[go: up one dir, main page]

WO2004052880A1 - Derives pyridine servant d'inhibiteurs de jnk et utilisation - Google Patents

Derives pyridine servant d'inhibiteurs de jnk et utilisation Download PDF

Info

Publication number
WO2004052880A1
WO2004052880A1 PCT/SE2003/001911 SE0301911W WO2004052880A1 WO 2004052880 A1 WO2004052880 A1 WO 2004052880A1 SE 0301911 W SE0301911 W SE 0301911W WO 2004052880 A1 WO2004052880 A1 WO 2004052880A1
Authority
WO
WIPO (PCT)
Prior art keywords
bipyridin
anilino
urea
alkyl
carboxamide
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/SE2003/001911
Other languages
English (en)
Inventor
Elisabeth Kallin
Niklas Plobeck
Britt-Marie Swahn
Arzel ERWAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Priority to AU2003302919A priority Critical patent/AU2003302919A1/en
Publication of WO2004052880A1 publication Critical patent/WO2004052880A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel pyridine derivatives, useful for treatment of various disorders.
  • the invention relates to methods for producing these compounds.
  • the invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing these compositions in the treatment of various disorders.
  • Protein kinases are important components of intracellular signalling pathways and kinases are involved in the regulation of a variety of cellular functions.
  • the MAP kinase signalling pathways are activated by engagement of a number of cell surface receptors.
  • the JNK pathway is activated specifically by stress or pro-inflammatory cytokines. Activators include LPS, the cytokines tumor necrosis factor (TNF- ⁇ ) and Interleukin-1 (TJL-1), osmotic shock, chemical stress and UV radiation (Cohen, P. Trends in Cell Biol. 7:353-361 1997).
  • TNF- ⁇ tumor necrosis factor
  • TJL-1 Interleukin-1
  • Targets of the JNK pathway include a number of transcription factors, such as but not exclusively c-jun and ATF-2 (Whitmarsh, A. and Davis, R. J. Mol. Med. 74:589-607 1998).
  • JNK1, JNK2 and JNK3 encode the JNK family of enzymes.
  • spliced forms of these genes can give rise to 10 distinct isoforms: four for JNK1, four for JNK2 and two for JNK3.
  • JNK1 and JNK2 are ubiquitously expressed in human tissues whereas JNK3 is selectively expressed in the brain, heart and testis (Dong, C. et al. Science 270: 1-4 1998).
  • JNKs 1 , 2 and 3 have been selectively knocked out in mice both singularly and in combination by both gene deletion and/or transgenic expression of dominant negative forms of the kinases (Dong, C. et al Science 282:2092-2095, 1998; Yang, D. et al Immunity 9:575-585 1998; Dong, C, et al Nature 405:91-94 2000; Yang, D. et al Nature 389:865-870 1997).
  • Mice with targeted disruption of the JNK3 gene develop normally and are protected from excitotoxin-induced apoptosis of neurons. This finding suggests that specific inhibitors of JNK 3 could be effective in the treatment of neurological disorders characterized by cell death such as Alzheimer's disease and stroke.
  • mice disrupted in either JNK 1 or 2 also develop normally.
  • Peripheral T cells from either type of mice can be activated to make TJL2, but in both cases, there is a defect in Thl cell development.
  • this is due to an inability to make gamma interferon (a key cytokine essential for the differentiation of Thl cells).
  • JNK2 -/- mice produce interferon gamma but are unable to respond to the cytokine.
  • JNK also plays a major role in apoptosis of cells (Davis RJ. Cell. 103:239-252, 2000). JNK is essential for UV induced apoptosis through the cytochrome C mediated pathway (Tournier, C. et al Science 288:870-8742000). Ischemia and ischemia coupled with re- perfusion as well as restricted blood flow itself have been shown to be accompanied by activation of JNK. Cell death can be prevented with dominant negative forms of JNK transfected into cells demonstrating a potential utility for JNK in conditions characterized by stress-induced apoptosis.
  • JNK Activation of the JNK pathway has been observed in a number of human tumors and transformed cell lines (Davis RJ. Cell. 103:239-252, 2000). Indeed, one of the major targets of JNK, c-jun, was originally identified as an oncogene indicating the potential of this pathway to participate in unregulated cell growth. JNK also regulates phosphorylation of p53 and thus modulates cell cycle progression (Chen T. et al Mol. Carcinogenesis 15:215-226, 1996). Inhibition of JNK may therefore be beneficial in some human cancers.
  • JNK signalling especially JNK3 has been implicated in areas of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, traumatic brain injury, as well as ischemic and haemorrhaging stroke.
  • JNK specific inhibitors useful in treating the various conditions associated with JNK activation.
  • the invention relates to compounds of the general Formula I
  • R .1 i s aryl or heteroaryl, each of which is optionally substituted with one or more of R
  • R ⁇ is R > 5 J , R°, COR", COR°, CONHR J , CONHR 0 , CON(R°) 2 , COOR 0 , COOR 0 , SO 2 R 3 or SO 2 R 6 ;
  • R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-6 alkyl, heterocycle, heterocycleC 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 trifluoroalkoxyl;
  • R 5 is aryl or heteroaryl, each of which is optionally substituted with one or more of R 7 , OR 7 , OCOR 7 , COOR 7 , COR 7 , CONR 7 R 8 , CONHOR 7 , NHCOR 7 , NR 7 R 8 , NHSO 2 R 7 , SO 2 R 7 , SO 2 NR 7 R 8 , SR 7 , R 7 SR 8 , CN, halogeno, oxygen and NO 2 ;
  • R 6 is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-6 alkyl, heterocycle, heterocycleCi. 6 alkyl, heteroarylC 1-6 alkyl, arylC 1-6 alkyl, C 1-6 alkoxyl, or C 2-6 alkenyl, wherein any of C 1-6 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-6 alkyl, heterocycle, heterocycleC ⁇ -6 alkyl, heteroarylC 1-6 alkyl, arylC 1-6 alkyl, C 1-6 alkoxyl and C 2-6 alkenyl is optionally substituted with one or more A;
  • R 7 and R 8 are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl) ⁇ .. 6 alkyl, C 2-6 alkenyl, aryl, heteroaryl, heteroarylC 1-6 alkyl, heterocycle, heterocycleC 1-6 alkyl, aryl, C 1-6 fluoroalkyl and C 1-6 chloroalkyl,wherein any of C 1-6 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-6 alkyl, C 2-6 alkenyl, heteroaryl, heteroarylC 1-6 alkyl, heterocycle and heterocycle . 6 alkyl is optionally substituted with one or more B;
  • R 9 and R 10 are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C ⁇ . . 6 alkyl, C 2-6 alkenyl, heterocycle, heterocycleC 1-6 alkyl, heteroaryl, heteroarylC 1-6 alkyl, aryl or arylC 1-6 alkyl, wherein any of C 1-6 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C ⁇ .,6 alkyl, C 2-6 alkenyl, heterocycle, heterocycleC 1-6 alkyl, heteroaryl, heteroarylC 1-6 alkyl, aryl or arylC 1-6 alkyl is optionally substituted with one or more B;
  • A is R 9 , OR 9 , OCOR 9 , COOR 9 , COR 9 , CONR 9 R 10 , CONHOR 9 , NHCOR 9 , NR 9 R 10 , NR 9 SO 2 R 10 , SO 2 R 9 , SO 2 NR 9 R 10 , SR 9 , R 9 SR 10 ,CN or halogeno;
  • B is C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino or halogeno;
  • alkyl includes both straight and branched chain alkyl groups.
  • C ⁇ alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, and hexyl.
  • C 3-8 cycloalkyl includes a non- aromatic, completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms.
  • examples of said cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkoxyl as used herein, unless stated otherwise includes “alkyl'O groups in which "alkyl” is as hereinbefore defined.
  • C 1-6 alkoxyl may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, hexyloxy.
  • C 1-6 trifluoroalkoxyl represents a C 1-6 alkoxyl substituted with three fluorine atoms.
  • alkenyl includes both straight and branched chain alkenyl groups but references to individual alkenyl groups such as 2-butenyl is specific for the straight chain version only. Unless otherwise stated, the term “alkenyl” advantageously refers to chains with 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms. C -6 alkenyl may be ethenyl, propenyl, 2-methylpropenyl, butenyl and 2- butenyl.
  • alkynyl includes both straight and branched chain alkynyl groups but references to individual alkynyl groups such as
  • 2-butynyl is specific for the straight chain version only. Unless otherwise stated, the term “alkynyl” advantageously refers to chains with 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms.
  • heterocycle includes a 3- to 10- membered non-aromatic partially or completely saturated hydrocarbon group, which contains one or two rings and at least one heteroatom.
  • heterocycle include, but are not limited to pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, oxazolyl, 2-oxazolidonyl, tetrahydropyranyl or tetrahydrofuranyl.
  • aryl may be a C 6 - 4 aromatic hydrocarbon and includes, but is not limited to, benzene, naphthalene, indene, anthracene, phenanthrene.
  • heteroaryl may be a monocyclic heteroaromatic, or a bicyclic fused-ring heteroaromatic group.
  • heteroaryl include, but are not limited to, pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, benzofuryl, 4-oxo-4,5,6,7-tetrahydro-l- benzofuryl, indolyl, isoindolyl, benzimidazolyl, 2-oxobenzoxazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl or triazolyl.
  • halogeno may be fluor, chlorine, bromine or iodine.
  • C 1-6 fluoroalkyl may be an alkyl substituted with one or more fluorine atoms.
  • fluoroalkyl include, but are not limited to, monofluoromethyl, trifluoromethyl, difluoromethyl and trifluoroethyl.
  • C 1-6 chloroalkyl may be an alkyl substituted with one or more chlorine atoms. Examples of said chloroalkyl include, but are not limited to, monochloromethyl, trichloromethyl, dichloromethyl and trichloroethyl.
  • R 1 is aryl or heteroaryl, optionally substituted with one or more of R 3 , OR 3 , NR 3 R 4 , halogeno or NO 2 ;
  • R 2 is R 5 , R 6 , COR 5 , COR 6 , CONHR 5 , CONHR 6 , COOR 6 or SO 2 R 6 ;
  • R >3 a a corpus of r R>4 are each independently hydrogen, C 1-6 alkyl or C 1-6 fluoroalkyl;
  • R 5 is aryl or heteroaryl each of which is optionally substituted with one or more of R 7 , OR 7 , COOR 7 , COR 7 , CONHOR 7 , NR 7 R 8 , SO 2 R 7 , SO 2 NR 7 R 8 , SR 7 , halogeno, oxygen and NO 2 ;
  • R 6 is hydrogen, C 1-6 alkyl, (C3 -8 cycloalkyl)C 1-6 alkyl, heterocycle, heterocycleC 1-6 alkyl, wherein any of C 1-6 alkyl, (C 3-8 cycloalkyl)C 1-6 alkyl or heterocycle is optionally substituted with one or more A;
  • R 7 and R 8 are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heterocycle, wherein any of C 1-6 alkyl is optionally substituted with one or more B;
  • R 9 and R 10 are each independently hydrogen, or . 6 alkyl, wherein any C 1-6 alkyl is optionally substituted with one or more B;
  • A is COOR 9 , COR 9 , CONR 9 R 10 , NHCOR 9 , NR 9 R 10 , SR 9 , R 9 SR 10 , or CN;
  • B is halogeno or di(C 1-6 alkyl)amino.
  • R 1 is aryl optionally substituted with one or more of R 3 , OR 3 and NR 3 R 4 .
  • R 5 is aryl, optionally substituted with one or more of R 7 , OR 7 , COOR 7 , COR 7 , CONHOR 7 , NR 7 R 8 , SO 2 R 7 , SO 2 NR 7 R 8 , SR 7 , halogeno, oxygen and NO 2 .
  • R 7 and R 8 are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, heterocycle, wherein C 1-6 alkyl is optionally substituted with one or more B, said B being halogeno.
  • R 6 is selected from hydrogen, C 1-6 alkyl, (C 3 .. 8 cycloalkyl)C 1-6 alkyl, heterocycle, heterocycleC 1-6 alkyl, wherein any of C 1-6 alkyl, (C 3-8 cycloalkyl)C 1-6 alkyl and heterocycle is optionally substituted with one or more A.
  • a compound of formula I wherein said A is selected from COOR 9 , COR 9 , CONR 9 R 10 , NHCOR 9 , NR 9 R 10 , SR 9 , R 9 SR 10 and CN; and R 9 and R 10 are each independently hydrogen or Ci- ⁇ alkyl.
  • the present invention relates to the use of compounds of formula I as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I. Such salts are possible, includes both pharmaceutically acceptable acid and base addition salts.
  • a suitable pharmaceutically-acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric; or, for example a salt of a compound of Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt, or a salt with an organic base.
  • Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
  • Certain compounds of the present invention may exist as tautomers. It is to be understood that the present invention encompasses all such tautomers.
  • N N'-Bis[3-(trifluoromethoxy)phenyl]-4,4'-bipyridine-2,2'-diamine; NN'-Bis(2-fluorophenyl)-4,4'-bipyridine-2,2'-diamine;
  • the present invention relates to novel pyridine derivatives, which are inhibitors of c-Jun ⁇ - terminal kinases (J ⁇ Ks). J ⁇ Ks have been implicated in mediating a number of disorders.
  • the invention relates to methods for producing these inhibitors.
  • the invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing these compositions in the treatment of various disorders.
  • a pharmaceutical composition comprising a compound of formula I, as a free base or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, for use in the prevention and/or treatment of conditions associated with c-Jun ⁇ -terminal kinases (J ⁇ Ks).
  • the composition may be in a form suitable for oral administration, for example as a tablet, for parenteral injection as a sterile solution or suspension.
  • the above compositions may be prepared in a conventional manner using pharmaceutically carriers or diluents.
  • Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man are approximately 0.01 to 250 mg kg body weight at peroral administration and about 0.001 to 250 mg/kg body weight at parenteral administration.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
  • a compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, can be used on its own but will usually be administered in the form of a pharmaceutical composition in which the formula I compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical composition may comprise from 0.05 to 99 %w (per cent by weight), for example from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • a diluent or carrier includes water, aqueous polyethylene glycol, magnesium carbonate, magnesium stearate, talc, a sugar (such as lactose), pectin, dextrin, starch, tragacanth, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose or cocoa butter.
  • a composition of the invention can be in tablet or injectable form.
  • the tablet may additionally comprise a disintegrant and/or may be coated (for example with an enteric coating or coated with a coating agentsuch as hydroxypropyl methylcellulose).
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula I, or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, a hereinbefore defined, with a pharmaceutically acceptable diluent or carrier.
  • An example of a pharmaceuticall composition of the invention is an injectable solution containing a compound of the invention, or a a pharmaceutically acceptable salt, solvate or solvate of salt thereof, as hereinbefore defined, and sterile water, and, if necessary, either sodium hydroxide or hydrochloric acid to bring the pH of the final composition to about pH 5, and optionally a surfactant to aid dissolution.
  • Liquid solution comprising a compound of formula I, or a salt thereof, dissolved in water.
  • the compounds of Formula I have activity as medicaments.
  • the compounds of formula I are potent JNK inhibitors and preferred compounds are selective JNK3 inhibitors.
  • the present invention provides a compound of Formula I for use as a medicament.
  • the present invention provides a compound of Formula I for use in the prevention or treatment of conditions associated with JNK activation.
  • the present invention provides a method of treating or preventing conditions associated with JNK activation comprising the administration of a therapeutically effective amount of a compound of Formula I to a mammal (particularly a human including a patient) in need thereof.
  • the present invention provides the use of a compound of Formula I in the manufacture of a medicament for the treatment of conditions associated with JNK activation.
  • Conditions that may be treated by the compounds of this invention, according to Formula I, or a pharmaceutical composition containing the same, include any condition associated with JNK activation.
  • Conditions associated with JNK activation include but are not limited to: central or peripheral neurological degenerative disorders including Alzheimer's disease, cognitive disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Frontotemporal dementia Parkinson's Type, Parkinson dementia complex of Gaum, HIV dementia, corticobasal degeneration, dementia pugilistica, Down's syndrome, postencephelatic parkinsonism, progressive supranuclear palsy, Pick's Disease, Niemann- Pick's Disease, epilepsy, a peripheral neuropathy, spinal cord injury, head trauma; autoimmune diseases including Multiple Sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, asthma, septic shock, transplant rejection; cardiovascular diseases including stroke, arterosclerosis, myocardial infarction, myocardial reperfusion injury; cancer including breast-,
  • JNK inhibitors of the instant invention may be capable of inhibiting the expression of inducible pro-inflammatory proteins. Therefore other conditions, which may be treated by the compounds of this invention, include edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.
  • the term “therapy” also includes “prevention” unless there are specific indications to the contrary.
  • the terms “therapeutic” and • “therapeutically” should be construed accordingly.
  • condition means any disorder and disease associated with JNK activity.
  • the compounds of formula I or salt thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of JNK inhibitor related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
  • the compounds of this invention may be prepared by methods known to those skilled in the art for analogous compounds, as illustrated by the general schemes and procedures below and by the preparative examples that follow.
  • the starting material compounds are commercially available, unless otherwise stated.
  • R 1 is as described above.
  • N,N'-bis-aryl-4.4'-bipyridine-2,2'-diamine The reaction is carried out at elevated temperature such as 120°C for an extended time such as 15 hours or in a microwave oven at 160°C for a shorter time such as lh. The reaction is monitored by chromatography until completion.
  • R 1 and R are as described above.
  • 4.4'-bipyridine-2,2'-diamine is reacted with an arylhalide with a transition metal catalyst such as a copper or a palladium catalyst in the presence of a base such as sodium tert-butoxide (palladium) or potassium phosphate (copper) in an ether or hydrocarbon solvent to give an N-aryl-4.4'-bipyridine-2,2'-diamine (intermediate).
  • the reaction is carried out at room temperature or at an elevated temperature such as 80 to 100°C for an extended time such as 15 hours or in a microwave oven at 160°C for a shorter time such as lh.
  • the reaction is monitored by chromatography until completion. After purification by chromatography the intermediate is subjected to a second arylation reaction to obtain a unsymmetrical N,N-diaryl-4.4'-bipyridine-2,2'-diamine.
  • R 1 , R 5 and R 6 are as described above.
  • the intermediate is reacted with a carboxylic acid in the presence of a peptide or amide coupling reagent such as TBTU and HOBt and a base such as , diisopropylethylamine in an inert solvent such as DMF.
  • a peptide or amide coupling reagent such as TBTU and HOBt
  • a base such as , diisopropylethylamine
  • the reaction is carried out at 25°C for a time of 1 to 8 days to give a carboxamide.
  • the intermediate is reacted with a carboxylic acid chloride in an inert solvent such as dichloromethane in the presence of a base or in a solvent such as pyridine at 0 to 25°C for lh to 12h to give a carboxamide.
  • carbamates and sulfonamides can be prepared from chlorocarbonates or sulfonylchlorides. The reaction is monitored by chromatography.
  • R 1 , R 5 and R 6 are as described above.
  • Method 4 the intermediate is reacted with a carboxylic acid as in Method 3 followed by reduction to the amine with a reducing agent such as lithium aluminium hydride or another hydride reagent in a solvent such as THF.
  • a reducing agent such as lithium aluminium hydride or another hydride reagent in a solvent such as THF.
  • the reaction is preferably carried out at elevated temperature such as 65°C for a time about 12 hours.
  • the intermediate is reacted with a carboxaldehyde in the presence of a reducing agent such as a borohydride reagent.
  • the reaction is carried out at a temperature such as 25 °C for a time of about 12 hours.
  • Method 5 the intermediate is reacted with an isocyanate in a solvent such as dioxane.
  • the reaction is preferably carried out at a temperature of 25°C for a time about 16 hours.
  • the present invention provides a process for the preparation of a compound of Formula I comprising the reaction of a compound of Formula LT:
  • R 1 is aryl or heteroaryl each of which is optionally substituted with one or more of the following R 3 , OR 3 , OCOR 3 , COOR 3 , COR 3 , CONR 3 R 4 , NHCOR 3 , NR 3 R 4 ,
  • R 3 and R 4 are each independently hydrogen, halogeno, C 1-6 alkyl, C 1-6 alkyl optionally substituted by NR 3 R 4 , C 3-8 cycloalkyl, C 3-6 alkenyl, C 3-6 alkenyl optionally substituted by NR 3 R 4 , (C 3-8 cycloalkyl)C 1-6 alkyl, heterocycle, hetrocycleC 1-6 alkyl, C 1-6 fluoroalkyl, or alternatively NR 3 R 4 can form a ring having 3 to 7 atoms, said ring optionally including one or more additional hetero atoms being optionally substituted with one or more A;
  • A is C 1-6 alkyl or halogeno
  • Compounds of Formula LT are novel, useful intermediates and are claimed as a further •aspect of the present invention.
  • Compounds according to Formula LT is exemplified by, but not limited to: N-Phenyl-4,4'-bipyridine-2,2'-di amine; N-(4-Fluorophenyl)-4,4'-bipyridine-2,2'-di amine; as a free base or a salt, solvate or solvate of salt thereof.
  • CDC1 3 1H NMR TMS (0.0 ppm) and 13 C the central peak of CDC1 3 (77.0).
  • CD 3 OD 1H NMR 3.31 ppm (central peak) and 13 C 49.0 ppm (central peak).
  • 2,2'-Dichloro-(4,4')-bipyridine 50 mg, 0.22 mmol
  • palladium acetate 5.6 mg, 0.022 mmol
  • bis[tri-(tert-butyl)phosphine]palladium 12.5 mg, 0.022 mmol
  • sodium tert- butoxide 60 mg, 0.61 mmol
  • 4-trifluoromethylaniline 0.3 mL, 2.4 mmol
  • 2,2'-dichloro-(4,4')-bipyridine 50 mg, 0.22 mmol
  • palladium acetate 5.6 mg, 0.022 ' mmol
  • bis[tri-(tert-butyl)phosphine]palladium 12.5 mg, 0.022 mmol
  • sodium tert-butoxide 60 mg, 0.61 mmol
  • 4-fluoroaniline 0.3 mL, 3.1 mmol
  • 2,2'-dichloro-(4,4')-bipyridine 50 mg, 0.22 mmol
  • palladium acetate 5.6 mg, 0.022 mmol
  • bis[tri-(tert-butyl)phosphine]palladium 12.5 mg, 0.022 mmol
  • sodium tert- butoxide 60 mg, 0.61 mmol
  • 3,4-difluoroaniline 0.5 mL, 4.0 mmol
  • 2,2'-dichloro-(4,4')-bipyridine 50 mg, 0.22 mmol
  • palladium acetate 5.6 mg, 0.022 mmol
  • bis[tri-(tert-butyl)phosphine]palladium 12.5 mg, 0.022 mmol
  • sodium tert- butoxide 60 mg, 0.61 mmol
  • 3-trifluoromethylaniline 0.5 mL, 4.0 mmol
  • Example 5 N,N , -Bis[3-(trifluoromethoxy)phenyl]-4,4'-bipyridine-2,2'-diamine 2,2'-dichloro-(4,4')-bipyridine (22.5 mg, 0.10 mmol), palladium acetate (3.0 mg, 0.013 mmol), bis[tri-(tert-butyl)phosphine]palladium (7.05 mg, 0.013 mmol), sodium tert- butoxide (36 mg, 0.375 mmol) and 3-trifluoromethoxylaniline (0.5 mL, 3.1 mmol) were flushed in a Schlenk tube for 10 min with nitrogen.
  • N,N'-Bis(2-fluorophenyl)-4,4 ' -bipyridine-2,2 ' -diamine 2,2'-dichloro-(4,4')-bipyridine (22.5 mg, 0.10 mmol), palladium acetate (3.0 mg, 0.013 mmol), bis[tri-(tert-butyl)phosphine]palladium (7.05 mg, 0.013 mmol), sodium tert- butoxide (36 mg, 0.375 mmol) and 2-fluorolaniline (0.5 mL, 5.2 mmol) were flushed in a Schlenk tube for 10 min with nitrogen.
  • 2,2'-dichloro-(4,4')-bipyridine 50 mg, 0.22 mmol
  • palladium acetate 5.6 mg, 0.022 mmol
  • bis[tri-(tert-butyl)phosphine]palladium 12.5 mg, 0.022 mmol
  • sodium tert- butoxide 60 mg, 0.61 mmol
  • 2-aminoaniline 144 mg, 1.33 mmol
  • Example 9 iy,N , -Bis(2-methoxyphenyl)-4,4'-bipyridine-2,2'-diamine 2,2'-dichloro-(4,4')-bipyridine (50 mg, 0.22 mmol), palladium acetate (5.6 mg, 0.022 mmol), bis[tri-(tert-butyl)phosphine]palladium (12.5 mg, 0.022 mmol), sodium tert-butoxide (60 mg, 0.61 mmol) and 2-methoxyaniline (0.5 mL, 4.4 mmol) were flushed in a Schlenk tube for 10 min with nitrogen.
  • Example 10 N,N'-Bis(2-ethoxyphenyl)-4,4'-bipyridine-2,2'-diamine 2,2'-dichloro-(4,4')-bipyridine (50 mg, 0.22 mmol), palladium acetate (5.6 mg, 0.022 mmol), bis[tri-(tert-butyl)phosphine]palladium (12.5 mg, 0.022 mmol), sodium tert- butoxide (60 mg, 0.61 mmol) and 2-ethoxyaniline (0.5 mL, 3.3 mmol) were flushed in a Schlenk tube for 10 min with nitrogen.
  • 4,4'-bipyridine-2,2'-diamine (described in J.Org.Chem. 1997 vol. 62 p. 2774-2781) (744 mg, 4.0 mmol), iodobenzene (0.448 mL, 4.0 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (208 mg, 0.2 mmol), 1,1'- bis(diphenylphosphino)ferrocene (220 mg, 0.4 mmol) and sodium tert-butoxide (538 mg, 5.6 mmol) were flushed under nitrogen for 20 min. in a 100 mL round bottom flask.
  • 4,4'-bipyridine-2,2'-diamine (187 mg, 1.0 mmol), 4-fluoroiodobenzene (222 mg, 1.0 mmol), copper iodide (10 mg, 0.05 mmol), potassium phosphate (425 mg, 2.0 mmol), ethylene glycol (111 ⁇ L, 2.0 mmol), 2-propanol (1.0 mL) and dry dimethylformamide (1.0 mL) were flushed in a screw-capped test tube for 10 min with nitrogen. The tube was sealed and put into the microwave oven at 160°C for lh. Water (5 mL) was added and the mixture was extracted with ethyl acetate (4 x 5 mL).
  • Ethyldiisopropylamine (129 mg, 1.0 mmol) was slowly added to a solution of ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-o-(benzotriazol-l-yl)uronium tetrafluoroborate (241 mg, 0.75 mmol), hydroxybenzotriazole (101 mg, 0.75 mmol) and 4-methoxycylohexanecarboxylic acid (78 mg, 0.5 mmol) in 3 mL of acetonitrile under nitrogen at 20 °C.
  • Oxalyl chloride (171 mg, 1.35 mmol) was slowly added to a solution of 4-methoxy- cylohexanecarboxylic acid (70 mg, 0.45 mmol) in 2 mL of dichloromethane under nitrogen at 20 °C. After 30 min of stirring, the mixture was concentrated under vacuum to afford a colorless oil which was diluted in 1.0 mL of dichloromethane. This solution was then added to a solution of N-(2-fluorophenyl-4,4'-bipyridine-2,2'-diamine (127 mg, 0.45 mmol) in 5 mL of pyridine.
  • Examples 20-27 Compounds 20-27 were prepared according to the procedure set forth in Example 19, using the appropriate bromoaryl or bromoheteroaryl derivative and N-phenyl-4,4'-bipyridine- 2,2'-diamine prepared as described in example 11.
  • Tetrahydrofuran-3-carboxylic acid (11.6 mg, 0.1 mmol) was dissolved in dichloromethane (0.5 ml) under nitrogen. Dimethylformamide (50 uL) is added. Oxalyl chloride (43 uL, 0.5 mmol) was dissolved in dichloromethane (0.5 ml) and added dropwise to the carboxylic acid. After 10 minutes of stirring the solution was evaporated to dryness, dissolved in dichloromethane (1 ml), and evaporated again to dryness.
  • 3-Piperidin-l-ylpropanoic acid (15.7 mg, 0.1 mmol) is weighed into a 5 ml glass tube.
  • Dichloromethane (1 mL) is added followed by dimethylformamide: dichloromethane (1:10, 50 uL).
  • Oxalyl chloride 43 uL, 0.5 mmol diluted with dichloromethane (60 uL) is added.
  • the mixture is agitated at room temperature under argon for 2 hours, or until bubbling has ceased and a homogenous solution is obtained.
  • the 15 N experiments were performed on a Bruker DRX600 NMR Spectrometer, operating at 600 MHz for proton 60 MHz for nitrogen- 15 and equipped with a 5mm TXI probe with Z-gradients. The experiments were performed at 22 degrees Centigrade.
  • N-phenyl-4,4'-bipyridine-2,2'-diamme 72 uL, 0.5 M in dioxane, 0.036 mmol
  • dioxane 200 uL
  • the plate was agitated on an orbital shaker at room temperature for 16 hours. Precipitated material was filtered off and dissolved in dimethylsulfoxide.
  • Example 170 N-(2 , -aniIino-4,4'-bipyridin-2-yl)piperidine-4-carboxamide Procedure as example 14. Reaction with l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid for 8 days. Reverse phase chromatography was followed by boc removal with TFA/ CH C1 2 1:1. A second reverse phase chromatography gave 16 mg (17%) of the title compound as the free base.
  • N-phenyl-4,4'-bipyridine-2,2'-diamine 50 mg, 0.19 mmol was dissolved in pyridine (2 mL) and acetyl chloride (14 ⁇ L, 0.20 mmol) was added at 0°C and stirred lh at 25°C followed by concentration in vacuo. Purification by reverse phase chromatography gave 16 mg (27%) of the title compound as the free base.
  • Tetrahydro-27 -pyran-4-carboxylic acid (83 mg, 0.64 mmol) was dissolved in 4 mL of thionyl chloride and the solution was stirred for 30 min at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 1 mL dichloromethane.
  • 3-Ethoxy-3-oxopropanoic acid 33 mg, 0.25 mmol
  • N-[(dimethylamino)(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate 142mg, 0.375 mmol
  • Diisopropylethylamine 64 mg, 87 ⁇ L, 0.575 mmol
  • 3-Thiomethoxy propanoic acid 33 mg, 0.25 mmol
  • N-[(dimethylamino)(377- [ 1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate 142mg, 0.375 mmol
  • Diisoprylethylamine 64 mg, 87 ⁇ L, 0.575 mmol
  • N-phenyl-4,4' - bipyridine-2,2'-diamine 131 mg, 0.50 mmol
  • dry N, N-dimethylformamide 2 mL
  • the mixture was poured on a saturated aqueous solution of ⁇ aHC ⁇ 3 (20 mL) and extracted with ethyl acetate (3x20 mL).
  • the organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum to afford a crude product which was purified by flash chromatography (ethyl acetate/methanol : 95/5). Yield : 87 % (207 mg).
  • N-phenyl- 4,4'-bipyridine-2,2'-diamine 65 mg, 0.25 mmol
  • dry N N-dimethylformamide lmL
  • the mixture was poured on a saturated aqueous solution of ⁇ aHC ⁇ 3 (5 mL) and extracted with ethyl acetate (3x10 mL).
  • the organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum to afford a crude product which was diluted in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) was added. After 15h stirring, the solvent were evaporated under vacuum.
  • the crude material was diluted in ethyl acetate and washed 3 times with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.
  • the crude material was purified by HPLC : column : XTerra® prep MSC 8 , gradient 20-80%B, 20mL/min, 40°C, (A-0.1M NHtOAc in 0.1% CH 3 CN aqueous solution, B-CH 3 CN). Yield : 12% (11 mg).
  • Example 187 N 1 -(2'-anilino-4,4 , -bipyridin-2-yl)cyclopropane-l,l-dicarboxamide l-(aminocarbonyl)cyclopropanecarboxylic acid (32 mg, 0.25 mmol) and N- [(dimethylamino)(3H-[ 1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N- methylmethanaminium hexafluorophosphate (142 mg, 0.375 mmol) were diluted in 4 mL of dry N, N-dimethylformamide under a nitrogen atmosphere.
  • Ethyldiisopropylamine (129 mg, 1.0 mmol) was slowly added to a solution of N,N,N',N'- tetramethyl-o-(benzotriazol-l-yl)uronium tetrafluoroborate (321 mg, 1.0 mmol), hydroxybenzotriazole (137 mg, 1.0 mmol) and l-acetylpiperidine-3-carboxylic acid (171 mg, 1.0 mmol) in 3 mL of DMF under nitrogen at 20 °C.
  • NNN'.N'-tetramethyluronium hexafluorophosphate (342 mg, 0.90 mmol) were diluted in 6 mL of dry ⁇ , ⁇ -dimethylformamide under a nitrogen atmosphere.
  • Diisopropylethylamine (74 mg, lOOuL, 0.575 mmol) was added dropwise.
  • a solution of N-(4- fluorophenyl)-4,4'-bipyridine-2,2'-diamine 140 mg, 0.50 mmol
  • dry ⁇ , ⁇ - dimethylformamide (2mL) was slowly added and the mixture stirred for 15h at 20 C.
  • Example 193 4-( ⁇ 2'-[(4-Fluorophenyl)amino]-4,4'-bipyridin-2-yl ⁇ amino)-4-oxobutanoic acid
  • Ethyl 4-( ⁇ 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl ⁇ amino)-4-oxobutanoate (50 mg, 0.12 mmol) was diluted in a mixture of ethanol/water/THF (5/5/3 mL). 2 mL of a 2M aqueous solution of sodium hydroxide were added and the reaction mixture was stirred for lh at room temperature.
  • N-phenyl-4,4'-bipyridine-2,2'-diamine 131 mg, 0.50 mmol was dissolved in 5 mL of methanol and 2-formylcyclopropanecarboxylic acid ethyl ester (85 mg, 0.60 mmol) was added. After cooling at 0°C, acetic acid was added until pH 4 and the reaction was stirred for 15 min at this temperature. Then sodium cyanoborohydride (38 mg, 0.60 mmol) was added and the mixture was allowed to warm to room temperature and the reaction was followed by TLC until completion. The solution was washed with a saturated aqueous solution of ⁇ aHC ⁇ 3 (20 mL) and extracted with ethyl acetate.
  • Example 202 N-phenyI-N'-(tetrahydro-2fl r -pyran-4-ylmethyl)-4,4'-bipyridine-2,2'-diamine N-(2'-anilmo-4,4'-bipyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide (59 mg, 0.157 mmol) was dissolved in THF (5 mL) under ⁇ 2 atmosphere and the solution was cooled at 0°C. A solution of DIB AL IM in hexane (2 ml, 2.0 mmol) was added dropwise and the solution was stirred at 25°C for 15h. H 2 O (2 mL) was added and stirring continued for 30 min.
  • N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide (43 mg, 0.12 mmol) was dissolved in THF (5 mL) under ⁇ 2 atmosphere and the solution was cooled at 0°C. A solution of DLB AL IM in hexane (2 ml, 2.0 mmol) was added dropwise and the solution was stirred at 25°C for 15h. H 2 O (2 mL) was added and stirring continued for 30 min. The solution was filtered on a celite pad and extracted with ethyl acetate. The organic layer was concentrated under vacuum and the crude material purified by HPLC. The product was treated with 1 eq.
  • the compounds of this invention may be assayed for their activity according to the following procedure:
  • a scintillation proximity assay (SPA) based on the inhibition of JNK3 catalyzed transfer of the ⁇ -phosphate group of [ ⁇ - 33 P] ATP to biotinylated ATF2, has been set up to identify inhibitory compounds.
  • the resulting 33 P-labeled biotinylated ATF2 is trapped on SPA beads surface coated with streptavidin.
  • the assay is performed in 96-well plates. Test compounds made up at 10 mM in DMSO and 1:3 serial dilutions are made in 100% DMSO. These serial dilutions are then diluted 1: 10 in assay buffer (50 mM MOPS pH 7.2, 150 mM, NaCI, 0.1 mM EGTA, 1 mM DTT, 6.25 mM ⁇ -glycerolphosphate) and 10 ⁇ l are transferred to assay plates (results in 2% DMSO final concentration in assay).
  • assay buffer 50 mM MOPS pH 7.2, 150 mM, NaCI, 0.1 mM EGTA, 1 mM DTT, 6.25 mM ⁇ -glycerolphosphate
  • JNK3/ATP enzyme solution (1.18 U/ml JNK3, 20 ⁇ M ATP, 2 mM Mg(Ac)2, 0.01 % Brij-35 in assay buffer) was added. The mixture was pre-incubated for 10 minutes at ambient temperature.
  • reaction was terminated by the addition of 200 ⁇ l per well of stop buffer/bead mix (0.4 mg/ml streptavidin coated SPA-beads in 50 mM EDTA, pH 7.6). Plates were sealed with a plastic cover and centrifuged (2000 rpm, 5 minutes) to settle the beads followed by counting in a Wallac 1450 microbetaTM.
  • the IC 50 values were calculated as the concentration of test compound at which the ATF2 phosphorylation is reduced to 50% of the control value.
  • Typical K, values for the compounds of the present invention are in the range of about 0.001 to about 10,000 nM.
  • Other values for Kj are in the range of about 0.001 to about
  • Ki 1000 nM. Further values for Ki are in the range of about 0.001 nM to about 300 nM.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés représentés par la formule (I) dans laquelle R1 est aryle ou hétéroaryle, chacun étant éventuellement substitué avec un ou plusieurs substituants du groupe R3, OR3, OCOR3, COOR3, COR3, CONR3R4, NHCOR3, NR3R4, NHSO2R3, SO2R3, SO2NR3R4, SR3, CN, halogeno ou NO2; et, R2 est R5, R6, COR5, COR6, CONHR5, CONHR6, CON(R6)2, COOR5, COOR6, SO2R5 ou SO2R6. L'invention concerne également un procédé de fabrication desdits composés, des intermédiaires employés dans ledit procédé, des formulations pharmaceutiques contenant lesdits composés thérapeutique actifs, et l'utilisation desdits composés en thérapie.
PCT/SE2003/001911 2002-12-09 2003-12-08 Derives pyridine servant d'inhibiteurs de jnk et utilisation Ceased WO2004052880A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003302919A AU2003302919A1 (en) 2002-12-09 2003-12-08 Pyridine derivatives as jnk inhibitors and their use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0203654-9 2002-12-09
SE0203654A SE0203654D0 (sv) 2002-12-09 2002-12-09 New compounds

Publications (1)

Publication Number Publication Date
WO2004052880A1 true WO2004052880A1 (fr) 2004-06-24

Family

ID=20289817

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2003/001911 Ceased WO2004052880A1 (fr) 2002-12-09 2003-12-08 Derives pyridine servant d'inhibiteurs de jnk et utilisation

Country Status (5)

Country Link
AR (1) AR042316A1 (fr)
AU (1) AU2003302919A1 (fr)
SE (1) SE0203654D0 (fr)
TW (1) TW200417546A (fr)
WO (1) WO2004052880A1 (fr)

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118543A1 (fr) * 2004-06-03 2005-12-15 Ono Pharmaceutical Co., Ltd. Inhibiteur des kinases et utilisation de cet inhibiteur
WO2007132307A1 (fr) 2006-05-09 2007-11-22 Pfizer Products Inc. Dérivés d'acide cycloalkylaminé et compositions pharmaceutiques à base de ceux-ci
JP2008526724A (ja) * 2004-12-31 2008-07-24 プロシディオン・リミテッド Ｇｐｃｒ作動薬としてのピリジン、ピリミジン、およびピラジンの誘導体
WO2008079933A3 (fr) * 2006-12-22 2008-12-04 Novartis Ag Composés organiques et leurs utilisations
WO2008082487A3 (fr) * 2006-12-20 2008-12-31 Schering Corp Nouveaux inhibiteurs de jnk
EP1613595A4 (fr) * 2003-04-04 2009-04-01 Irm Llc Nouveaux composes et compositions utilises comme inhibiteurs de la proteine kinase
WO2009107391A1 (fr) * 2008-02-27 2009-09-03 武田薬品工業株式会社 Composé contenant un cycle aromatique à 6 chaînons
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
EP2308866A1 (fr) 2009-10-09 2011-04-13 Bayer CropScience AG Phenylpyri(mi)dinylpyrazoles et leur utilisation comme fongicides
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
WO2012101063A1 (fr) * 2011-01-28 2012-08-02 Novartis Ag Composés de n-acyl pyridine biaryl et leurs utilisations
WO2012101064A1 (fr) * 2011-01-28 2012-08-02 Novartis Ag Composés à base de n-acyl-pyrimidine-biaryl convenant comme inhibiteurs de protéine kinase
WO2012035421A3 (fr) * 2010-09-17 2012-09-07 Purdue Pharma L.P. Composés de pyridine et ses utilisations
WO2012175513A1 (fr) 2011-06-20 2012-12-27 Bayer Intellectual Property Gmbh Thiénylpyri(mi)dinylpyrazole
WO2013050434A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyri(mi)dinylpyrazole
WO2013050437A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyridinylpyrazole et hétérocyclylpyrimidinylpyrazole utilisés comme fongicides
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
US8778951B2 (en) 2009-07-30 2014-07-15 Novartis Ag Heteroaryl compounds and their uses
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US20150315180A1 (en) * 2012-11-03 2015-11-05 Boehringer Ingelheim International Gmbh Inhibitors of cytomegalovirus
WO2016055790A1 (fr) * 2014-10-08 2016-04-14 Redx Pharma Plc Dérivés n-pyridinyl acétamide comme inhibiteurs de la oie de signalisation wnt
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
CN113227077A (zh) * 2018-12-13 2021-08-06 英特维特国际股份有限公司 一种制备1-[(3r,4s)-4-氰基四氢吡喃-3-基]-3-[(2-氟-6-甲氧基-4-吡啶基)氨基]吡唑-4-甲酰胺的方法
CN115417809A (zh) * 2022-09-05 2022-12-02 天津药明康德新药开发有限公司 一种4,4-二吡咯-2,2-联吡啶的制备方法
US11643408B2 (en) 2014-10-08 2023-05-09 Redx Pharma Plc N-pyridinyl acetamide derivatives as inhibitors of the WNT signaling pathway
CN116836153A (zh) * 2023-06-16 2023-10-03 厦门大学 一种CDK9-Cyclin T1蛋白相互作用抑制剂及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004012A (en) * 1975-10-14 1977-01-18 Sterling Drug Inc. 3-Cyano-5-(pyridinyl)-2(1H)-pyridinones
WO1997032589A1 (fr) * 1996-03-07 1997-09-12 Novartis Ag Combinaisons destinees au traitement de maladies proliferatives
WO1999032448A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Compose de pyridine et de pyridazine substituees et leurs utilisations pharmaceutiques
WO2002046184A1 (fr) * 2000-12-05 2002-06-13 Vertex Pharmaceuticals Incorporated Inhibiteurs de kinases c-jun n-terminales (jnk) et d'autres proteines kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004012A (en) * 1975-10-14 1977-01-18 Sterling Drug Inc. 3-Cyano-5-(pyridinyl)-2(1H)-pyridinones
WO1997032589A1 (fr) * 1996-03-07 1997-09-12 Novartis Ag Combinaisons destinees au traitement de maladies proliferatives
WO1999032448A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Compose de pyridine et de pyridazine substituees et leurs utilisations pharmaceutiques
WO2002046184A1 (fr) * 2000-12-05 2002-06-13 Vertex Pharmaceuticals Incorporated Inhibiteurs de kinases c-jun n-terminales (jnk) et d'autres proteines kinases

Cited By (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
EP1613595A4 (fr) * 2003-04-04 2009-04-01 Irm Llc Nouveaux composes et compositions utilises comme inhibiteurs de la proteine kinase
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
WO2005118543A1 (fr) * 2004-06-03 2005-12-15 Ono Pharmaceutical Co., Ltd. Inhibiteur des kinases et utilisation de cet inhibiteur
JP2008526724A (ja) * 2004-12-31 2008-07-24 プロシディオン・リミテッド Ｇｐｃｒ作動薬としてのピリジン、ピリミジン、およびピラジンの誘導体
JP4916452B2 (ja) * 2004-12-31 2012-04-11 プロシディオン・リミテッド Ｇｐｃｒ作動薬としてのピリジン、ピリミジン、およびピラジンの誘導体
US7671043B2 (en) 2006-05-09 2010-03-02 Pfizer Inc Cycloalkylamino acid derivatives
EP2258700A1 (fr) * 2006-05-09 2010-12-08 Pfizer Products Inc. Dérivés d'acides aminés cycloalkyles et compositions pharmaceutiques les contenant
WO2007132307A1 (fr) 2006-05-09 2007-11-22 Pfizer Products Inc. Dérivés d'acide cycloalkylaminé et compositions pharmaceutiques à base de ceux-ci
NL2000627C2 (nl) * 2006-05-09 2009-03-17 Pfizer Prod Inc Cycloalkylaminoderivaten.
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
WO2008082487A3 (fr) * 2006-12-20 2008-12-31 Schering Corp Nouveaux inhibiteurs de jnk
US8278337B2 (en) 2006-12-20 2012-10-02 Merck Sharp & Dohme Substituted pyridines that are JNK inhibitors
WO2008079933A3 (fr) * 2006-12-22 2008-12-04 Novartis Ag Composés organiques et leurs utilisations
JP2010514689A (ja) * 2006-12-22 2010-05-06 ノバルティス アーゲー 癌、炎症およびウイルス感染症の処置のためのｃｄｋ阻害剤としてのヘテロアリール−ヘテロアリール化合物
US9469640B2 (en) 2007-07-17 2016-10-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9844539B2 (en) 2007-07-17 2017-12-19 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US10426760B2 (en) 2007-07-17 2019-10-01 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2009107391A1 (fr) * 2008-02-27 2009-09-03 武田薬品工業株式会社 Composé contenant un cycle aromatique à 6 chaînons
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
US8778951B2 (en) 2009-07-30 2014-07-15 Novartis Ag Heteroaryl compounds and their uses
US8741920B2 (en) 2009-08-03 2014-06-03 Hoffmann-La Roche, Inc. Process for the manufacture of pharmaceutically active compounds
EP2308866A1 (fr) 2009-10-09 2011-04-13 Bayer CropScience AG Phenylpyri(mi)dinylpyrazoles et leur utilisation comme fongicides
WO2011042389A2 (fr) 2009-10-09 2011-04-14 Bayer Cropscience Ag Phenylpyri(mi)dinylazoles
EP2784071A1 (fr) 2009-10-09 2014-10-01 Bayer CropScience AG 3-phenyl-4-pyri(mi)dinyl-1h-pyrazoles et leur utilisation comme fongicides
EP2784073A1 (fr) 2009-10-09 2014-10-01 Bayer CropScience AG 3-phenyl-4-pyri(mi)dinyl-1h-pyrazoles et leur utilisation comme fongicides
EP2784072A1 (fr) 2009-10-09 2014-10-01 Bayer CropScience AG 3-phenyl-4-pyri(mi)dinyl-1h-pyrazoles et leur utilisation comme fongicides
EP2784070A1 (fr) 2009-10-09 2014-10-01 Bayer CropScience AG 3-phenyl-4-pyri(mi)dinyl-1h-pyrazoles et leur utilisation comme fongicides
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
JP2013538227A (ja) * 2010-09-17 2013-10-10 パーデュー、ファーマ、リミテッド、パートナーシップ ピリジン化合物およびその使用
US9056832B2 (en) 2010-09-17 2015-06-16 Purdue Pharma L.P. Pyridine compounds and the users thereof
US9611222B2 (en) 2010-09-17 2017-04-04 Purdue Pharma L.P. Pyridine compounds and the uses thereof
US20130303526A1 (en) * 2010-09-17 2013-11-14 Purdue Pharma L.P. Pyridine Compounds and the Uses Thereof
WO2012035421A3 (fr) * 2010-09-17 2012-09-07 Purdue Pharma L.P. Composés de pyridine et ses utilisations
WO2012101063A1 (fr) * 2011-01-28 2012-08-02 Novartis Ag Composés de n-acyl pyridine biaryl et leurs utilisations
WO2012101064A1 (fr) * 2011-01-28 2012-08-02 Novartis Ag Composés à base de n-acyl-pyrimidine-biaryl convenant comme inhibiteurs de protéine kinase
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US12076322B2 (en) 2011-02-07 2024-09-03 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US8865735B2 (en) 2011-02-21 2014-10-21 Hoffman-La Roche Inc. Solid forms of a pharmaceutically active substance
WO2012175513A1 (fr) 2011-06-20 2012-12-27 Bayer Intellectual Property Gmbh Thiénylpyri(mi)dinylpyrazole
WO2013050437A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyridinylpyrazole et hétérocyclylpyrimidinylpyrazole utilisés comme fongicides
WO2013050434A1 (fr) 2011-10-06 2013-04-11 Bayer Intellectual Property Gmbh Hétérocyclylpyri(mi)dinylpyrazole
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
JP2015536947A (ja) * 2012-11-03 2015-12-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング サイトメガロウイルスの阻害剤
EP2914591B1 (fr) * 2012-11-03 2017-10-11 Boehringer Ingelheim International GmbH Inhibiteurs de cytomégalovirus
US20150315180A1 (en) * 2012-11-03 2015-11-05 Boehringer Ingelheim International Gmbh Inhibitors of cytomegalovirus
US9284310B2 (en) * 2012-11-03 2016-03-15 Boehringer Ingelheim International Gmbh Inhibitors of cytomegalovirus
US10202375B2 (en) 2014-10-08 2019-02-12 Redx Pharma Plc N-pyridinyl acetamide derivatives as Wnt signalling pathway inhibitors
WO2016055790A1 (fr) * 2014-10-08 2016-04-14 Redx Pharma Plc Dérivés n-pyridinyl acétamide comme inhibiteurs de la oie de signalisation wnt
JP2017530985A (ja) * 2014-10-08 2017-10-19 レッドエックス ファーマ ピーエルシー Ｗｎｔシグナル経路阻害剤としてのＮ‐ピリジニルアセトアミド誘導体
US10793562B2 (en) 2014-10-08 2020-10-06 Redx Pharma Plc N-pyridinyl acetamide derivatives as Wnt signalling pathway inhibitors
CN106795157B (zh) * 2014-10-08 2019-07-23 莱德克斯制药公共有限公司 作为Wnt信号传送途径的抑制剂的N-吡啶基乙酰胺衍生物
CN106795157A (zh) * 2014-10-08 2017-05-31 莱德克斯制药公共有限公司 作为Wnt信号传送途径的抑制剂的N‑吡啶基乙酰胺衍生物
US11459326B2 (en) 2014-10-08 2022-10-04 Redx Pharma Plc N-pyridinyl acetamide derivatives as Wnt signalling pathway inhibitors
EP4071150A1 (fr) * 2014-10-08 2022-10-12 Redx Pharma Plc Dérivés n-pyridinyle acétamide comme inhibiteurs de la voie de signalisation wnt
US12202826B2 (en) 2014-10-08 2025-01-21 Redx Pharma Plc N-pyridinyl acetamide derivatives as inhibitors of the Wnt signaling pathway
US11643408B2 (en) 2014-10-08 2023-05-09 Redx Pharma Plc N-pyridinyl acetamide derivatives as inhibitors of the WNT signaling pathway
CN113227077A (zh) * 2018-12-13 2021-08-06 英特维特国际股份有限公司 一种制备1-[(3r,4s)-4-氰基四氢吡喃-3-基]-3-[(2-氟-6-甲氧基-4-吡啶基)氨基]吡唑-4-甲酰胺的方法
CN113227077B (zh) * 2018-12-13 2024-10-29 英特维特国际股份有限公司 一种制备1-[(3r,4s)-4-氰基四氢吡喃-3-基]-3-[(2-氟-6-甲氧基-4-吡啶基)氨基]吡唑-4-甲酰胺的方法
US12479835B2 (en) 2018-12-13 2025-11-25 Intervet Inc. Process for preparing 1-([3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide
CN115417809A (zh) * 2022-09-05 2022-12-02 天津药明康德新药开发有限公司 一种4,4-二吡咯-2,2-联吡啶的制备方法
CN116836153A (zh) * 2023-06-16 2023-10-03 厦门大学 一种CDK9-Cyclin T1蛋白相互作用抑制剂及其应用

Also Published As

Publication number Publication date
AR042316A1 (es) 2005-06-15
TW200417546A (en) 2004-09-16
SE0203654D0 (sv) 2002-12-09
AU2003302919A1 (en) 2004-06-30

Similar Documents

Publication Publication Date Title
WO2004052880A1 (fr) Derives pyridine servant d'inhibiteurs de jnk et utilisation
KR102475498B1 (ko) 리신 특이적 데메틸라아제-1의 억제제
KR102438302B1 (ko) 리신 특이적 데메틸라제-1의 억제제
KR102400920B1 (ko) 리신 특이적 데메틸라제-1의 억제제
RU2606497C2 (ru) Тиазолилфенилбензолсульфонамидопроизводные в качестве ингибиторов киназ
KR101663277B1 (ko) TNIK, IKKε 및 TBK1 억제제로서의 피라졸계 유도체 및 이를 포함하는 약학적 조성물
JP3989444B2 (ja) 新規な化合物
KR101913441B1 (ko) 키나제 억제제로서 치환된 피라졸로-퀴나졸린 유도체
KR102450671B1 (ko) 리신 특이적 데메틸라제-1의 저해제
US20050113370A1 (en) Therapeutic substituted indazole derivatives
TW202016094A (zh) 週期素依賴性激酶抑制劑
MX2011006171A (es) Compuestos de carbazol carboxamida utiles como inhibidores de cinasa.
JP2007507428A (ja) 置換ベンズアゾールおよびＲａｆキナーゼのインヒビターとしてのその使用
KR20030010739A (ko) 아자인돌 유도체, 이의 제조방법 및 항종양제로서의 이의용도
JP2003532730A (ja) 細胞増殖抑制剤として有用な１，１−ジオキソイソチアゾリジンを持つインダゾール
KR20160131119A (ko) TrkA 키나제 억제제, 조성물 및 그의 방법
JP2013530237A (ja) Ｒｈｏキナーゼインヒビター
KR20160079092A (ko) Gsk-3 억제제로서 유용한 치환된 피리딘 유도체
WO2013100672A1 (fr) Dérivé d'indazole 3,6-disubstitué ayant une activité d'inhibition de protéine kinase
EP3523292A1 (fr) Composés hétéroaryle et leur utilisation en tant qu'inhibiteurs de mer
KR20120133377A (ko) 단백질 키나아제 억제제로서 3,4-디아릴피아졸의 설폰아미도 유도체
WO2005003123A1 (fr) Derives de pyridine comme inhibiteurs specifiques de jnk
WO2007022305A2 (fr) 2-aminoimidazopyridines destinees a traiter des maladies neurodegeneratives
CA3008653C (fr) Inhibiteurs de la tyrosine kinase de bruton
KR100406634B1 (ko) 3,5-디아미노인다졸 유도체, 그의 제조방법 및 사이클린의존성 키나아제 저해제로서의 그의 용도

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP