IxDP 0.8% NP40 buffer containing protease inhibitors (1 tablet for 25mL buffer; EDTA-free protease inhibitor cocktail; Roche Diagnostics 1873580) was added in order to reach a final protein concentration of lOmg/mL total protein. The diluted cell lysate was stored on ice. Mixed Molt4/Ramos lysate was prepared by combining one volume of Molt4 lysate and two volumes of Ramos lysate (ratio 1 :2).
  • the filter plate was placed on top of a collection plate (Greiner bio-one, PP-microplate 96 well V-shape, 65120) and the beads were then eluted with 20 ⁇ of sample buffer (100 mM Tris, pH 7.4, 4% SDS, 0.00025% bromophenol blue, 20%) glycerol, 50 mM DTT).
  • sample buffer 100 mM Tris, pH 7.4, 4% SDS, 0.00025% bromophenol blue, 20%
  • glycerol 50 mM DTT
  • kinases in the eluates were detected and quantified by spotting on nitrocellulose membranes and using a first antibody directed against the kinase of interest and a fluorescently labelled secondary antibody (anti-rabbit IRDyeTM antibody 800 (Licor, # 926- 32211).
  • the Odyssey Infrared Imaging system from LI-COR Biosciences (Lincoln, Iowa, USA) was operated according to instructions provided by the manufacturer (Schutz-Geschiller et al., 2004. Quantitative, two-color Western blot detection with infrared fluorescence. Published May 2004 by LI-COR Biosciences, www.licor.com).
  • the nitrocellulose membrane (BioTrace NT; PALL, #BTNT30R) was first blocked by incubation with Odyssey blocking buffer (LICOR, 927-40000) for 1 hour at room temperature. Blocked membranes were then incubated for 16 hours at the temperature shown in table 4 with the first antibody diluted in Odyssey blocking buffer (LICOR #927-40000). Afterwards the membrane was washed twice for 10 minutes with PBS buffer containing 0.2% Tween 20 at room temperature. The membrane was then incubated for 60 minutes at room temperature with the detection antibody (anti-rabbit IRDyeTM antibody 800, Licor, # 926-32211) diluted in Odyssey blocking buffer (LICOR #927-40000).
  • the detection antibody anti-rabbit IRDyeTM antibody 800, Licor, # 926-32211
  • the membrane was washed twice for 10 minutes each with 1 x PBS buffer containing 0.2% Tween 20 at room temperature. Then the membrane was rinsed once with PBS buffer to remove residual Tween 20. The membrane was kept in PBS buffer at 4°C and then scanned with the Odyssey instrument. Fluorescence signals were recorded and analysed according to the instructions of the manufacturer.
  • Table 7 Inhibition values (IC 50 in ⁇ ) as determined in the KinobeadsTM assay (Activity level: A ⁇ ⁇ . ⁇ ; ⁇ . ⁇ ⁇ B ⁇ ⁇ ; ⁇ ⁇ C ⁇ ⁇ ; D > ⁇ ).
  • STAT5 phosphorylation represents one of the proximal events in the signalling cascade downstream of JAK3 activation. Therefore STAT5 phosphorylation is an appropriate readout to assess the mechanistic effect of JAK3 inhibition.
  • Stimulation of human YT cells, an NK- like cell line, with interleukin-2 (IL-2) results in phosphorylation of STAT5 at tyrosine residue 694 (Tyr694) that can be quantitatively measured by immunodetection with specific antibodies and an appropriate detection method, in this case AlphaScreen assay technology.
  • Human YT cells were grown in RPMI medium (Lonza, BE 12- 167) with 2mM L-Glutamine (Invitrogen, 25030-024) and 10% heat-inactivated FBS (Invitrogen, 10106-169) and kept in a humidified incubator (37°C, 5% C0 2 ). Cells were harvested by centrifugation, washed once with HBSS (Invitrogen, 14180-046), resuspended in HBSS at 1.5xl0 6 cells/ml and 0.9xl0 4 cells were seeded in 6 ⁇ 1 per well in a 96 well White plate (PerkinElmer, 6005569).
  • Test compounds were dissolved in DMSO and a 1 :3 dilution series (9 steps) was prepared. To generate a dose response curve, 3 ⁇ 1 of fourfold concentrated compound in 4% DMSO/HBSS were added to each cell sample in the 96 well plate resulting in a final DMSO concentration of 1% DMSO. Cells were incubated for one hour in a humidified incubator (37°C, 5% C0 2 ). To each well 3 ⁇ 1 of a fourfold concentrated IL-2 solution (Recombinant human IL-2, Peprotech 200-02; 120 nM solution in HBSS) was added and incubated for 30 minutes at room temperature. Cells were lysed by adding 3 ⁇ 1 of 5x lysis buffer (SureFire lysis buffer; Perkin Elmer, TGRS5S10K) and incubated for 10 minutes at room temperature with gentle shaking.
  • the SureFire phospho-STAT5 (Tyr694/Tyr699) kit was used according to instructions provided by the manufacturer (Perkin Elmer, TGRS5S10K). Acceptor beads were added as recommended by the manufacturer (Reactivation buffer / Activation buffer / Acceptor beads at a ratio of 40: 10: 1) and incubated at room temperature for 1.5 hours with gentle shaking. Then donor beads were added as recommended (Dilution buffer / Donor beads at a ratio of 20: 1) and incubated at room temperature for 1.5 hours with gentle shaking. Plates were read on an Envision instrument (Perkin Elmer) with the AlphaScreen protocol. Data were analysed in BioAssay using the nonlinear regression for a sigmoidal dose-response with a variable slope.
  • Table 8 provides data for selected compounds of the invention in the pSTAT5 cell assay.
  • Table 8 Inhibition values (IC 50 in ⁇ ) as determined in the pSTAT5 cell assay (Activity level: A ⁇ ⁇ . ⁇ ; ⁇ . ⁇ ⁇ B ⁇ ⁇ ; ⁇ ⁇ C ⁇ 10 ⁇ ; D > 10 ⁇ ).

Abstract

La présente invention concerne des composés de formule (I), dans laquelle X1 à X5, Y, Z1 à Z4 et R ont la signification telle que citée dans la description et les revendications. De tels composés sont utiles en tant qu'inhibiteurs de JAK pour le traitement ou la prophylaxie de troubles immunologiques, inflammatoires, auto-immunitaires, allergiques, et de maladies médiées immunologiquement. L'invention concerne également des compositions pharmaceutiques comprenant lesdits composés, la préparation de tels composés, ainsi que leur utilisation en tant que médicaments.
PCT/EP2012/064510 2011-07-29 2012-07-24 Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak WO2013017479A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP11176011 2011-07-29
EP11176011.2 2011-07-29

Publications (1)

Publication Number Publication Date
WO2013017479A1 true WO2013017479A1 (fr) 2013-02-07

Family

ID=46548497

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/064510 WO2013017479A1 (fr) 2011-07-29 2012-07-24 Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak

Country Status (1)

Country Link
WO (1) WO2013017479A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016514711A (ja) * 2013-03-19 2016-05-23 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ヤヌスキナーゼ阻害剤としての非環式シアノエチルピラゾロピリドン
RU2655380C2 (ru) * 2013-03-19 2018-05-28 Мерк Шарп И Доум Корп. Циклоалкилнитрилпиразолопиридоны в качестве ингибиторов янус-киназы
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035985A1 (fr) 1997-02-12 1998-08-20 The Regents Of The University Of Michigan Proteines-marqueurs pour le cancer du poumon et utilisation de ces dernieres
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000047212A1 (fr) 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2001032651A1 (fr) 1999-11-05 2001-05-10 Astrazeneca Ab Derives de quinazoline utilises en tant qu'inhibiteurs du facteur de croissance endotheliale vasculaire (vegf)
WO2001042246A2 (fr) 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine
WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2006063820A1 (fr) 2004-12-16 2006-06-22 Novartis Ag Composés de type pyrazolo-hétéroaryles pouvant être employés dans le traitement de maladies dues à tnf-alpha et il-1
WO2006134056A1 (fr) 2005-06-14 2006-12-21 Cellzome Ag Procede d'identification de nouveaux composes interagissant avec les enzymes
WO2007107318A1 (fr) 2006-03-21 2007-09-27 Novartis Ag Combinaisons
WO2007137867A1 (fr) 2006-06-01 2007-12-06 Cellzome Ag Procédés pour identifier des molécules interagissant avec la kinase zap-70 et pour purifier celle-ci
WO2007140222A2 (fr) * 2006-05-26 2007-12-06 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
WO2008009458A1 (fr) 2006-07-21 2008-01-24 Novartis Ag Composés de 2,4-di(arylamino)-pyrimidine-5-carboxamide comme inhibiteurs des jak kinases
WO2008060301A1 (fr) 2006-11-16 2008-05-22 Pharmacopeia , Llc Dérivés de purine substitués en 7, destinés à l'immunosuppression
WO2008094575A2 (fr) * 2007-01-30 2008-08-07 Biogen Idec Ma Inc. Modulateurs de kinases mitotiques
WO2008118822A1 (fr) 2007-03-23 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions et procédés d'inhibition de la voie de jak
WO2008118823A2 (fr) 2007-03-26 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions et procédés pour l'inhibition de la voie jak
WO2009008992A2 (fr) 2007-07-06 2009-01-15 Osi Pharmaceuticals Inc. Traitement anticancéreux en combinaison
WO2010039939A1 (fr) 2008-10-02 2010-04-08 Incyte Corporation Inhibiteurs des janus kinases pour le traitement du syndrome de l’œil sec et autres maladies de l’œil
WO2010118986A1 (fr) 2009-04-14 2010-10-21 Cellzome Limited Composés de pyrimidine substitués par fluoro en tant qu'inhibiteurs de jak3
WO2011019780A1 (fr) 2009-08-11 2011-02-17 Bristol-Myers Squibb Company Azaindazoles comme modulateurs de la kinase btk et leur utilisation
WO2011048082A1 (fr) 2009-10-20 2011-04-28 Cellzome Limited Analogues d'hétérocyclyl pyrazolopyrimidine en tant qu'inhibiteurs de jak

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035985A1 (fr) 1997-02-12 1998-08-20 The Regents Of The University Of Michigan Proteines-marqueurs pour le cancer du poumon et utilisation de ces dernieres
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000047212A1 (fr) 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2001032651A1 (fr) 1999-11-05 2001-05-10 Astrazeneca Ab Derives de quinazoline utilises en tant qu'inhibiteurs du facteur de croissance endotheliale vasculaire (vegf)
WO2001042246A2 (fr) 1999-12-10 2001-06-14 Pfizer Products Inc. Composes a base de pyrrolo[2,3-d]pyrimidine
WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2006063820A1 (fr) 2004-12-16 2006-06-22 Novartis Ag Composés de type pyrazolo-hétéroaryles pouvant être employés dans le traitement de maladies dues à tnf-alpha et il-1
WO2006134056A1 (fr) 2005-06-14 2006-12-21 Cellzome Ag Procede d'identification de nouveaux composes interagissant avec les enzymes
WO2007107318A1 (fr) 2006-03-21 2007-09-27 Novartis Ag Combinaisons
WO2007140222A2 (fr) * 2006-05-26 2007-12-06 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
WO2007137867A1 (fr) 2006-06-01 2007-12-06 Cellzome Ag Procédés pour identifier des molécules interagissant avec la kinase zap-70 et pour purifier celle-ci
WO2008009458A1 (fr) 2006-07-21 2008-01-24 Novartis Ag Composés de 2,4-di(arylamino)-pyrimidine-5-carboxamide comme inhibiteurs des jak kinases
WO2008060301A1 (fr) 2006-11-16 2008-05-22 Pharmacopeia , Llc Dérivés de purine substitués en 7, destinés à l'immunosuppression
WO2008094575A2 (fr) * 2007-01-30 2008-08-07 Biogen Idec Ma Inc. Modulateurs de kinases mitotiques
WO2008118822A1 (fr) 2007-03-23 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions et procédés d'inhibition de la voie de jak
WO2008118823A2 (fr) 2007-03-26 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions et procédés pour l'inhibition de la voie jak
WO2009008992A2 (fr) 2007-07-06 2009-01-15 Osi Pharmaceuticals Inc. Traitement anticancéreux en combinaison
WO2010039939A1 (fr) 2008-10-02 2010-04-08 Incyte Corporation Inhibiteurs des janus kinases pour le traitement du syndrome de l’œil sec et autres maladies de l’œil
WO2010118986A1 (fr) 2009-04-14 2010-10-21 Cellzome Limited Composés de pyrimidine substitués par fluoro en tant qu'inhibiteurs de jak3
WO2011019780A1 (fr) 2009-08-11 2011-02-17 Bristol-Myers Squibb Company Azaindazoles comme modulateurs de la kinase btk et leur utilisation
WO2011048082A1 (fr) 2009-10-20 2011-04-28 Cellzome Limited Analogues d'hétérocyclyl pyrazolopyrimidine en tant qu'inhibiteurs de jak

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
ASAKURA ET AL., WORLD J GASTROENTEROL., vol. 13, no. 15, 2007, pages 2145 - 9
CHANGELIAN ET AL., SCIENCE, vol. 302, no. 5646, 2003, pages 875 - 888
CHEN ET AL., BIOORG. MED. CHEM. LETTERS, vol. 16, no. 21, 2006, pages 5633 - 5638
D'CRUZ ET AL., LANCET, vol. 369, no. 9561, 2007, pages 587 - 596
FESU, IMMUNOI. REV. ZZJ, 2008, pages 132 - 142
FIRESTEIN, NATURE, vol. 423, 2003, pages 356 - 361
GHORESCHI ET AL., NATURE IMMUNOL., vol. 4, 2009, pages 356 - 360
HANAHAN; WEINBERG: "The Hallmarks of Cancer", CELL, vol. 100, 2000, pages 57 - 70
HEMMER ET AL., NAT. REV. NEUROSCIENCE, vol. 3, 2002, pages 291 - 301
JACKSON, CANADIAN JOURNAL OPHTHALMOLOGY, vol. 44, no. 4, 2009, pages 385 - 394
JEONG ET AL., CLIN. CANCER RES., vol. 14, 2008, pages 3716 - 3721
JIANG ET AL., J. MED. CHEM., vol. 51, no. 24, 2008, pages 8012 - 8018
LEMP: "The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop", THE OCULAR SURFACE, vol. 5, no. 2, 2007, pages 75 - 92
MACCHI ET AL., NATURE, vol. 377, no. 6544, 1995, pages 65 - 68
NEUBAUER ET AL., CELL, vol. 93, no. 3, 1998, pages 397 - 409
O'SHEA ET AL., NAT. REV. DRUG DISCOV., vol. 3, no. 7, 2004, pages 555 - 64
PAPAGEORGIOU; WIKMAN, TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 25, no. 11, 2004, pages 558 - 62
R.V. FUCINI ET AL., BIOORG. & MED. CHEM. LETT., vol. 18, 2008, pages 5648 - 5652
RODIG ET AL., CELL, vol. 93, no. 3, 1998, pages 373 - 83
SCHINDLER ET AL., J. BIOL. CHEM., vol. 282, no. 28, 2007, pages 20059 - 63
SCHON ET AL., NEW ENGL. J. MED., vol. 352, 2005, pages 1899 - 1912
SCHUTZ-GESCHWENDENER ET AL.: "Quantitative, two-color Western blot detection with infrared fluorescence", 2004, LI-COR BIOSCIENCES
SRIVASTAVA ET AL.: "Uveitis: Mechanisms and recent advances in therapy", CLINICA CHIMICA ACTA, 2010
WALTERS ET AL., CANCER CELL, vol. 10, no. 1, 2006, pages 65 - 75
YAMAOKA ET AL.: "The Janus kinases (Jaks", GENOME BIOLOGY, vol. 5, no. 12, 2004, pages 253
YANG ET AL., BIOORG. MED. CHEM. LETTERS, vol. 17, no. 2, 2007, pages 326 - 331

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016514711A (ja) * 2013-03-19 2016-05-23 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ヤヌスキナーゼ阻害剤としての非環式シアノエチルピラゾロピリドン
EP2976341A4 (fr) * 2013-03-19 2016-10-12 Merck Sharp & Dohme Cyanoéthylpyrazolo pyridones acycliques en tant qu'inhibiteurs de janus kinase
RU2655380C2 (ru) * 2013-03-19 2018-05-28 Мерк Шарп И Доум Корп. Циклоалкилнитрилпиразолопиридоны в качестве ингибиторов янус-киназы
US10059705B2 (en) 2013-03-19 2018-08-28 Merck Sharp & Dohme Corp. Acyclic cyanoethylpyrazolo pyridones as janus kinase inhibitors
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands

Similar Documents

Publication Publication Date Title
AU2012288892B2 (en) Heterocyclyl pyrimidine analogues as JAK inhibitors
JP5744887B2 (ja) Ｊａｋ阻害剤としてのヘテロシクリルピラゾロピリミジン類似体
WO2013017480A1 (fr) Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak
AU2012357038B2 (en) Pyrimidine-2,4-diamine derivatives as kinase inhibitors
AU2012311504B2 (en) Pyrazolo[4,3-C]pyridine derivatives as kinase inhibitors
WO2011134831A1 (fr) Composés de pyrazole comme inhibiteurs de jak
US9040545B2 (en) Heterocyclyl pyrazolopyrimidine analogues as selective JAK inhibitors
WO2012000970A1 (fr) Triazolopyridines en tant qu'inhibiteurs de tyk2
WO2011029807A1 (fr) Composés de pyrimidine ortho-substitués en tant qu'inhibiteurs de jak
WO2012143320A1 (fr) Composés (7h-pyrrolo[2,3-d]pyrimidin-2-yl)amine comme inhibiteurs de la jak3
US20140296234A1 (en) Pyrimidine derivatives as mtor inhibitors
WO2013017479A1 (fr) Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak
RU2564419C1 (ru) Гетероциклические аналоги пиримидина в качестве ингибиторов jak
AU2011246596A1 (en) Pyrazole compounds as JAK inhibitors
EP2606050A2 (fr) Analogues de la hétérocyclyl pyrazolopyrimidine comme inhibiteurs sélectifs de la jak

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12737839

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12737839

Country of ref document: EP

Kind code of ref document: A1