WO2004052880A1 - Pyridine derivatives as jnk inhibitors and their use - Google Patents

Pyridine derivatives as jnk inhibitors and their use Download PDF

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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
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bipyridin
anilino
urea
alkyl
carboxamide
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PCT/SE2003/001911
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French (fr)
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Elisabeth Kallin
Niklas Plobeck
Britt-Marie Swahn
Arzel ERWAN
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Astrazeneca Ab
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    • 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.

Abstract

The present invention relates to new compounds of formula (I) whrein: R1 is aryl or heteroaryl, each of which is optionally substituted with one or more of R3, OR3, OCOR3, COOR3, COR3, CONR3R4, NHCOR3, NR3R4, NHSO2R3, SO2R3, SO2NR3R4, SR3, CN, halogeno or NO2; R2 is R5, R6, COR5, COR6, CONHR5, CONHR6, CON(R6)2, COOR5, COOR6, SO2R5 or SO2R6; a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Description

Pyridine derivatives as JΪTK inhibitors and their use
TECHNICAL FIELD
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.
BACKGROUND TO THE INVENTION
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. One of these pathways, the JNK pathway is activated specifically by stress or pro-inflammatory cytokines. Activators include LPS, the cytokines tumor necrosis factor (TNF-α) and Interleukin-1 (TJL-1), osmotic shock, chemical stress and UV radiation (Cohen, P. Trends in Cell Biol. 7:353-361 1997). 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).
Three different genes: JNK1, JNK2 and JNK3; encode the JNK family of enzymes. Alternatively spliced forms of these genes can give rise to 10 distinct isoforms: four for JNK1, four for JNK2 and two for JNK3. (Gupta, S. et al EMBO J. 15:2760-2770 1996). 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. In the case of JNK1 -/- mice, this is due to an inability to make gamma interferon (a key cytokine essential for the differentiation of Thl cells). In contrast, JNK2 -/- mice produce interferon gamma but are unable to respond to the cytokine. Similar defects in T cell biology (normal JJ 2 production but a block in Thl cell differentiation) are seen in T cells disrupted in the MKK7 gene confirming this role for the JNK pathway in T cell differentiation (Dong, C, et al Nature 405:91-94 2000).
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.
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.
Based on current knowledge 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. Thus there is a high unmet medical need for JNK specific inhibitors useful in treating the various conditions associated with JNK activation.
DISCLOSURE OF THE INVENTION
It has been found that compounds of the Formula I, which are substituted pyridine compounds, are particularly effective and thereby suitable in the treatment of the various conditions.
In one aspect, the invention relates to compounds of the general Formula I
Figure imgf000004_0001
wherein:
R .1 i :s aryl or heteroaryl, each of which is optionally substituted with one or more of R
ORJ, OCORJ, COORJ,
Figure imgf000004_0002
NHCORJ, NR 3JτR,4, NHSO2RJ, SO2RJ, SO2NR3R4, SR3, CN, halogeno and NO2;
RΔ is R >5J, R°, COR", COR°, CONHRJ, CONHR0, CON(R°)2, COOR0, COOR0, SO2R3 or SO2R6; R3 and R4 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleC1-6 alkyl, C1-6 fluoroalkyl, C1-6 trifluoroalkoxyl;
R5 is aryl or heteroaryl, each of which is optionally substituted with one or more of R7, OR7, OCOR7, COOR7, COR7, CONR7R8, CONHOR7, NHCOR7, NR7R8, NHSO2R7, SO2R7, SO2NR7R8, SR7, R7SR8, CN, halogeno, oxygen and NO2;
R6 is hydrogen, C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleCi.6 alkyl, heteroarylC1-6 alkyl, arylC1-6 alkyl, C1-6 alkoxyl, or C2-6 alkenyl, wherein any of C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleCι-6 alkyl, heteroarylC1-6 alkyl, arylC1-6 alkyl, C1-6 alkoxyl and C2-6 alkenyl is optionally substituted with one or more A;
R7 and R8 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)^.. 6 alkyl, C2-6 alkenyl, aryl, heteroaryl, heteroarylC1-6 alkyl, heterocycle, heterocycleC1-6 alkyl, aryl, C1-6 fluoroalkyl and C1-6 chloroalkyl,wherein any of C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-6 alkyl, C2-6 alkenyl, heteroaryl, heteroarylC1-6 alkyl, heterocycle and heterocycle .6 alkyl is optionally substituted with one or more B;
R9 and R10 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)Cι..6 alkyl, C2-6 alkenyl, heterocycle, heterocycleC1-6 alkyl, heteroaryl, heteroarylC1-6 alkyl, aryl or arylC1-6 alkyl, wherein any of C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)Cι.,6 alkyl, C2-6 alkenyl, heterocycle, heterocycleC1-6 alkyl, heteroaryl, heteroarylC1-6 alkyl, aryl or arylC1-6 alkyl is optionally substituted with one or more B;
A is R9, OR9, OCOR9, COOR9, COR9, CONR9R10, CONHOR9, NHCOR9, NR9R10, NR9SO2R10, SO2R9, SO2NR9R10, SR9, R9SR10 ,CN or halogeno;
B is C1-6 alkyl, C1-6 alkoxyl, C1-6 alkylamino, di(C1-6 alkyl)amino or halogeno;
as a free base or a salt, solvate or solvate of salt thereof. Listed below are definitions of various terms used in the specification and claims to describe the present invention.
For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined' or 'defined hereinbefore' the said group encompasses the first occurring and broadest definition as well as each and all of the preferred definitions for that group.
For the avoidance of doubt it is to be understood that in this specification 'C1-6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups. C όalkyl 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.
In this specification, unless stated otherwise, the term "C3-8 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.
The term "alkoxyl" as used herein, unless stated otherwise includes "alkyl'O groups in which "alkyl" is as hereinbefore defined. C1-6alkoxyl 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. C1-6 trifluoroalkoxyl represents a C1-6 alkoxyl substituted with three fluorine atoms.
In this specification, unless stated otherwise, the term "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 -6alkenyl may be ethenyl, propenyl, 2-methylpropenyl, butenyl and 2- butenyl.
In this specification, unless stated otherwise, the term "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.
In this specification, unless stated otherwise, the term "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. Examples of said heterocycle include, but are not limited to pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, oxazolyl, 2-oxazolidonyl, tetrahydropyranyl or tetrahydrofuranyl.
In this specification, unless stated otherwise, the term "aryl" may be a C6- 4 aromatic hydrocarbon and includes, but is not limited to, benzene, naphthalene, indene, anthracene, phenanthrene.
In this specification, unless stated otherwise, the term "heteroaryl" may be a monocyclic heteroaromatic, or a bicyclic fused-ring heteroaromatic group. Examples of said 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.
In this specification, unless stated otherwise, the term halogeno may be fluor, chlorine, bromine or iodine.
In this specification, unless stated otherwise, the term "C1-6 fluoroalkyl" may be an alkyl substituted with one or more fluorine atoms. Examples of said fluoroalkyl include, but are not limited to, monofluoromethyl, trifluoromethyl, difluoromethyl and trifluoroethyl. In this specification, unless stated otherwise, the term "C1-6 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.
In one aspect of the present invention, there is provided a compound of formula I, wherein R1 is aryl or heteroaryl, optionally substituted with one or more of R3, OR3, NR3R4, halogeno or NO2;
R2 is R5, R6, COR5, COR6, CONHR5, CONHR6, COOR6 or SO2R6;
R >3 a „„nd A r R>4 are each independently hydrogen, C1-6 alkyl or C1-6 fluoroalkyl;
R5 is aryl or heteroaryl each of which is optionally substituted with one or more of R7, OR7, COOR7, COR7, CONHOR7, NR7R8, SO2R7, SO2NR7R8, SR7, halogeno, oxygen and NO2;
R6 is hydrogen, C1-6 alkyl, (C3-8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleC1-6 alkyl, wherein any of C1-6 alkyl, (C3-8 cycloalkyl)C1-6 alkyl or heterocycle is optionally substituted with one or more A;
R7 and R8 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, aryl, heterocycle, wherein any of C1-6 alkyl is optionally substituted with one or more B;
R9 and R10 are each independently hydrogen, or .6 alkyl, wherein any C1-6 alkyl is optionally substituted with one or more B;
A is COOR9, COR9, CONR9R10, NHCOR9, NR9R10, SR9, R9SR10 , or CN;
B is halogeno or di(C1-6 alkyl)amino. In another aspect of the present invention, there is provided a compound of formula I, wherein R1 is aryl optionally substituted with one or more of R3, OR3 and NR3R4.
In one embodiment of this aspect there is provided a compound of formula I, wherein R1 is aryl and said aryl is phenyl.
In yet another aspect of the present invention, there is provided a compound of formula I, wherein R3 is selected from C1-6 fluoroalkyl, methyl and halogeno.
In yet another aspect of the present invention, there is provided a compound of formula I, wherein R2 is selected from R5, COR5 and CONHR5.
In one embodiment of this aspect there is provided a compound of formula I, wherein R5 is aryl, optionally substituted with one or more of R7, OR7, COOR7, COR7, CONHOR7, NR7R8, SO2R7, SO2NR7R8, SR7, halogeno, oxygen and NO2.
In another embodiment of this aspect there is provided a compound of formula I, wherein R7 and R8 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, aryl, heterocycle, wherein C1-6 alkyl is optionally substituted with one or more B, said B being halogeno.
In yet another aspect of the present invention, there is provided a compound of formula I, wherein R2is selected from R6, COR6, CONHR6 and SO2R6.
In one embodiment of this aspect there is provided a compound of formula I, wherein R6 is selected from hydrogen, C1-6 alkyl, (C3..8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleC1-6 alkyl, wherein any of C1-6 alkyl, (C3-8 cycloalkyl)C1-6 alkyl and heterocycle is optionally substituted with one or more A.
In another embodiment of this aspect there is provided a compound of formula I, wherein said A is selected from COOR9, COR9, CONR9R10, NHCOR9, NR9R10, SR9, R9SR10 and CN; and R9 and R10 are each independently hydrogen or Ci-β 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.
Thus, in another embodiment of the present invention there is provided a compound of formula I in the form of a pharmaceutically acceptable salt.
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.
Specific compounds of Formula I are: N,N'-Bis[4-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-diamine;
NN'-Bis(4-fluorophenyl)-4,4'-bipyridine-2,2'-diamine;
N,N'-Bis(3,4-difluorophenyl)-4,4'-bipyridine-2,2'-diamine;
NN'-Bis[3-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-di amine;
N)N'-Bis[3-(trifluoromethoxy)phenyl]-4,4'-bipyridine-2,2'-diamine; NN'-Bis(2-fluorophenyl)-4,4'-bipyridine-2,2'-diamine;
NN'-Bis(2-methylphenyl)-4,4'-bipyridine-2,2'-diamine;
N,N'-Bis(2-aminρphenyl)-4,4'-bipyridine-2,2'-diamine; NN'-Bis(2-methoxyphenyl)-4,4'-bipyridine-2,2'-diamine;
NN'-Bis(2-ethoxyphenyl)-4,4'-bipyridine-2,2'-diamine;
N-(2'-anilino-4,4'-bipyridin-2-yl)-tran.y-4-methoxycyclohexanecarboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-cw-4-methoxycyclohexanecarboxamide; N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl } -trαrø.y-4-methoxy- cyclohexanecarboxamide;
N- { 2'- [(4-fluorophenyl) amino] -4,4'-bipyridin-2-yl } -cw-4-methoxy- cyclohexanecarboxamide;
N-(6-methylpyridin-2-yl)-N-phenyl-4,4'-bipyridine-2,2'-diamine; N-phenyl-N-pyridin-2-yl-4,4'-bipyridine-2,2'-diamine;
N-(4-[(4-methylpiperazin-l-yl)sulfonyl]phenyl}-N-phenyr-4,4'-bipyridine-2,2'-diamine;
Ν-phenyl-Ν'-pyridin-3-yl-4,4'-bipyridine-2,2'-diamine;
N-phenyl-N'-pyrimidin-2-yl-4,4'-bipyridine-2,2,-di amine;
N-phenyl-N'-pyrimidin-5-yl-4,4'-bipyridine-2,2,-diamine; (2E)- 1 - { 4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]phenyl } -3-(dimethylamino)prop-2-en- 1 - one;
4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-N-(2-pyrrolidin-l-ylethyl)benzenesulfonamide;
4-[(2,-anilino-4,4'-bipyridin-2-yl)amino]-N-(2-morpholin-4-ylethyl)benzenesulfonamide;
N- (4-[(4-ethylpiperazin- 1 -yl)sulfonyl]phenyl } -N'-phenyl-4,4'-bipyridine-2,2,-di amine; N-phenyl-N'-pyridin-4-yl-4,4'-bipyridine-2,2'-diarnine;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-piperidin-l-ylpropanamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)nicotinamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-4-(dimethylamino)benzamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-2,6-dimethoxynicotinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-lH-indole-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)pyridine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-furamide; N-(2'-anilino-4,4'-bipyridin-2-yl)- 1 ,2,3-thiadiazole-4-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)isoxazole-5-carboxamide;
'N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methylisoxazole-3-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)pyrazine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-l-methyl-lH-imidazole-4-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-furamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-methoxybenzamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-5-bromo-2-furamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-(methylthio)nicotinamide;
Methyl 4-{[(2'-anilino-4,4'-bipyridin-2-yl)amino]carbonyl}benzoate;
3-(acetylamino)-N-(2'-anilino-4,4'-bipyridin-2-yl)benzamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-l-benzofuran-3-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-5-[(pyridin-2-ylthio)methyl]-2-furamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)nicotinamide 1 -oxide;
N-(2'-anilino-4,4,-bipyridin-2-yl)-3-hydroxypyridine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-6-bromopyridine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)isonicotinamide 1 -oxide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-hydroxynicotinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-6-hydroxypyridine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-benzoylpyridine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-6-methylpyridine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3,5-dimethylisoxazole-4-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-methoxynicotinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-methyl-l,2,3-thiadiazole-5-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-chloroisonicotinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methylisoxazole-4-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-methylisoxazole-4-carboxamide; N-(2,-anilino-4,4'-bipyridin-2-yl)-l-methyl-lH-pyrrole-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-chloronicotinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-chloro-lH-indole-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-chloro-lH-pyrazole-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methyl-lH-pyrazole-3-carboxamide; (2E)-N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(3-furyl)acrylamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(2-oxo-l,3-benzoxazol-3(2H)-yl)propanamide;
N'-(2'-anilino-4,4'-bipyridin-2-yl)-N,N-dimethylsuccinamide; -bipyridin-2-yl)-2-[(4-chlorophenyl)sulfonyl]acetamide;
-bipyridin-2-yl)-5-oxoprolinamide;
•bipyridin-2-yl)-3-methoxypropanamide;
-bipyridin-2-yl)-4-methoxycyclohexanecarboxamide;
-bipyridin-2-yl)-3-methoxypropanamide;
-bipyridin-2-yl)tetrahydrofuran-3 -carboxamide ;
-bipyridin-2-yl)-4-(dimethylamino)butanamide;
-bipyridin-2-yl)nicotinamide ;
-bipyridin-2-yl)-4-(dimethylamino)benzamide;
-bipyridin-2-yl)-2,6-dimethoxynicotinamide;
-bipyridin-2-yl)- 1 H-indole-2-carboxamide;
-bipyridin-2-yl)-5-methylpyrazine-2-carboxamide;
-bipyridin-2-yl)pyridine-2-carboxamide;
-bipyridin-2-yl)-3-furamide; •bipyridin-2-yl)-N-phenylurea;
-bipyridin-2-yl)-Ν'-phenylurea;
-bipyridin-2-yl)-N'- [ 1 -(4-bromophenyl)ethyl]urea;
-bipyridin-2-yl)-N'-thien-3-ylurea;
-bipyridin-2-yl)-N'-(2-methylphenyl)urea;
-bipyridin-2-yl)-N'-(4-methylphenyl)urea;
-bipyridin-2-yl)-N'-(3-fluorophenyl)urea;
-bipyridin-2-yl)-N'-(2-fluorophenyl)urea;
-bipyridin-2-yl)-N'-(4-fluorophenyl)urea;
-bipyridin-2-yl)-N'-[4-(chloromethyl)phenyl]urea;
-bipyridin-2-yl)-N'-(3-cyanophenyl)urea;
-bipyridin-2-yl)-N'-(4-cyanophenyl)urea;
-bipyridin-2-yl)-N'-(2-cyanophenyl)urea;
-bipyridin-2-yl)-N'-(2,3-dimethylphenyl)urea;
-bipyridin-2-yl)-N'-(2,5-dimethylphenyl)urea;
-bipyridin-2-yl)-N'-(4-ethylphenyl)urea;
Figure imgf000013_0001
-bipyridin-2-yl)-N'-(3-ethylphenyl)urea; N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-methoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-fluoro-2-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-fluorobenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-fluoro-5-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-fluorobenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorophenyl)urea;
N-(2 '-anilino-4,4'-bipyridin-2-yl) -N'-(3 -chloroρhenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorobenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,5-difluorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,4-difluorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,4-dichlorobenzyl)urea;
N-(4-acetylphenyl)-N'-(2'-anilino-4,4'-bipyridin-2-yl)urea;
N-(3-acetylphenyl)-N'-(2'-anilino-4,4'-bipyridin-2-yl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-isopropylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N,-(2-isopropylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-ethyl-6-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-mesitylurea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-propylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(dimethylamino)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-l,3-benzodioxol-5-ylurea;
N-(2'-anilino-4,4,-bipyridin-2-yl)-N'-(4-methoxy-2-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methoxy-5-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-ethoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methoxybenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-nitrophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-nitrophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[3-(methylthio)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(methylthio)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methylbenzyl)urea;
'N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-chloro-2-methylphenyl)urea; N-(2,-anilino-4,4'-bipyridin-2-yl)-N'-(2-chloro-5-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorobenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-chloro-4-fluorophenyl)urea;
N-(2'-anilino-4,4'-biρyridin-2-yl)-N'-(2,3,4-trifluorophenyl)urea; N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-butylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-isoρropyl-6-methylphenyl)ure
N-(2'-anilino-4,4'-biρyridin-2-yl)-N'-(2-tert-butylphenyl)urea;
Methyl 4-( { [(2'-anilino-4,4'-bipyridin-2-yl)amino]carbonyl } amino)be
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,4-dimethoxyphenyl)urea; N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,5-dimethoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-chloro-4-methoxyphenyl)urea
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(difluoromethoxy)phenyl]urea
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[2-(trifluoromethyl)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[3-(trifluoromethyl)phenyl]urea; N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(trifluoromethyl)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,5-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,5-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,4-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,3-dichlorophenyl)urea; N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,4-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-bromo-3-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,6-dichloropyridin-4-yl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-butyl-2-methylphenyl)urea;
N-(2'-anilino-4,4'-biρyridin-2-yl)-N'-[5-methyl-2-(trifluoromethyl)-3-f ethyl 3-( { [(2'-anilino-4,4'-bipyridin-2-yl)amino]carbonyl } amino)benzc
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-butoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,6-diisopropylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methylbenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-chloro-2,4-dimethoxyphenyl)uι N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-{4-[(trifluoromethyl)thio]phenyl}ι
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[3,5-bis(trifluoromethyl)phenyl]uι
' l-acetyl-N-(2'-anilino-4,4,-bipyridin-2-yl)piperidine-4-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-5-oxoprolinamide;
N3-acetyl-N1-(2'-anilino-4,4'-bipyridin-2-yl)-β-alaninamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-4-carboxamide;
3-amino-N-(2'-anilino-4,4'-bipyridin-2-yl)butanamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-L-prolinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)acetamide;
Methyl 2'-anilino-4,4'-bipyridin-2-ylcarbamate;
N-(2'-anilino-4,4'-bipyridin-2-yl)methanesulfonamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)cyclohexanecarboxamide; l-Acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-2-carboxamide; l-Acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-3-carboxamide;
Ethyl 4-[(2'-anilino-4,4,-bipyridin-2-yl)amino]-4-oxobutanoate;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-2-carboxamide;
(.S')-3 N2-acetyl-Nl-(2'-anilino-4,4'-bipyridin-2-yl)methioninamide; N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;
Ethyl 3 - [(2'-aniliho-4,4'-bipyridin-2-yl)amino] -3 -oxopropanoate ;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(methylthio)propanamide;
(±)N-(2'-anilino-4,4'-bipyridin-2-yl)-2-pyrrolidin-2-ylacetamide; (3S)-3-amino-N-(2'-anilino-4,4'-bipyridin-2-yl)-4-cyanobutanamide; NI -(2'-anilino-4,4'-bipyridin-2-yl)cyclopropane- 1 , 1 -dicarboxamide;
(35 -l-acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide (+) and (-);
N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl }tetrahydrofuran-3-carboxamide;
N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}tetrahydro-2H-pyran-4-carboxamide; Ethyl 4-({2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}amino)-4-oxobutanoate;
4-( { 2'-[(4-Fluorophenyl)amino]-4,4'-bipyridin-2-yl } amino)-4-oxobutanoic acid;
N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl } -3-(methylthio)propanamide;
(±)- 1 -Acetyl-N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl }piperidine-3-carboxamide;
(3R)-l-Acetyl-N-{2,-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3- carboxamide;
(35)-l-acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3- carboxamide; l-Acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}pyrrolidine-3-carboxamide; 3-(Aminosulfonyl)-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}benzamide; Ethyl 2- { [(2'-anilino-4,4'-bipyridin-2-yl)amino]methyl } cyclopropanecarboxylate; 2-{ [(2'-Anilino-4,4'-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylic acid; N-phenyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-4,4'-bipyridine-2,2'-diamine; N-phenyl-N-(tetrahydrofuran-3-ylmethyl)-4,4'-bipyridine-2,2'-di amine;
as a free base or a salt, solvate or solvate of salt thereof.
The present invention relates to novel pyridine derivatives, which are inhibitors of c-Jun Ν- terminal kinases (JΝKs). JΝKs 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.
Pharmaceutical compositions
According to one aspect of the present invention there is provided 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 Ν-terminal kinases (JΝKs).
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. In general 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. Dependent on the mode of administration, 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.
Figure imgf000019_0001
Medical use
The compounds of Formula I have activity as medicaments. In particular 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. In particular 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.
In a further aspect 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-, colorectal, pancreatic, prostate cancer.
In addition, 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.
In the context of the present specification, the term "therapy" also includes "prevention" unless there are specific indications to the contrary. The terms "therapeutic" and • "therapeutically" should be construed accordingly.
The term "condition", unless stated otherwise, means any disorder and disease associated with JNK activity.
Non-medical use
In addition to their use in therapeutic medicine, 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.
Methods of preparation
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.
Synthetic scheme Method 1:
Figure imgf000021_0001
wherein R1 is as described above.
In Method 1, 2,2'-dichloro-(4,4')-bipyridine is reacted with an amine with a transition metal catalyst such as a palladium catalyst in an ether or hydrocarbon solvent to give a
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.
Synthetic scheme Method 2:
Figure imgf000022_0001
intermediate
wherein R1 and R are as described above.
In Method 2, 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.
Consequently, in one aspect of the present invention there is provided a process for the preparation of a compound of formula la, wherein R1 and R5 are as defined above;
Figure imgf000023_0001
II la comprising the steps: reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R1-!) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and
reacting a compound of Formula II in a second arylation reaction with an arylhalide (R5- Br) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") to obtain a compound of formula la.
Synthetic scheme Method 3:
Figure imgf000024_0001
intermediate
Figure imgf000024_0002
wherein R1, R5 and R6 are as described above.
In Method 3, 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. The reaction is carried out at 25°C for a time of 1 to 8 days to give a carboxamide. Alternatively, 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. Analogously, carbamates and sulfonamides can be prepared from chlorocarbonates or sulfonylchlorides. The reaction is monitored by chromatography.
Consequently, in another aspect of the present invention there is provided a process for the preparation of a compound of formula lb, lc or Id, wherein R1, R5 and R6 are as defined above;
Figure imgf000025_0001
comprising the steps: reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R1-!.) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and
reacting said compound of Formula II with a carboxylic acid ("R5COOH alt R6COOH") in the presence of a amide coupling reagent and a base in an inert solvent to obtain a compound according to formula lb; or
reacting said compound of Formula II with a carboxylic acid chloride ("R5OCOCl alt R6OCOCl") in an inert solvent in the presence of a base in a solvent to obtain a compound according to formula lc; or
reacting said compound of Formula II with a chlorocarbonate or sulfonylchloride ("R5SO2Cl or R6SO2Cl") to obtain a compound according to formula Id. Synthetic scheme Method 4:
Figure imgf000026_0001
intermediate reducing agent
R°CHO alt R6CHO reducing agent
Figure imgf000026_0002
wherein R1, R5 and R6 are as described above.
In 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. The reaction is preferably carried out at elevated temperature such as 65°C for a time about 12 hours. Alternatively, 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.
Consequently, in another aspect of the present invention there is provided a process for the preparation of a compound of formula le wherein R , R and R are as defined above;
Figure imgf000027_0001
comprising the steps: reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R1-!) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and
reacting said compound of Formula II with a carboxylic acid ("R5COOH alt R6COOH") followed by reduction to the amine with a reducing agent in a solvent to obtain a compound according to formula le; or
reacting said compound of Formula II with a carboxaldehyde ("R5CHO alt R6CHO") in the presence of a reducing agent to obtain a compound according to formula le.
Synthetic scheme Method 5:
Figure imgf000028_0001
intermediate
In 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.
Consequently, there is provided a process for the preparation of a compound of formula If, wherein R1, R5 and R6 are as defined above;
Figure imgf000028_0002
comprising the steps: reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R1-!) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and reacting said compound of Formula II with an isocyanate ("R5NCO alt R6NCO") in a solvent, to obtain a compound according to Formula If.
In another aspect the present invention provides a process for the preparation of a compound of Formula I comprising the reaction of a compound of Formula LT:
Figure imgf000029_0001
wherein is R1 is aryl or heteroaryl each of which is optionally substituted with one or more of the following R3, OR3, OCOR3, COOR3, COR3, CONR3R4, NHCOR3, NR3R4,
NHSO2R3, SO2R3, SO2NR3R4, SR3, CN, halogeno or NO2;
R3 and R4 are each independently hydrogen, halogeno, C1-6 alkyl, C1-6 alkyl optionally substituted by NR3R4, C3-8 cycloalkyl, C3-6 alkenyl, C3-6 alkenyl optionally substituted by NR3R4, (C3-8 cycloalkyl)C1-6 alkyl, heterocycle, hetrocycleC1-6 alkyl, C1-6 fluoroalkyl, or alternatively NR3R4 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 C1-6 alkyl or halogeno;
as a free base or a salt, solvate or solvate of salt thereof.
Compounds of Formula LT may be prepared as described in Methods 2 or 3.
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.
WORKING EXAMPLES
The invention will now be described in more detail with the following examples that are not to be construed as limiting the invention.
All chemicals and reagents were used as received from suppliers. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a BRUKER DPX 400 (400 MHz) spectrometer using the following solvents and references.
CDC13 : 1H NMR TMS (0.0 ppm) and 13C the central peak of CDC13 (77.0). CD3OD : 1H NMR 3.31 ppm (central peak) and 13C 49.0 ppm (central peak).
OMSO-dδ: 1H NMR 2.50 ppm (central peak) and 13C 39.51 ppm (central peak).
Mass spectra (TSP) were recorded on a Finigan MAT SSQ 7000 spectrometer.
Mass spectra (El) were recorded on a Finigan MAT SSQ 710 spectrometer.
LC-MS were recorded on a Waters Alliance 2790 + ZMD spectrometer equipped with software Mass Lynx 3.5.
Flash column chromatography was carried out on silica gel 60 (230-400 mesh).
Example 1 N^,-Bis[4-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-diamine (i) 2-Chloro-3-iodopyridine
2,2,6,6-tetramethylpiperidine (17 mL, 14 g, 0.1 mol) and 2-chloropyridine (9.5 mL, 11.5 g, 0.1 mol) were consecutively added at -78°C to n-butyllithium 1.6 M in hexanes (62.5 mL, 0.1 mol) in 150 mL of tetrahydrofuran. After 2h at -78°C, the mixture was treated with a solution of iodine (25.5 g, 0.1 mol) in THF (50 mL) and stirred for 30 min before being partitioned between water (100 mL) and diethyl ether (3 x 50 mL). The combined organic layers were washed with a saturated aqueous solution of sodium thiosulfate (2 x 50 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to afford a crude solid which was purified by flash chromatography (heptane/ethyl acetate 90/10). Yield: 72% (17.3 g), yellow solid. 1H NMR (CDC13): δ 8.38 (dd, J = 4.6/1.7 Hz, IH), 8.16 (dd, J = 8.0/1.6 Hz, IH), 6.96 ( dd, J = 8.0/4.6 Hz, IH). 13C NMR (CDC13): δ 154.5, 148.9, 148.8, 123.2, 94.9.
MS (El) m/z 240 (M+l).
(ii) 2-Chloro-4-iodopyridine
A solution of 2-chloro-3-iodopyridine (12 g, 50 mmol) in 20 mL of THF was slowly added to a cold (-78°C) lithium diisopropylamide solution (prepared by the addition of n- butyllithium 1.6 M (31.25 mL, 50 mmol) in hexanes to a solution of diisopropylamine (7 mL, 50 mmol) in THF (100 mL). After 3h, water (20 mL) was added to the mixture, which was extracted with ether (2 x 100 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum (20°C) to afford a brown solid, which was purified by filtration over silica (ethyl acetate/heptane 8/2). Yield: 95% (11.4 g), pale yellow needles. 1H NMR (CDC13): δ 8.07 (d, J = 5.3 Hz, IH), 7.76 (d, J = 1.1 Hz, IH), 7.59 (dd, J = 5.0 / 1.1 Hz, IH). 13C NMR (CDC13): δ 151.7, 149.6, 133.0, 131.5, 106.6. MS (El) m/z 240 (M+l).
(iii) 2,2'-Dichloro-(4,4')-bipyridine n-Butyllithium 1.6M in hexanes (6.25 mL, 10.0 mmol) was slowly added to a cold (-78 °C) solution of 2-chloro-4-iodopyridine (4.79 g, 20.0 mmol) in 200 mL of THF. After 20 min at -78°C, a solution of trimethyltin chloride (2.0 g, 10.0 mmol) in 10 mL of THF was added dropwise. After 30 min, the ice bath was removed and the mixture was allowed to reach room temperature. After lh, water (10 mL) was added and the solution was extracted with ether (2 x 50 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to afford an orange oil. This crude product was diluted with toluene (50 mL) and flushed with nitrogen for 10 min. Then tetrakis(triphenylphosphine)palladium (578 mg, 0.5 mmol) was added and the mixture was heated at 110°C for 3 days. The mixture was filtered at room temperature and the precipitate was washed with water (2 x 20 mL), heptane (3 x 30 mL) and dried under vacuum to afford a white solid. Yield: 53 % (1.20 g). 1H NMR (CDCI3): δ 8.55 (d, J = 5.1 Hz, 2H), 7.57 (d, J = 1.3 Hz, 2H), 7.45 (dd, J = 5.1/1.3 Hz, 2H). 13C NMR (CDC13): δ 152.81, 150.71, 147.35, 122.14, 120.21. MS (TSP) m/z 225, 227(M+1).
(iv) N^V,-Bis[4-(trifluoromethyl)phenyl]-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 4-trifluoromethylaniline ( 0.3 mL, 2.4 mmol ) were flushed in a schlenk tube for 10 min with nitrogen. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with ethyl acetate (5 x 10 mL) and water (3 x 5 mL). The organic layers were separated, dried over magnesium sulfate and filtered. Silica gel was added to the filtrate, the solvents were evaporated under vacuum and the crude product purified by flash chromatography (ethyl acetate/heptane 8/2) to afford the title compound 12 mg (19 %) as a yellow solid. 1H NMR (DMSO-d6): δ 9.72 (s, 2H), 8.36 (d, J = 5.2 Hz, 2H), 7.93 (d, J = 8.4 Hz, 4H), 7.62 (d, J = 8.5 Hz, 4H), 7.18 (s, 2H), 7.16 (d, J = 5.1 Hz, 2H). 19F NMR (DMSO-d6): δ -60.09 (s, 6F). MS (TSP) m/z 475 (M+l).
Example 2
N,N'-Bis(4-fluorophenyl)-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 4-fluoroaniline (0.3 mL, 3.1 mmol) were flushed in a Schlenk tube for 10 min with nitrogen. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with ethyl acetate (5 x 10 mL) and water (3 x 5 mL). The resulting powder was dried under vacuum to yield 48 mg (59 %) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.46 (s, 2H), 8.23 (d, J = 5.3 Hz, 2H), 7.73 (m, 4H), 7.09 (m, 6H), 6.99 (dd, J = 1.0/5.3 Hz, 2H). 19F NMR (DMSO-d6): δ -123.27 (m, 2F). Example 3 N,N'-Bis(3,4-difluorophenyl)-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 3,4-difluoroaniline (0.5 mL, 4.0 mmol) were flushed in a Schlenk tube for 10 min with nitrogen. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with toluene (5 x 10 mL), water (3 x 5 mL) and dichloromethane (5 x 2 mL). The resulting powder was dried under vacuum to yield 35 mg (66%) of the title compound as a slightly brown solid. 1H ΝMR (DMSO-d6): δ 9.71 (s, 2H), 8.29 (d, J = 5.3 Hz, 2H), 8.07 (ddd, J = 7.8/6.4/1.9 Hz, 2H), 7.38-7.28 (m, 4H), 7.12 (s, 2H), 7.06 (d, J = 5.4 Hz, 2H). 19F ΝMR (DMSO-d6): δ -138.17 (m, 2F), -149.26 (m, 2F). MS (TSP) m/z 411 (M+l).
Example 4
N,N,-Bis[3-(trifluoromethyl)phenyl]-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 3-trifluoromethylaniline (0.5 mL, 4.0 mmol) were flushed in a Schlenk tube for 10 min with nitrogen. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with toluene (5 x 10 mL), water (3 x 5 mL) and dichloromethane (5 x 2 mL). The resulting powder was dried under vacuum to yield 80 mg (76 %) of the title compound. 1H ΝMR (DMSO-d6): δ 9.86 (s, 2H), 8.34 (d, J = 5.3 Hz, 2H), 8.28 (s, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.19 (s, 2H), 7.10 (dd, J = 5.4/1.5 Hz, 2H). 19F ΝMR (DMSO-d6): δ -61.57 (s, 6F). MS (TSP) m/z 475 (M+l).
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. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with toluene (5 x 10 mL), water (3 5 mL) and dichloromethane (5 x 2 mL). The resulting powder was dried under vacuum to yield 35 mg (70 %) of the title compound. 1H NMR (DMSO-d6): δ 9.75 (s, 2H), 8.34 (d, J = 5.3 Hz, 2H), 8.01 (s, 2H), 7.60 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 8.3 Hz, 2H), 7.17 (s, 2H), 7.11 (d, J = 5.3 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H). 19F NMR (DMSO-d6): δ -56.80 (s, 6F). MS (TSP) m/z 507 (M+l).
Example 6
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. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with water (3 x 5 mL) and ethyl acetate (5 x 2 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to afford a brown solid which was purified by flash chromatography (heptane/ethyl acetate 7/3) to yield 19 mg (50 %) of the title compound. 1H NMR (CDC13): δ 8.32 (d, J = 5.1 Hz, 2H), 8.05 (t, J = 8.1 Hz, 2H), 7.17-7.12 (m, 4H), 7.04-6.96 (m, 6H), 6.73 (bs, 2H). 19F NMR (CDCI3): δ -130.25 (m, 2F). 13C NMR (CDC13): δ 155.93, 153.54 (d, J = 243.7 Hz), 148.99, 148.01, 128.60 (d, J = 10.5 Hz), 124.47 (d, J = 3.6 Hz), 122.84 (d, J = 7.4 Hz), 121.10, 115.40 (d, J = 19.5 Hz), 113.66, 106.96. MS (TSP) m/z 375 (M+l).
Example 7
/V,N'-Bis(2-methylphenyl)-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-methylaniline (0.5 mL, 4.0 mmol ) were flushed in a Schlenk tube for 10 min with nitrogen. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with water (3 x 5 mL) and ethyl acetate (5 x 2 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to afford a brown solid which was purified by flash chromatography (heptane/ethyl acetate 1/1) to yield the title compound. 1H NMR (DMSO-d6): δ 8.31 (s, 2H), 8.14 (d, J = 5.3 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.4 Hz, 2H), 7.15 (t, J = 7.4 Hz, 2H), 6.99 (t, J = 7.6 Hz, 2H), 6.95 (s, 2H), 6.91 (d, J = 5.3 Hz, 2H), 1.98 (s, 6H). MS (TSP) m/z 367 (m+l).
Example 8 N,N'-Bis(2-aminophenyl)-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-aminoaniline (144 mg, 1.33 mmol) were flushed in a Schlenk tube for 10 min with nitrogen. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with ethyl acetate (5 x 10 mL), methanol (3 5 mL) and water (5 x 2 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to afford a brown solid which was purified by flash chromatography (heptane/ethyl acetate 1/1) to yield 27 mg (33 %) of the title compound. 1H NMR (MeOD- d4): δ 8.05 (d, J = 5.4 Hz, 2H), 7.13 (dd, J = 7.7/1.2 Hz, 2H), 7.04 (td, J = 8.1/1.5 Hz, 2H), 6.88 (d, J = 1.2 Hz, 2H), 6.87 (dd, J = 3.2/1.5 Hz, 2H), 6.72 (td, J = 7.7/1.5 Hz, 2H), 6.69 (s, 2H). 13C NMR (MeOD-d4): δ 160.05, 149.75, 149.44, 144.75, 128.04, 127.93, 127.27, 119.78, 118.02, 112.81, 107.20. MS (TSP) m/z 369 (M+l).
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. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with ethyl acetate (5 x 10 mL), methanol (3 x 5 mL) and water (5 x 2 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to afford a brown solid which was purified by flash chromatography (heptane/ethyl acetate 8/2) to yield 40 mg (46 %) of the title compound. 1H NMR (DMSO-d6): δ 8.29-8.25 (m, 4H), 8.22 (d, J = 5.7 Hz, 2H), 7.35 (m, 2H), 7.02-7.01 (m, 4H), 6.96-6.88 (m, 4H), 3.85 (s, 6H). MS (TSP) m/z 399 (M+l).
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. Then, 1 mL of dry dioxane was added, the tube sealed and the mixture stirred at 120°C for 15h. The mixture was then cooled to 20°C, filtered and the solid washed with ethyl acetate (5 x 10 mL), methanol (3 x 5 mL) and water (5 2 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to afford a brown solid which was purified by flash chromatography (heptane/ethyl acetate 8/2) to yield 35 mg (37 %) of the title compound. XH NMR (DMSO- d6): δ 8.22 (d, J = 4.9 Hz, 2H), 8.21 (m, 2H), 8.12 (s, 2H), 7.32 (s, 2H), 7.03 (dd, J = 5.4/1.2 Hz, 2H), 7.00 (dd, J = 7.9/1.9 Hz, 2H), 6.94-6.87 (m, 4H), 4.10 (q, J = 7.0 Hz, 4H), 1.36 (t, J = 7.0 Hz, 6H). MS (TSP) m/z 427 (M+l).
Example 11 7V-Phenyl-4,4'-bipyridine-2,2'-diamine
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. Then, 20 mL of dry DMF were added and the mixture stirred at 100°C for 15h. The mixture was cooled down to room temperature, filtered over a celite pad, silica gel was added to the filtrate and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (ethyl acetate/methanol/triethylamine 94/3/3) to yield 277 mg (26 %) of the title compound. 1H NMR (DMSO-d6): δ 9.16 (s, IH), 8.22 (d, J = 5.3 Hz, IH), 8.01 (d, J = 5.3 Hz, IH), 7.68 (d, J = 7.9 Hz, 2H), 7.26 (t, J = 8.1 Hz, 2H), 7.03 (s, IH), 6.94 (dd, J = 5.1/0.9 Hz, IH), 6.89 (t, J = 7.3 Hz, IH), 6.73 (dd, J = 5.1/1.1 Hz, IH), 6.68 (s, IH), 6.10 (s, 2H). 13C NMR (DMSO-d6): δ 160.94, 157.00, 149.23, 148.60, 147.29, 146.65, 141.94, 129.04, 120.99, 118.54, 112.22, 109.86, 108.00, 105.23. MS (TSP) m/z 263 (M+l).
Example 12
N-(4-Fluorophenyl)-4,4'-bipyridine-2,2'-diamine :
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 μL, 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). The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to afford a brown solid which was purified by flash chromatography (ethyl acetate/methanol/triethylamine 94/3/3) to yield 98 mg (35 %) of the title compound. 1H NMR (DMSO-d6): δ 9.17 (s, IH), 8.20 (d, J = 5.3 Hz, IH), 8.00 (d, J = 5.3 Hz, IH), 7.70-7.68 (m, IH), 7.11 (t, J = 8.8 Hz, 2H), 7.08 (s, IH), 6.95 (dd, J = 5.3/1.4 Hz, IH), 6.74 (dd, J = 5.2/1.5 Hz, IH), 6.08 (s, 2H). 19F NMR (DMSO-d6): δ - 123.25 (m, IF). MS (TSP) m/z 281 (M+l).
Example 13
N-(2 ' -anilino-4,4 ' -bipyridin-2-yl) -trans -4-methoxycyclohexanecarboxamide Ethyldiisopropylamine (129 mg, 1.0 mmol) was slowly added to a solution of N,N,N',N'- 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. After 5min, this solution was added to a solution of N-phenyl-4,4'-bipyridine-2,2'-diamine (131 mg, 0.5 mmol) in 2 mL of dimethylformamide under nitrogen. After 4 days of stirring, the reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate (5mL). The aqueous layer was extracted with dichloromethane. The organic layers were dried over magnesium sulfate, the solvent removed under reduced pressure to afford a crude product, which was purified by reversed phase chromatography to yield 6 mg of the title compound. 1H ΝMR (CDC13): δ 8.51 (s, IH), 8.32 (s, IH), 8.31 (d, J = 4.9 Hz, IH), 8.28 (d, J = 5.0 Hz, IH), 7.42-7.34 (m, 4H), 7.23 (dd, J = 1.6/5.1 Hz, IH), 7.10 (m, 2H), 7.01 (dd, J = 1.5/5.2 Hz, IH), 6.89 (s, IH), 3.38 (s, 3H), 3.19 (m, IH), 2.29 (m, IH), 2.20-1.89 (m, 3H), 1.75 (m, IH), 1.64 (m, 2H), 1.30 (m, 2H). MS (TSP) m/z 403 (M+l).
Example 14 N-(2'-anilino-4,4'-bipyridin-2-yl)-cw-4-methoxycyclohexanecarboxamide
Ethyldiisopropylamine (129 mg, 1.0 mmol) was slowly added to a solution of Ν,Ν,Ν',Ν'- 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. After 5min, this solution was added to a solution of N-phenyl-4,4'-bipyridine-2,2'-diamine (131 mg, 0.5 mmol) in 2 mL of dimethylformamide under nitrogen. After 4 days of stirring, the reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate (5mL). The aqueous layer was extracted with dichloromethane. The organic layers were dried over magnesium sulfate, the solvent removed under reduced pressure to afford a crude product, which was purified by reversed phase chromatography to yield 8 mg of the title compound. 1H ΝMR (CDCI3): δ 8.53 (s, IH), 8.31 (d, J = 5.1 Hz, IH), 8.28 (d, J = 5.2 Hz, IH), 8.19 (s, IH), 7.42-7.34 (m, 4H), 7.21 (dd, J = 1.5/5.2 Hz, IH), 7.10 (m, 2H), 7.01 (dd, J = 1.3/5.2 Hz, IH), 6.84 (s, IH), 3.49 (m, IH), 3.33 (s, 3H), 2.37 (IH), 2.05-1.89 (m, 4H), 1.80-1.76 (m, 2H), 1.55-1.47 (m, 2H). MS (TSP) m/z 403 (M+l).
Example 15 N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}-trαns-4-methoxy- cyclohexanecarboxamide
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. After 5 min of stirring, 5 mL of a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer extracted with dichloromethane. The organic layers were dried with magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product, which was purified by reversed phase chromatography to yield 10 mg of the title compound. 1H ΝMR (CDCfe): δ 8.49 (s, IH), 8.32 (d, J = 5.3 Hz, IH), 8.27(d, J = 5.2 Hz, IH), 8.17 (s, IH), 7.40-7.36 (m, 2H), 7.21 (dd, J = 1.5/5.2 Hz, IH), 7.08 (m, 2H), 7.00 (dd, J = 1.4/5.3 Hz, IH), 6.94 (s, IH), 6.66 (s, IH), 3.39 (s, 3H), 3.20 (m, IH), 2.30-2.06 (m, 5H), 1.64 (m, 2H), 1.30 (m, 2H). 19F ΝMR (CDC13): δ -119.48 (m, IF). MS (ES) m/z 421 (M+l).
Example 16
N-{2'-[(4-fluorophenyI)amino]-4,4,-bipyridin-2-yl}-cw-4-methoxy- cyclohexanecarboxamide 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. After 5 min of stirring, 5 mL of a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer extracted with dichloromethane. The organic layers were dried with magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product, which was purified by reversed phase chromatography to yield 17 mg of the title compound. 1H NMR (CDC13): δ 8.52 (d, J = 0.8 Hz, IH), 8.31 (d, J = 5.2 Hz, IH), 8.27 (s, IH), 8.26 (d, J = 5.5 Hz, IH), 7.40-7.37 (m, 2H), 7.19 (dd, J = 1.6/5.2 Hz, IH), 7.08 (m, 2H), 6.98 (dd, J = 1.5/5.3 Hz, IH), 6.95 (s, IH), 6.85 (s, IH), 3.48 (m, IH), 3.33 (s, 3H), 2.38 (m, IH), 2.05-1.93 (m, 4H), 1.77 (m, 2H), 1.51 (m, 2H). 19F NMR (CDC13): δ -119.91 (m, IF). MS (ES) m/z 421 (M+l).
Example 17 N-(6-methylpyridin-2-yl)-N'-phenyl-4,4'-bipyridine-2,2'-diamine
To a mixture of (N-phenyl-4,4'-bipyridine-2,2'-diamine (53 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol), 1.1'- bis(diphenylphosphino)ferrocene (11 mg, 0.02 mmol) and sodium tert-butoxide (14.4 mg, 0.15 mmol) in 2 ml dry dioxane under nitrogen was added 2-bromo-6-methylpyridine (34.5 mg, 0.20 mmol). The mixure was stirred under argon for 14 h at 100 °C, filtered, evaporated under reduced pressure, and chromatographed on silica in isooctane:ethyl acetate 1:1. Appropriate fractions were combined and concentrated to dryness to yield 40 mg (56 %) of the title compound as a pale syrup. 1H NMR (CDC13) δ 8.27 (d, J=5.4 Hz, 2H), 7.98 (s, IH, NH), 7.87 (s, IH), 7.47 (t, J=7.7 Hz, IH), 7.34 (s, 2H), 7.33 (d, J=1.5 Hz, 2H), 7.31 (s, IH, NH), 7.28 (d, 8.2 Hz, IH), 7.10 (s, IH), 7.06 (m, IH), 6.95 (ddd, J=1.6/ 5.3/ 9.65, 2H), 6.70 (d, 7.5 Hz, IH), 2.40 (s, 3H).
HPLC-MS (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound with m/z 354 (M+l). C22H19N5, MW=353.4.
Example 18
N-phenyl-N' -pyridin-2-yI-4,4' -bipyridine-2,2' -diamine
To a mixture of (N-phenyl-4,4'-bipyridine-2,2'-diamine (27 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol), 1.1'- bis(diphenylphosphino)ferrocene (11 mg, 0.02 mmol) and sodium tert-butoxide (14.4 mg, 0.15 mmol) in 2 ml dry dioxane under nitrogen was added 2-bromopyridine (15.8 mg, 0.10 mmol). The mixure was stirred under argon for 14 h at 95 °C, filtered, evaporated under reduced pressure, and chromatographed on C8-silica using an automated preparative HPLC system (Waters 2767/2525) with a gradient of 35% - 100% acetonitrile in 0.05M aqueous ammonium acetate. Appropriate fractions were combined and concentrated to dryness to yield 2 mg (6 %) of the title compound HPLC-MS (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound with m/z 340 (M+l). C21H17N5, MW=339.4
Example 19 N-{4-[(4-methylpiperaζin-l-yl)sulfonyl]phenyl}-N'-phenyI-4,4,-bipyridine-2,2l- diamine
To a mixture of (Ν-phenyl-4,4'-bipyridine-2,2'-diamine (27 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol), 1.1'- bis(diphenylphosphino)ferrocene (11 mg, 0.02 mmol) and sodium tert-butoxide (14.4 mg, 0.15 mmol) in 2 ml dry dioxane under nitrogen was added l-[(4-bromophenyl)sulfonyl]-4- methylpiperazine (32 mg, 0.10 mmol). The mixure was stirred under argon for 16 h at 95 °C, filtered, evaporated under reduced pressure, and chromatographed on C8-silica (Waters XTerra MS C8, 19x300mm, 7um) using an automated preparative HPLC system (Gilson autopreparative HPLC, diode array detection) with a gradient of 20% - 60% acetonitrile in 0.1 M aqueous ammonium acetate for 13 minutes at 20ml/min. Appropriate fractions were combined and concentrated to dryness to yield 26.6 mg (53 %) of the title compound. The material was dissolved in methanol and IM hydrochloric acid (0.5 mL) was added. The solution was evaporated to dryness, dissolved in water and freeze dried. 1H NMR (D2O) δ 7.86 - 6.80 (15H), 3.65 (d, J = 12.0 Hz, 2H), 3.38 (d, 2H), 3.02 (m, 2H), 2.69 (s, 3H), 2.59 (m, 2H).
HPLC-MS (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound with m/z 501 (M+l). C27H28N6O2S, MW=500.6.
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.
Figure imgf000042_0001
Example 28 N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide
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. Pyridine (2 mL) was added, followed by N-phenyl-4,4'-bipyridine-2,2'-diamine (26 mg, 0.1 mmol) in dry tetrahydrofurane (0.5 mL). The mixture was stirred 16 h at room temperature. HPLC-MS (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid. UV-diode array detector, CLΝD and MSD-ESI detection) shows a single compound with m/z 361 (M+l). C21H20Ν4O2, MW=360.4. 1H NMR (CD3OD): δ 10.51 (s, IH), 8.86 (s, IH), 8.40 (s, IH), 8.31 (d, J = 5.2 Hz, IH), 7.95 (d, J = 6.5 Hz, IH), 7.45-7.00 (m, 8H), 4.01-3.90 (m, 3H), 3.77 (m, IH), 3.15 (m, IH), 2.20 (m, 2H).
Example 29 N-(2'-anilino-4,4l-bipyridin-2-yl)-3-piperidin-l-ylpropanamide
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. Then 250 uL of this solution (corresponding to 0.02 mmol carboxylic acid) is transferred to a 1 mL polystyrene tube in a 96 -well format box and evaporated to dryness under a stream of heated nitrogen (3 minutes, 35°C). The remaining syrup is dissolved in dichloromethane (100 uL), and N-phenyl-4,4'-bipyridine-2,2'-diamine (5.2 mg, 0.02 mmol) in pyridine (300 uL) is added. The well is capped and agitated on an orbital shaker for 16 hours at room temperature under nitrogen. The solution is evaporated to dryness under a stream of heated nitrogen (5 minutes, 50°C), The crude material is dissolved in methanol, filtered and chromatographed on C8-silica using an automated preparative HPLC system (Waters 2767/2525) with a gradient of 35%-100% acetonitrile in 0.05M aqueous ammonium acetate. Appropriate fractions were combined and concentrated to dryness to yield 3.9 mg (49 %) of the title compound. HPLC-MS (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid. UV-diode array detector, CLΝD and MSD-ESI detection) shows a single compound with m/z 402 (M+l). C24H27Ν5O, MW=401.5.
Compounds 30-73 were prepared according to the procedure set forth in Example 29, using the appropriate carboxylic acid and N-phenyl-4,4'-bipyridine-2,2'-diamine prepared as described in example 11.
Example 30-73
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Example 74
N-(2 ' -anilino-4, ' -bipyridin-2-yl)-3-methoxypropanamide
General procedure:
To a mixture of 3-Methoxypropanoic acid (11 mg, 0.1 mmol), N-phenyl-4,4'-bipyridine-2,2'- diamine (26 mg, 0.1 mmol), hydroxybenzotriazole (14 mg, 0.1 mmol), polystyrene bound diisopropylamine (Ν,Ν-(Diisopropyl)aminomethylpolystyrene, 32 mg, 0.12 mmol) and polystyrene bound carbodiimide (N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene, 158 mg, 0.3 mmol) was added 2 mL dimethylformamide 1. The mixture was stirred at 120°C for 48h under argon. Filtering and evaporation gave a brown syrup which was dissolved in dimethylsulfoxide (200 uL) and subjected to chromatography on C8-silica using an automated preparative HPLC system (Waters 2767/2525) with a gradient of 25% - 45% acetonitrile in 0.05M aqueous ammonium acetate. Appropriate fractions were combined and concentrated to dryness under vacuum to yield 5.3 mg of the title compound. HPLC-MS (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound with m/z 349 (M+l). C20H20N4O2, MW=348.4.
Examples 75-85
Compounds 75-85 were prepared according to the procedure set forth in Example 74, using the appropriate carboxylic acid and N-phenyl-4,4'-bipyridine-2,2'-diamine prepared as described in example 11.
Figure imgf000048_0001
Figure imgf000049_0001
Example 86 N-(2'-anilino-4,4'-bipyridin-2-yl)-Nl-phenylurea
" Procedure A: To a solution of and N-phenyl-4,4'-bipyridine-2,2'-diamine (131 mg, 0.5 mmol) in dioxane (5 mL) under nitrogen was added phenyl isocyanate (60 mg, 0.5 mmol) dissolved in dioxane (1 mL). The mixture was stirred at room temperature for 16 hours. Precipitated material was filtered off and verified by ΝMR and HPLC-MS to be the title compound (104 mg, 55%) in 96% purity (uv-detection). . 1H ΝMR (DMSO-D6) δ 8.40 (d, J=5.6 Hz, IH), δ 8.30 (d, J=5.6 Hz, IH), 7.99(d, J=5.1 Hz, IH), 7.73 (d, J=8.1 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.30 (m, 5H), 7.15 (s, IH, ΝH), 7.04 (m, 2H), 6.92 (t, 7.1 Hz, IH). 13C ΝMR (DMSO-D6) δ 156.7, 152.1, 148.5, 147.5, 145.9, 141.5, 139.0, 138.9, 128.9, 128.7, 122.6, 120.7, 118.8, 118.7, 118.1, 115.3, 111.8, 108.8, 107.9. 15Ν ΝMR (DMSO-D6) δ -275.0, - 260.4, -269.5, -113.3, 108.1. The chemical shifts and positions of the nitrogen atoms were determined using 15N HSQC and 15N HMBC in combination with 1H-1H COSY. 15N chemical shifts are given relative external nitro methane at 0.0 ppm. The 15N 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.
HPLC-MS (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound with m/z 382 (M+l). C24H27N5O, MW=381.4.
Procedure B:
To a solution of phenyl isocyanate (72 uL, 0.5 M in dioxane, 0.036 mmol) in a 2 mL deep- well 96-well plate was added N-phenyl-4,4'-bipyridine-2,2'-diamme (7.9 mg, 0.03 mmol) in dioxane (200 uL) under nitrogen. The plate was agitated on an orbital shaker at room temperature for 16 hours. Precipitated material was filtered off and dissolved in dimethylsulfoxide. Analysis and quantification of the product was done using an Agilent HP 1100 HPLC-MS system (Waters Exterra C8-column, 8.6 min gradient of 0-100% methanol containing 0.1% trifluoroacetic acid) equipped with UV-diode array detector, CLND (nitrogen detector) and MSD-ESI detector.
Compounds 87-166 were prepared according to the procedure set forth in Procedure B, using the appropriate isocyanate derivative and N-phenyl-4,4'-bipyridine-2,2'-diamine prepared as described in example 11.
Example 87-166
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Example 167 l-acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-4-carboxamide
Procedure as example 14. Reaction with l-acetylpiperidine-4-carboxylic acid for 5 days. Purification on silica gel (0 to 10% MeOH in CH2C12) gave 5 mg (5%) of the title compound. The product was treated with 1 eq. trifluoroacetic acid and freeze dried to give the TFA salt. MS (ES) m/z 416 (M+l).
Example 168 N-(2'-anilino-4,4'-bipyridin-2-yl)-5-oxoprolinamide
Procedure as example 14. Reaction with D,L-pyroglutamic acid for 5 days gave 12 mg (13%) of the title compound. The product was treated with 1 eq. TFA and freeze dried to give the trifluoroacetic acid salt. 1H NMR (CD3OD): δ 8.54 - 8.48 (m, 2H), 7.98 (d, J = 6.5
Hz, IH), 7.56 -7.35 (m, 7H), 7.30 (dd, J = 6.5, 2 Hz, IH), 4.44 (m, IH), 2.65 - 2.15 (m,
4H), 1.30 (m, IH).
MS (ES) m/z 374 (M+l).
Example 169
N3-acetyl-N1-(2'-anilino-4,4'-bipyridm-2-yl)-β-aIaninamide
Procedure as example 14. Reaction with N-acetyl-β-alanine for 5 days gave 30 mg (31%) of the title compound. The product was treated with 1 eq. TFA and freeze dried to give the trifluoroacetic acid salt. 1H ΝMR (CD3OD): δ 8.50 - 8.46 (m, 2H), 7.96 (d, J = 6.5 Hz, IH),
7.59 -7.39 (m, 7H), 7.33 (dd, J = 6.5, 1.5 Hz, IH), 3.53 (m, 2H), 2.68 (m, 2H), 1.92 (s, 3H).
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 C12 1:1. A second reverse phase chromatography gave 16 mg (17%) of the title compound as the free base. 1H ΝMR (CD3OD): δ 8.42 (s, IH), 8.37 (d, J = 5 Hz, IH), 8.19 (d, J = 5.5 Hz, IH), 7.54 (m, 2H), 7.37 (dd, J = 5.5, 1.5 Hz, IH), 7.29 (m, 2H), 7.10 (s, IH), 7.03 (dd, J = 5.5, 1.5 Hz, IH), 6.97 (m, IH), 3.11 (m, 2H), 2.64 (m, 3H), 1.87 (m, 2H), 1.73 (m, 2H).
Example 171
3-amino-N-(2' -anilino-4,4' -bipyridin-2-yl)butanamide Procedure as example 14. Reaction with (+/-)-3-[(tert-butoxycarbonyl)amino]butanoic acid for 5 days followed by Ν-boc removal as for 26757 gave 10 mg (11%) of title compound. The product was treated with 1 eq. HCl (aq.) and freeze dried to give the HCl salt. 1H ΝMR (CD3OD): δ 8.43 (s, IH), 8.36 (d, J = 5 Hz, IH), 8.19 (d, J = 5 Hz, IH), 7.53 (m, 2H), 7.36 (dd, J = 5, 2 Hz, IH), 7.28 (m, 2H), 7.09 (s, IH), 7.02 (dd, J = 5.5, 1.5 Hz, IH), 6.97 (m, IH), 3.40 (m, IH), 3.34 (s, 3H), 2.60-2.43 (m, 2H), 1.18 (d, J = 6.5 Hz, 3H). MS (ES) m/z 348 (M+l). Example 172
_V-(2' -anilino-4,4' -bipyridin-2-yl)-L-prolinamide
Procedure as example 14. Reaction with l-(tert-butoxycarbonyl)-L-proline for 8 days followed by N-boc removal as for 26757 gave 7 mg (9%) of the title compound. The product was treated with 1 eq. HCl (aq.) and freeze dried to give the HCl salt. 1H NMR (CD3OD): δ 8.48 (s, IH), 8.37 (d, J = 5 Hz, IH), 8.20 (d, J = 5.5 Hz, IH), 7.53 (m, 2H), 7.40 (dd, J = 5, 1.5 Hz, IH), 7.29 (m, 2H), 7.10 (s, IH), 7.03 (dd, J = 5, 1.5 Hz, IH), 6.97 (m, IH), 3.86 (m, IH), 3.03 (m, 2H), 2.23 (m, IH), 1.93 (m, IH), 1.79 (m, 2H). MS (ES) m/z 360 (M+l).
Example 173 N-(2'-anilino-4,4'-bipyridin-2-yl)acetamide
N-phenyl-4,4'-bipyridine-2,2'-diamine (50 mg, 0.19 mmol) was dissolved in pyridine (2 mL) and acetyl chloride (14 μL, 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. 1H ΝMR (CD3OD): δ 8.50 (m, IH), 8.16 (s, IH), 8.01 (d, J = 5 Hz, IH), 7.68 (m, IH), 7.59 (m, 2H), 7.52-7.44 (m, 4H), 7.36 (m, IH), 3.22 (s, 3H). MS (ES) m/z 305 (M+l).
Example 174
Methyl 2' -anilino-4,4' -bipyridin-2-ylcarbamate
Procedure as example 173. Methyl chloroformate (16 μL, 0.20 mmol) was added at 0°C followed by a second portion (5 mL) after 12 h and stirring was continued for 2 d at 25°C. Purification by silica gel chromatography (0 to 10% MeOH in EtOAc) gave 5 mg (8%) of the title compound. The product was treated with 1 eq. HCl (aq.) and freeze dried to give the HCl salt. 1H ΝMR (CD3OD): δ 8.45 (m, IH), 8.13 (s, IH), 7.97 (d, J = 6.5 Hz, IH), 7.58 (m, 2H), 7.51 (m, IH), 7.48-7.43(m, 4H), 7.35 (m, IH), 3.84 (s, 3H). MS (ES) m/z 322 (M+l).
Example 175
_V-(2' -anilino-4,4' -bipyridin-2-yI)methanesulfonamide Procedure as example 173. Methanesulfonylchloride (16 μL, 0.20 mmol) was added at 0°C and stirring was continued for 3 d at 25°C. Purification by silica gel chromatography (0 to 5% MeOH in EtOAc) was followed by reverse phase chromatography to give 2 mg (3%) of the title compound. The product was treated with 1 eq. HCl (aq.) and freeze dried to give the HCl salt. 1H NMR (CD3OD): δ 8.46 (m, IH), 7.96 (d, J = 6.5 Hz, IH), 7.56 (m, 2H), 7.47-7.28 (m, 7H, 3.29 (s, 3H). MS (ES) m/z 341 (M+l).
Example 176 N-(2' -anilino-4,4' -bipyridin-2-yl)cyclohexanecarboxamide
Procedure as example 173. Cyclohexanecarbonyl chloride (28 μL, 0.20 mmol) was added at 0°C and stirring was continued for 12 h at 25°C. Purification by reverse phase chromatography gave 4 mg (5%) of the title compound. The product was treated with 1 eq. HCl (aq.) and freeze dried to give the HCl salt. 1H NMR (CD3OD): δ 8.46 (m, 2H), 8.00 (d, J = 6.5 Hz, IH), 7.55-7.40 (m, 5H), 7.35 (m, 2H), 7.27 (m, IH), 2.50 (m, IH), 1.97-1.22 (m, 10H). MS (ES) m/z 373 (M+l).
Example 177 l-Acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-2-carboxamide
Procedure as example 14. Reaction with l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (described in Costa, Brian R. de; Dominguez, Celia; He, Xiao-shu; Williams, Wanda; Radesca, Lilian; Bowen, Wayne; J.Med.Chem; 35; 23; 1992; 4334-4343.) for 7 days was followed by workup and treatment with TFA/ CH2C12 , 1:1 for 30 min. Purification with reverse phase chromatography gave 5 mg (13 μmol) of the N-boc deprotected product
1 which was dissolved in CH2C12 (2 mL) together with triethyla ine (2.1 μL, 15 μmol) and treated with acetic anhydride (1.4 μL, 14 μmol). After stirring 12 h at 25°C and evaporation of the solvent in vacuo, purification with reverse phase chromatography gave 2 mg (1%, 3 steps) of the title compound. The product was treated with 1 eq. HCl (aq.) and freeze dried to give the HCl salt. 1H NMR (CD3OD): δ 8.40 (m, 2H), 8.20 (m, IH), 7.54 (m, 2H), 7.40 (m, IH), 7.29 (m, 2H), 7.11 (m, IH), 7.04 (m, 1H), 6.97 (m, IH), 2.20 (s, 3H), 2.20-0.98
(m, 9H).
MS (ES) m/z 416 (M+l).
Example 178 l-Acetyl-N-(2'-anilino-4,4'-bipyridm-2-yl)piperidine-3-carboxamide
Procedure as example 14. Reaction with l-acetylpiperidine-3-carboxylic acid ( described in : Zalucky et al., J. Pharm. Sci., 1965, 54, 687-693) for 5 days. Purification with reverse phase chromatography gave 3 mg (3%) of the title compound. The product was treated with 1 eq. HCl (aq.) and freeze dried to give the HCl salt. 1H ΝMR (CD3OD): δ 8.52-8.42 (m, 2H), 7.95 (d, J = 6.5 Hz, IH), 7.58 (m, 3H), 7.51-7.42 (m, 4H), 7.34 (dd, J = 7, 2 Hz, IH), 4.53 (m, IH), 4.19 (m, IH), 3.98-3.84 (m, 2H), 2.99 (m, IH), 2.13 (s, 3H), 2.13-1.26 (m, 4H). MS (ES) m/z 416 (M+l).
Example 179
Ethyl 4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-4-oxobutanoate
4-Ethoxy-4-oxobutanoic acid (36 mg, 0.25 mmol) and N-[(dimethylamino)(3H- [l,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- dimethylforma ide under a nitrogen atmosphere. Diisopropylethylamine (64 mg, 87μL, 0.575 mmol) was added dropwise. After lh stirring, a solution of N-phenyl-4,4'- bipyridine-2,2'-diamine (65 mg, 0.25 mmol) in dry N, N-dimethylformamide (lmL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCO3 (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 purified by flash chromatography (ethyl acetate/methanol : 98/2). Yield : 25 % (25 mg). 1H NMR (400 MHz, CDC13) :δ 9.04 (s, 1 H), 8.45 (s, 1 H), 8.30 (d, 7=6.1 Hz, 1 H), 8.25 (d, 7=4.5 Hz, 1 H), 7.43 - 7.32 (m, 5 H), 7.20 - 7.14 (m, 1 H), 7.09 - 7.05 (m, 2 H), 6.96 (d, 7=5.6 Hz, 1 H), 4.16 (q, 7=7.1 Hz, 2 H), 2.76 - 2.66 (m, 4 H), 1.27 - 1.22 (t, 7=7.1 Hz, 3 H). 13C NMR (101 MHz, CDC13) :δ 172.64 (s, 1 C), 170.50 (s, 1 C), 156.58 (s, 1 C), 152.20 (s, 1 C), 148.38 (s, 1 C), 148.08 (s, 1 C), 147.85 (s, 1 C), 139.97 (s, 1 C), 129.40 (s, 4 C), 123.30 (s, 1 C), 120.66 (s, 1 C), 117.56 (s, 1 C), 113.07 (s, 1 C), 111.89 (s, 1 C), 106.39 (s, 1 C), 60.87 (s, 1 C), 31.97 (s, 1 C), 29.03 (s, I C), 14.15 (s. l C). MS (TSP) m/z (M+l) : 343, 391.
Example 180 N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-2-carboxamide (El) and (E2)
Tetrahydrofuran-2-carboxylic acid (58 mg, 0.25 mmol) and N-[(dimethylamino)(377-
[l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (285 mg, 0.75 mmol) were diluted in 6 mL of dry N, N- dimethylformamide under a nitrogen atmosphere. Diisopropylethylamine (129 mg, 174 μL, 1.0 mmol) was added dropwise. After lh stirring, a solution of N-phenyl-4,4'- bipyridine-2,2'-diamine (131 mg, 0.50 mmol) in dry N, N-dimethylformamide (2 mL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCθ3 (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 : 98/2). Yield : 44 % (81 mg) of the racemate. Both enantiomers were separated on a chiral column to afford : 25 mg of El and 22 mg of E2. XH NMR (400 MHz, CDC13) :δ 9.12 (s, 1 H), 8.51 (s, 1 H), 8.36 (d, 7=4.5 Hz, 1 H), 8.30 (d, 7=6.1 Hz, 1 H), 7.42 - 7.34 (m, 4 H), 7.23 (d, 7=3.5 Hz, 1 H), 7.11 - 7.04 (m, 2 H), 7.01 (d, 7=5.1 Hz, 1 H), 6.64 (s, 1 H), 4.50 (dd, 7=8.6, 5.6 Hz, 1 H), 4.12 - 4.03 (m, 1 H), 4.02 - 3.92 (m, 1 H), 2.44 - 2.33 (m, 1 H), 2.19 (td, 7=13.4, 6.1 Hz, 1 H), 2.02 - 1.90 (m, 2 H). 13C NMR (101 MHz, CDCI3) :δ 172.32 (s, 1 C), 156.63 (s, 1 C), 151.55 (s, 1 C), 149.15 (s, 1 C), 148.74 (s, 1 C), 148.62 (s, 1 C), 140.15 (s, 1 C), 129.38 (s, 2 C), 123.10 (s, 1 C), 120.38 (s, 2 C), 117.92 (s, 1 C), 113.29 (s, 1 C), 111.51 (s, 1 C), 106.26 (s, 1 C), 78.52 (s, 1 C), 69.76 (s, 1 C), 31.87 (s, l C), 25.58 (s, 1 C). MS (TSP) m/z (M+l): 361.
Example 181
(5)-3 N2-acetyl-iV1-(2'-anilino-4,4'-bipyridin-2-yl)methioninaπιide (Sj-N-acetyl-L-methionine (96 mg, 0.50 mmol) and N-[(dimethylamino)(377- [l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (285 mg, 0.75 mmol) were diluted in 6 mL of dry N, N- dimethylformamide under a nitrogen atmosphere. Diisopropylethylamine (129 mg, 174 μL, 1.0 mmol) was added dropwise. After lh stirring, a solution of N-phenyl-4,4'- bipyridine-2,2'-diamine (131 mg, 0.50 mmol) in dry N N-dimethylformamide (2 mL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCO3 (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 : 98/2). Yield : 25 % (54 mg). 1H NMR (400 MHz, CDC13) :δ 9.27 (s, 1 H), 8.42 (s, 1 H), 8.33 (d, 7=5.1 Hz, 1 H), 8.26 (d, 7=5.6 Hz, 1 H), 7.42 - 7.33 (m, 4 H), 7.22 (d, 7=5.6 Hz, 1 H), 7.11 - 7.05 (m, 3 H), 6.97 (d, 7=5.6 Hz, 1 H), 6.44 (d, 7=8.1 Hz, 1 H), 4.85 - 4.77 (m, 1 H), 2.67 - 2.56 (m, 2 H), 2.27 - 2.18 (m, 1 H), 2.13 (s, 3 H), 2.09 - 2.00 (m, 4 H). 13C NMR (101 MHz, CDC13) :δ 170.50 (s, 1 C), 170.20 (s, 1 C), 156.69 (s, 1 C), 151.73 (s, 1 C), 148.96 (s, 1 C), 148.89 (s, 1 C), 148.36 (s, 1 C), 147.51 (s, 1 C), 140.08 (s, 1 C), 129.40 (s, 2 C), 123.17 (s, 1 C), 120.44 (s, 2 C), 118.07 (s, 1 C), 113.11 (s, 1 C), 111.95 (s, 1 C), 106.22 (s, 1 C), 53.35 (s, 1 C), 31.20 (s, 1 C), 30.29 (s, 1 C), 23.22 (s, 1 C), 15.38 (s, 1 C). MS (TSP) m/z (M+l) : 436.
Example 182 N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydro-2flr-pyran-4-carboxamide
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.
This solution was added dropwise to a solution of N-phenyl-4,4'-bipyridine-2,2'-diamine
(160 mg, 0.61 mmol) in 10 mL of pyridine. After lh stirring, the solvent was removed under vacuum and the crude product was purified by HPLC : column : XTerra® prep MSCs, gradient 20-80%B, 20mL/min, 40°C, (A-0. IM ΝH4OAc in 0.1 % CH3CN aqueous solution, B-CH3CN). Yield : 48% (110 mg). 1H NMR (400 MHz, CDCI3) :δ 8.49 (s, 1 H),
'8.32 (d, 7=6.1 Hz, 1 H), 8.28 (d, 7=4.5 Hz, 1 H), 8.05 (s, 1 H), 7.42 - 7.33 (m, 4 H), 7.23 - 7.19 (m, 1 H), 7.09 - 7.03 (m, 2 H), 6.99 (d, 7=5.6 Hz, 1 H), 6.71 (s, 1 H), 4.10 - 4.02 (m, 2 H), 3.51 - 3.41 (m, 2 H), 2.59 - 2.49 (m, 1 H), 1.95 - 1.84 (m, 4 H). 13C NMR (101 MHz, CDC13) :δ 172.97 (s, 1 C), 156.66 (s, 1 C), 152.05 (s, 1 C), 149.20 (s, 1 C), 148.43 (s, 1 C), 147.38 (s, 1 C), 140.17 (s, 1 C), 129.38 (s, 2 C), 123.07 (s, 1 C), 120.35 (s, 2 C), 117.82 (s, 1 C), 113.24 (s, 1 C), 111.70 (s, 1 C), 106.29 (s, 1 C), 67.07 (s, 2 C), 43.26 (s, 1 C), 29.01 (s, 2 C). MS (TSP) m/z (M+l) : 375.
Example 183 Ethyl 3-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-3-oxopropanoate
3-Ethoxy-3-oxopropanoic acid (33 mg, 0.25 mmol) and N-[(dimethylamino)(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (142mg, 0.375 mmol) were diluted in 4 mL of dry N, N- dimethylformamide under a nitrogen atmosphere. Diisopropylethylamine (64 mg, 87μL, 0.575 mmol) was added dropwise. After lh stirring, a solution of N-phenyl-4,4'- bipyridine-2,2'-diamine (65 mg, 0.25 mmol) in dry N N-dimethylformamide (lmL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCU3 (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 purified by flash chromatography (ethyl acetate/methanol : 98/2). Yield : 27 % (25 mg). 1H NMR (400 MHz, CDC13) :δ 9.59 (s, 1 H), 8.42 (s, 1 H), 8.35 (d, 7=6.1 Hz, 1 H), 8.28 (d, 7=6.1 Hz, 1 H), 7.41 - 7.32 (m, 4 H), 7.23 - 7.22 (m, 1 H), 7.10 - 7.04 (m, 2 H), 7.01 - 6.95 (m, 1 H), 6.81 (s, 1 H), 4.27 (q, 7=7.1 Hz, 2 H), 3.51 (s, 2 H), 1.32 (t, 7=7.1 Hz, 4 H). MS (TSP) m/z (M+l) : 377.
Example 184 N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(methylthio)propanamide
3-Thiomethoxy propanoic acid (33 mg, 0.25 mmol) and N-[(dimethylamino)(377- [ 1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (142mg, 0.375 mmol) were diluted in 4 mL of dry N N- dimethylformamide under a nitrogen atmosphere. Diisoprylethylamine (64 mg, 87μL, 0.575 mmol) was added dropwise. After lh stirring, a solution of N-phenyl-4,4'- bipyridine-2,2'-diamine (65 mg, 0.25 mmol) in dry N, N-dimethylformamide (lmL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCθ3 (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 purified by flash chromatography (ethyl acetate/methanol : 98/2). Yield : 27 % (25 mg). 1H NMR (400 MHz, CDC13) :δ 8.67 (s, IH), 8.47 (s, 1 H), 8.32 (d, 7=5.1 Hz, 1 H), 8.28 (d, 7=5.1 Hz, 1 H), 7.42 - 7.31 (m, 4 H), 7.20 (d, 7=5.1 Hz, 1 H), 7.09 - 7.02 (m, 2 H), 6.98 (d, 7=5.6 Hz, 1 H), 2.92 - 2.85 (m, 2 H), 2.72 (t, 7=7.1 Hz, 2 H), 2.15 (s, 3 H). 13C NMR (101 MHz, CDC13) :δ 156.63 (s, 1 C),
149.13 (s, 1 C), 148.83 (s, 1 C), 148.39 (s, 1 C), 147.36 (s, 1 C), 147.35 (s, 1 C), 140.13 (s, 1 C), 129.34 (s, 2 C), 122.95 (s, 1 C), 120.33 (s, 1 C), 120.19 (s, 2 C), 117.78 (s, 1 C), 113.17 (s, 1 C), 111.75 (s, 1 C), 106.28 (s, 1 C), 37.35 (s, 1 C), 37.32 (s, 1 C), 29.39 (s, 1 C). MS (TSP) m/z (M+l) : 365.
Example 185 (±)N-(2'-anilino-4,4'-bipyridin-2-yl)-2-pyrrolidin-2-ylacetamide
[l-(tert-butoxycarbonyl)pyrrolidin-2-yl] acetic acid (163 mg, 0.75 mmol) andN- [(dimethylamino)(3H-[ 1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N- methylmethanaminium hexafluorophosphate (380 mg, 1.0 mmol) were diluted in 4 mL of dry N, N-dimethylformamide under a nitrogen atmosphere. Diisopropylethylamine (193 mg, 258 μL, 1.5 mmol) was added dropwise. After lh stirring, a solution of N-phenyl-4,4' - bipyridine-2,2'-diamine (131 mg, 0.50 mmol) in dry N, N-dimethylformamide (2 mL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCθ3 (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). This compound (207 mg) was diluted in 10 mL dichloromethane under nitrogen atmosphere and the solution was cooled to 0°C. Trifluoroacetic acid (2 mL) was added dropwise and the solution stirred for 15h at 20°C. The solvents were removed under vacuum. The resulting material was diluted in MeOH (10 mL) and mixed with Dowex. After filtration the solution was concentrated under vacuum the crude material purified by HPLC column : XTerra® prep MSC8, gradient 20- 80%B, 20mL/min, 40°C, (A-0.1M NH4OAc in 0.1% CH3CN aqueous solution, B- CH3CN). Yield : 38% (71 mg). 1H NMR (400 MHz, CDC13) :δ 8.44 (s, 1 H), 8.34 (d, 7=4.5 Hz, 1 H), 8.28 (d, 7=6.1 Hz, 1 H), 7.42 - 7.33 (m, 4 H), 7.16 (d, 7=3.5 Hz, 1 H), 7.09 - 7.02 (m, 2 H), 6.99 (d, 7=5.1 Hz, 1 H), 6.77 (s, 1 H), 3.63 - 3.51 (m, 1 H), 3.09 - 3.02 (m, 2 H), 2.54 - 2.42 (m, 2 H), 2.05 - 1.96 (m, 1 H), 1.94 - 1.82 (m, 1 H), 1.76 (ddd, 7=12.6, 9.1, 7.1 Hz, I H), 1.56- 1.44 (m, 1 H). MS (TSP) m/z (M+l) : 374.
Example 186 (35)-3-amino-N-(2'-anilino-4,4'-bipyridin-2-yl)-4-cyanobutanamide
(3S)-5-amino-3-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (57 mg, 0.25 mmol) and N-[(dimethylamino)(3i7-[ 1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N- methylmethanaminium hexafluorophosphate (142mg, 0.375 mmol) were diluted in 4 mL of dry N N-dimethylformamide under a nitrogen atmosphere. Diisopropylethylamine (64 mg, 87μL, 0.575 mmol) was added dropwise. After lh stirring, a solution of N-phenyl- 4,4'-bipyridine-2,2'-diamine (65 mg, 0.25 mmol) in dry N N-dimethylformamide (lmL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCθ3 (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 MSC8, gradient 20-80%B, 20mL/min, 40°C, (A-0.1M NHtOAc in 0.1% CH3CN aqueous solution, B-CH3CN). Yield : 12% (11 mg). 1H NMR (400 MHz, MeOD-d4) :δ 8.44 (s, 1 H), 8.36 (dd, 7=5.3, 0.8 Hz, 1 H), 8.18 (dd, 7=5.5, 0.8 Hz, 1 H), 7.55 - 7.51 (m, 2 H), 7.36 (dd, 7=5.3, 1.6 Hz, 1 H), 7.31 - 7.26 (m, 3 H), 7.09 (dd, 7=1.6, 0.8 Hz, 1 H), 7.02 (dd, 7=5.4, 1.7 Hz, 1 H), 6.99 - 6.94 (m, 1 H), 3.61 - 3.53 (m, 1 H), 2.73 - 2.63 (m, 4 H). 13C NMR (101 MHz, MeOD-d4) :δ 171.85 (s, 1 C), 158.52 (s, 1 C), 153.82 (s, 1 C), 149.88 (s, 1 C), 149.72 (s, 1 C), 149.39 (s, 1 C), 148.64 (s, 1 C), 142.40 (s, 1 C), 129.91 (s, 2 C), 123.02 (s, 1 C), 120.63 (s, 2 C), 119.00 (s, 1 C), 118.66 (s, 1 C), 113.34 (s, 1 C), 113.01 (s, 1 C), 109.09 (s, 1 C), 46.82 (s, 1 C), 43.47 (s, 1 C), 26.06 (s, 1 C). MS (TSP) m/z (M+l): 373.
Example 187 N1-(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. Diisopropylethylamine (64 mg, 87μL, 0.575 mmol) was added dropwise. After lh stirring, a solution of N-phenyl- 4,4'-bipyridine-2,2'-diamine (65 mg, 0.25 mmol) in dryN N-dimethylformamide (lmL) was slowly added and the mixture stirred for 15h at 20°C. The mixture was poured on a saturated aqueous solution of ΝaHCθ3 (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 purified by flash chromatography (ethyl acetate/methanol : 98/2). Yield : 48 % (45 mg). IH NMR (400 MHz, MeOD-d4) :δ 8.43 (s, 1 H), 8.37 (d, 7=5.1 Hz, 1 H), 8.19 (d, 7=5.6 Hz, 1 H), 7.53 (d, 7=7.6 Hz, 2 H), 7.41 - 7.36 (m, 1 H), 7.32 - 7.25 (m, 2 H), 7.09 (s, 1 H), 7.03 (d, 7=7.1 Hz, 1 H), 7.00 - 6.94 (m, 1 H), 1.71 - 1.64 (m, 2 H), 1.57 - 1.48 (m, 2 H). MS (TSP) m/z (M+l) : 374.
Example 188
(35) - 1 -acetyl-iV-(2' -anilino-4,4 ' -bipyridin-2-yl)piperidine-3-carboxamide
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. After 5min, this solution was added to a solution of N-phenyl-4,4' -bipyridine-2,2'-diamine (200 mg, 0.76 mmol) in 2 mL of dimethylformamide under nitrogen. After 2 days of stirring, the reaction was quenched with a 2M aqueous solution of potassium carbonate (5 mL). The aqueous layer was extracted with dichloromethane. After evaporation of the solvent, the resulting oil was purified by HPLC. Yield : 53 mg (17%). 1H NMR (MeOD-d4) :δ 8.52-8.42 (m, 2H), 7.95 (d, J = 6.5 Hz, IH), 7.58 (m, 3H), 7.51-7.42 (m, 4H), 7.34 (dd, J = 7, 2 Hz, IH), 4.53 (m, IH), 4.19 (m, IH), 3.98-3.84 (m, 2H), 2.99 (m, IH), 2.13 (s, 3H), 2.13-1.26 (m, 4H). MS (ES) m/z (M+l) : 416.
Example 189
_V-(2' -anilino-4,4' -bipyridin-2-yl)tetrahydrofuran-3-carboxamide (+) and (-) 1 -Hydroxybenzotriazole (104 mg, 0.76 mmol), 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethymronium tetrafluoroborate (244 mg, 0.76 mmol) and tetrahydrofuran-3- carboxylic acid (72μL, 0.76 mmol) were diluted in dry NN-dimethylformamide (4 mL) under a nitrogen atmosphere. Diisopropylethylamine (264 μL, 1.52 mmol) was added dropwise. After 30 min stirring, a solution of N-phenyl-4,4'-bipyridine-2,2'-diamine (200 mg, 0.76 mmol) in dry NN-dimethylformamide (2 mL) was slowly added and the solution was stirred for 3 days at room temperature. The reaction mixture was poured on a aqueous solution of potassium carbonate (2M, 10 mL) and extracted with dichloromethane. 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 : gradient 100/0 to 90/10). Yield : 21 % (59 mg). The racemic mixture was separated by chiral chromatography to afford 10 mg of the (+) enantiomer and 10 mg of the (-) enantiomer.
1H ΝMR (400 MHz, CDC13) :δ 10.56 (s, 1 H), 8.96 (s, 1 H), 8.45 (s, 1 H), 8.36 (d, 7=5.6 Hz, 1 H), 8.01 (d, 7=6.1 Hz, 1 H), 7.49 - 7.41 (m, 2 H), 7.37 - 7.30 (m, 3 H), 7.18 (s, 1 H), 7.12 (d, 7=4.5 Hz, 1 H), 7.06 (d, 7=6.1 Hz, 1 H), 4.05 - 3.95 (m, 3 H), 3.87 - 3.79 (m, 1 H), 3.25 - 3.16 (m, 1 H), 2.30 - 2.21 (m, 2 H). MS (ES) m/z (M+l) : 361.
Example 190 N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}tetrahydrofuran-3-carboxamide
1 -Hydroxybenzotriazole (51 mg, 0.38 mmol), 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (122 mg, 0.38 mmol) and tetrahydrofuran-3- carboxylic acid (24μL, 0.25 mmol) were diluted in dry NN-dimethylformamide (3 mL) under a nitrogen atmosphere. Diisopropylethylamine (87 μL, 0.50 mmol) was added dropwise. After 30 min stirring, a solution of N-(4-fluorophenyl)-4,4'-bipyridine-2,2'- diamine (70 mg, 0.25 mmol) in dry NN-dimethylformamide (2 mL) was slowly added and the solution was stirred for 3 days at room temperature. The reaction mixture was poured on a saturated aqueous solution of sodium bicarbonate (10 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 purified by flash chromatography (ethyl acetate/methanol : 98/2). Yield : 32 % (30 mg). The racemic mixture was separated by chiral chromatography to afford 10 mg of the (-) enantiomer and 12 mg of the (+) enantiomer.1H ΝMR (400 MHz, MeOD-d ) :δ 8.37 (s, 1 H), 8.32 (d, 7=5.1 Hz, 1 H), 8.12 (d, 7=5.1 Hz, 1 H), 7.49 (dd, 7=9.1, 4.5 Hz, 2 H), 7.31 (d, 7=5.1 Hz, 1 H), 7.00 - 6.94 (m, 4 H), 3.97 (t, 7=8.1 Hz, 1 H), 3.92 - 3.85 (m, 2 H), 3.81 - 3.71 (m, 1 H), 2.18 (q, 7=7.1 Hz, 2 H). 19F ΝMR (376 MHz, MeOD-d4) :δ -124.05 (m, 1 F). MS (ES) m/z (M+l) : 379.
Example 191 N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}tetrahydro-2flr-pyran-4- carboxamide Tetrahydro-27 -pyran-4-carboxylic acid (97.5 mg, 0.75 mmol) was dissolved in 5 mL of thionyl chloride and the solution stirred for 30 min at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 2 mL dichloromethane. This solution was added dropwise to a solution of N-(4-fluorophenyl)-4,4'-bipyridine-2,2'- diamine (70 mg, 0.25 mmol) in 10 mL of pyridine. After lh stirring, the solvent was removed under vacuum and the crude product was purified by HPLC column : XTerra® prep MSCs, gradient 20-80%B, 20mL/min, 40°C, (A-0.1M ΝH4OAc in 0.1% CH3CN aqueous solution, B-CH3CN). Yield : 47% (130 mg). 1H NMR (400 MHz, DMSO-d6) :δ 10.63 (s, 1 H), 9.31 (s, IH), 8.49 (s, 1 H), 8.43 (d, 7=5.1 Hz, 1 H), 8.25 (d, 7=5.6 Hz, 1 H), 7.76 - 7.69 (m, 2 H), 7.45 - 7.40 (m, 1 H), 7.14 - 7.06 (m, 4 H), 3.94 - 3.87 (m, 2 H), 2.83 - 2.73 (m, 1 H), 1.74 - 1.64 (m, 4 H). MS (TSP) m/z (M+l) : 393. Example 192
Ethyl 4-({2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}amino)-4-oxobutanoate
4-Ethoxy-4-oxobutanoic acid (95 mg, 0.65 mmol) and 7-(7-azabenzotriazol-l-yl)-
NNN'.N'-tetramethyluronium hexafluorophosphate (342 mg, 0.90 mmol) were diluted in 6 mL of dry Ν,Ν-dimethylformamide under a nitrogen atmosphere. Diisopropylethylamine (74 mg, lOOuL, 0.575 mmol) was added dropwise. After lh stirring, a solution of N-(4- fluorophenyl)-4,4'-bipyridine-2,2'-diamine (140 mg, 0.50 mmol) in dry Ν,Ν- dimethylformamide (2mL) was slowly added and the mixture stirred for 15h at 20 C. The mixture was poured on a saturated aqueous solution of NaHCO3 (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 purified by flash chromatography (ethyl acetate/methanol : 98/2). Yield : 35 % (72 mg). 1H NMR (400 MHz, DMSO- d6) :δ 10.71 (s,' l H), 9.31 (s, 1 H), 8.46 - 8.37 (m, 2 H), 8.25 (d, 7=5.6 Hz, 1 H), 7.72 (dd, 7=9.1, 5.1 Hz, 2 H), 7.47 - 7.37 (m, 1 H), 7.14 - 7.04 (m, 4 H), 4.08 - 3.98 (m, 2 H), 2.71 (d, 7=7.1 Hz, 2 H), 2.60 (d, 7=7.1 Hz, 2 H), 1.19 - 1.11 (m, 3 H). MS (TSP) m/z (M+l) : 409.
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. The solution was concentrated under vacuum, filtered and the filtrate was extracted with ethyl acetate. The aqueous layer was acidified with acetic acid to pH 4 and then extracted with ethyl acetate (3x10 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum to afford the acid. Yield : 88% (40 mg). IH NMR (400 MHz, DMSO- d6) :δl 1.14 (s, 1 H), 9.34 (s, 1 H), 8.46 (s, 1 H), 8.44 - 8.37 (m, 1 H), 8.24 (d, 7=5.3 Hz, 1 H), 7.78 - 7.67 (m, 2 H), 7.38 (dd, 7=5.2, 1.7 Hz, 1 H), 7.15 - 7.04 (m, 4 H), 2.65 - 2.56 (m, 2 H), 2.46 - 2.37 (m, 2 H). MS (TSP) m/z (M+l) : 381.
Example 194 N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}-3-(methylthio)propanamide
3-(Methylthio)propanoic acid (21 mL, 24 mg, 0.25 mmol) was slowly added to 1 mL of a IM oxalyl chloride solution in dichloromethane under nitrogen atmosphere at 0°C. After 30 min stirring, the solvent was removed under vacuum and the afforded oil was diluted in 0.5 mL of dry dichloromethane. This solution was added dropwise to a solution of N-(4- fluorophenyl)-4,4'-bipyridine-2,2'-diamine (70 mg, 0.25 mmol) in pyridine (5mL). After lh stirring at 20°C, the mixture was filtered and the solvent evaporated under vacuum. The crude material was purified by flash chromatography (ethyl acetate/ethanol . 98/2). Yield : 38% (36 mg). 1H ΝMR (400 MHz, CDC13) :δ 8.46 (s, 1 H), 8.34 - 8.30 (m, 1 H), 8.26 (d, 7=5.3 Hz, 1 H), 8.24 (s, 1 H), 7.40 - 7.34 (m, 2 H), 7.20 (dd, 7=5.2, 1.7 Hz, 1 H), 7.09 - 7.02 (m, 2 H), 6.98 (dd, 7=5.3, 1.6 Hz, 1 H), 6.92 (s, 1 H), 6.55 (s, 1 H), 2.89 (t, 7=6.8 Hz, 2 H), 2.72 (t, 7=6.9 Hz, 2 H), 2.17 (s, 3 H). MS (TSP) m/z (M+l) : 383.
Example 195
(i)-l-Acetyl-N-{2,-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3- carboxamide
(±)-l-Acetylpiperidine-3-carboxylic acid (85 mg, 0.5 mmol) was dissolved in 3 mL of thionyl chloride and the solution was stirred for lh at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 1.0 mL dichloromethane. This solution was added dropwise to a solution of N-(4-fluorophenyl)-4,4'-bipyridine-2,2'- diamine (140 mg, 0.5 mmol) in 7 mL of pyridine. After 10 min stirring, the solvent was removed under vacuum and the crude product was purified by flash chromatography (ethyl acetate/methanol : 95/5 to 90/10). Yield : 17% (38 mg). 1H ΝMR (400 MHz, CDC13) :δ 8.86 (s, 1 H), 8.44 (s, 1 H), 8.33 - 8.28 (m, 1 H), 8.26 - 8.21 (m, 1 H), 7.40 - 7.34 (m, 2 H), 7.23 - 7.15 (m, 1 H), 7.07 - 7.01 (m, 2 H), 6.96 (m, 2 H), 6.92 (s, 1 H), 4.60-4.50 (m, 1 H), 3.95-3.70 (m, 1 H), 3.42 - 2.70 (m, 2 H), 2.58-2.52 (m, 1 H), 2.14 - 2.06 (m, 4 H), 2.00- 1.80 (m, 2 H), 1.52 (m, 1 H). MS (TSP) m/z (M+l): 434.
Example 196 (3R)-l-Acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3- carboxamide
(3R)-l-acetylpiperidine-3-carboxylic acid (75 mg, 0.44 mmol) was dissolved in 5 mL of thionyl chloride and the solution was stirred for lh at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 1.5 mL dichloromethane. This solution was added dropwise to a solution of N-(4-fluorophenyl)-4,4'-bipyridine-2,2'- diamine (115 mg, 0.41 mmol) in 5 mL of pyridine. After 10 min stirring, the solvent was removed under vacuum and the crude product was purified by HPLC column : XTerra® prep MSCs, gradient 20-60%B, 20mL/min, 40°C, (A-0.1M ΝH4OAc in 0.1% CH3CN aqueous solution, B-CH3CN). Yield : 46% (82 mg). 1H NMR (400 MHz, CDC13) :δ 8.86 (s, 1 H), 8.44 (s, 1 H), 8.33 - 8.28 (m, 1 H), 8.26 - 8.21 (m, 1 H), 7.40 - 7.34 (m, 2 H), 7.23
- 7.15 (m, 1 H), 7.07 - 7.01 (m, 2 H), 6.96 (m, 2 H), 6.92 (s, 1 H), 4.60-4.50 (m, 1 H), 3.95- 3.70 (m, 1 H), 3.42 - 2.70 (m, 2 H), 2.58-2.52 (m, 1 H), 2.14 - 2.06 (m, 4 H), 2.00-1.80 (m, 2 H), 1.52 (m, 1 H). MS (TSP) m/z (M+l): 434.
Example 197
(35)-l-acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3- carboxamide (35)-l-acetylpiperidine-3-carboxylic acid (75 mg, 0.44 mmol) was dissolved in 5 mL of thionyl chloride and the solution was stirred for lh at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 1.5 mL dichloromethane. This solution was added dropwise to a solution of N-(4-fluorophenyl)-4,4'-bipyridine-2,2'- diamine (115 mg, 0.41 mmol) in 5 mL of pyridine. After 10 min stirring, the solvent was removed under vacuum and the crude product was purified by HPLC column : XTerra® prep MSC8, gradient 20-60%B, 20mL/min, 40°C, (A-0.1M ΝH OAc in 0.1% CH3CN aqueous solution, B-CH3CN). Yield : 58% (102 mg). 1H NMR (400 MHz, CDC13) :δ 8.86 (s, 1 H), 8.44 (s, 1 H), 8.33 - 8.28 (m, 1 H), 8.26 - 8.21 (m, 1 H), 7.40 - 7.34 (m, 2 H), 7.23
- 7.15 (m, 1 H), 7.07 - 7.01 (m, 2 H), 6.96 (m, 2 H), 6.92 (s, 1 H), 4.60-4.50 (m, 1 H), 3.95- 3.70 (m, 1 H), 3.42 - 2.70 (m, 2 H), 2.58-2.52 (m, 1 H), 2.14 - 2.06 (m, 4 H), 2.00-1.80 (m,
2 H), 1.52 (m, 1 H).
MS (TSP) m/z (M+l): 434. Example 198 l-Acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}pyrrolidine-3- carboxamide (El) and (E2) l-Acetylpyrrolidine-3-carboxylic acid (97 mg, 0.62 mmol) was dissolved in 5 mL of thionyl chloride and the solution was stirred for lh at room temperature. The solvent was removed under vacuum and the resulting oil was dissolved in 1.5 mL dichloromethane. This solution was added dropwise to a solution of N-(4-fluorophenyl)-4,4'-bipyridine-2,2'- diamine (141 mg, 0.51 mmol) in 5 mL of pyridine. After lh stirring, the solvent was removed under vacuum and the crude product was purified by HPLC : XTerra® prep MSCs, gradient 20-50%B, 20mL/min, 40°C, (A-0.1M ΝH4OAc in 0.i% CH3CN aqueous solution, B-CH3CN). Yield : 37% (80 mg). This racemate was then purified on a chiral column to afford 2 enantiomers El (6 mg) and E2 (6 mg). 1H NMR (400 MHz, CDC13) :δ 8.67 - 8.58 (m, 1 H), 8.49 - 8.40 (m, 1 H), 8.34 - 8.28 (m, 1 H), 8.28 - 8.20 (m, 1 H), 7.41 - 7.34 (m, 2 H), 7.25 - 7.18 (m, 1 H), 7.09 - 7.02 (m, 2 H), 6.99 - 6.95 (m, 1 H), 6.95 - 6.87
(m, 2 H), 3.87-3.73 (m, 3 H), 3.57 - 3.47 (m, 1 H), 3.26 - 3.04 (m, 1 H), 2.44 - 2.23 (m, 2
H), 2.09 - 2.05 (m, 3 H).
MS (TSP) m/z (M+l) : 420.
Example 199 3-(Aminosulfonyl)-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}benzamide
3-(Aminosulfonyl)benzoic acid (56 mg, 0.28 mmol) was diluted in thionyl chloride (5 mL) and the mixture was heated at reflux for 4h. The solvent was evaporated and the crude material dissolved in 1 mL dichloromethane. This solution was added dropwise to a solution of N-(4-fluorophenyl)-4,4'-bipyridine-2,2'-diamine (77 mg, 0.27 mmol) in 5 mL of pyridine. After 2h stirring, the resulting mixture was concentrated in vacuo and the crude material purified by HPLC : XTerra® prep MSC8, gradient 20-80%B, 20mL/min, 40°C, (A-0.1M ΝH4OAc in 0.1% CH3CN aqueous solution, B-CH3CN). Yield : 1.5% (2 mg).1H NMR (400 MHz, MeOD-d4) : δ 8.58 (s, 1 H), 8.51 (s, 1 H), 8.47 (d, 7=5.3 Hz, 1 H), 8.23 - 8.17 (m, 2 H), 8.13 (d, 7=8.4 Hz, 1 H), 7.73 (t, 7=7.8 Hz, 1 H), 7.60 - 7.52 (m, 2 H), 7.47 (dd, 7=5.2, 1.5 Hz, 1 H), 7.11 - 7.00 (m, 4 H). MS (TSP) m/z (M+l): 464. Example 200
Ethyl 2-{[(2,-anilino-4,4'-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylate
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 ΝaHCθ3 (20 mL) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The crude product was purified by flash chromatography (ethyl acetate/methanol : 98/2). Yield : 62% (120 mg) as a yellow powder. 1H NMR (400 MHz, MeOD-d4) : δ 8.10 (d, 7=5.6 Hz, 1 H), 7.95 (t, 7=5.6 Hz, 1 H), 7.45 (d, 7=8.1 Hz, 2 H), 7.26 - 7.21 (m, 2 H), 6.98 (s, 1 H), 6.94 - 6.90 (m, 2 H), 6.75 - 6.70 (m, 2 H), 4.04 (q, 7=7.1 Hz, 2 H), 3.56-3.19 (m, 2 H), 1.70 - 1.64 (m, 1 H), 1.61 - 1.53 (m, 1 H), 1.21 - 1.15 (m, 3 H), 1.13 - 1.07 (m, 1 H), 0.92 - 0.84 (m, 1 H). MS (ES) m/z (M+l) : 389.
Example 201 2-{[(2'-Anilino-4,4'-bipyridin-2-yl)aniino]methyl}cyclopropanecarboxyIic acid
Ethyl 2-{[(2'-anilino-4,4'-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylate (120 mg, 0.31 mmol) was dissolved in a mixture of THF/H2O (2:1) (6mL). Then, potassium hydroxide (21 mg, 0.37 mmol) was added and the mixture stirred for 20h at 20°C. THF was evaporated and the aqueous layer extracted with ethyl acetate (2x10 mL). The aqueous layer was diluted (with 5 mL H2O) and acidified with acetic acid until pH 5. The acidic mixture was extracted with ethyl acetate (2x10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to afford the acid as a pure product. Yield : 54% (60 mg). 1H NMR (400 MHz, CDC13) :δ 8.18 (d, 7=5.6 Hz, 1 H), 7.98 (d, 7=5.6 Hz, 1 H), 7.61 (s, 1 H), 7.39 - 7.30 (m, 4 H), 7.11 - 7.03 (m, 2 H), 6.88 (d, 7=4.0 Hz, 1 H), 6.71 (d, 7=5.6 Hz, 1 H), 6.52 (s, 1 H), 3.50 (dd, 7=13.1, 6.1 Hz, 1 H), 3.00 - 2.90 (m, 1 H), 1.78 (d, 7=6.1 Hz, 1 H), 1.66 - 1.55 (m, 1 H), 1.37 - 1.28 (m, 1 H), 0.92 - 0.85 (m, 1 H). MS (TSP) m/z (M+l) : 361.
Example 202 N-phenyI-N'-(tetrahydro-2flr-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 Ν2 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. H2O (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. Yield : 71 % (40 mg). 1H NMR (400 MHz, CDC13) :δ 8.22 (d, 7=5.3 Hz, 1 H), 8.08 (d, 7=5.3 Hz, 1 H), 7.37 - 7.27 (m, 5 H), 7.11 - 7.02 (m, 2 H), 6.90 (d, 7=5.3 Hz, 1 H), 6.71 (d, 7=5.3 Hz, 1 H), 6.48 (s, 1 H), 5.24 (s, 1 H), 3.98 (dd, 7=11.1, 3.5 Hz, 2 H), 3.42 - 3.33 (m, 2 H), 3.20 (d, 7=3.5 Hz, 2 H), 1.91 - 1.80 (m, 1 H), 1.70 (dd, 7=13.0, 1.9 Hz, 2 H), 1.36 (m, 2 H). 13C NMR (101 MHz, CDC13) :δ 159.20 (s, 1 C), 156.67 (s, 1 C), 148.70 (s, 1 C), 148.61 (s, 1 C), 148.28 (s, 1 C), 148.15 (s, 1 C), 140.09 (s, 1 C), 129.41 (s, 2 C), 123.25 (s, 1 C), 120.68 (s, 2 C), 113.03 (s, 1 C), 110.85 (s, 1 C), 105.70 (s, 1 C), 104.11 (s, 1 C), 67.65 (s, 2 C), 48.14 (s, 1 C), 35.07 (s, 1 C), 30.88 (s, 2 C). MS (ES) m/z (M+l) : 361.
Example 203
N-phenyl-N' -(tetrahydrofuran-3-yImethyl) -4,4 ' -bipyridine-2,2' -diamine
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide (43 mg, 0.12 mmol) was dissolved in THF (5 mL) under Ν2 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. H2O (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. HCl (aq.) and freeze dried to give the HCl salt. Yield : 61% (28 mg). 1H NMR (400 MHz, MeOD-d4) :δ 8.16 (d, 7=5.6 Hz, 1 H), 7.90 (d, 7=6.6 Hz, 1 H), 7.47 (d, 7=8.6 Hz, 2 H), 7.32 - 7.24 (m, 2 H), 7.10 (s, 1 H), 7.06 -6.97 (m, 3 H), 3.91 - 3.80 (m, 2 H), 3.77 - 3.68 (m, 1 H), 3.57 (dd, 7=8.6, 5.1 Hz, 1 H), 3.33 (d, 7=7.6 Hz, 2 H), 2.60 (s, 1 H), 2.12 (d, 7=13.1 Hz, 1 H), 1.68 (s, 1 H). MS (ES) m/z (M+l) : 347.
List of abbreviations
SPA scintillation proximity assay
ATP adenosine triphosphate
ATF Activating transcription factor
MOPS 3-[N-Morpholino]-propanesulfonic acid
EGTA Ethylene glycol-bis(β-aminoethylether)-N,N,N',N,-tetraacetic acid
DTT dithiothreitol
JNK Jun N-terminal kinases
MAP mitogen-activated protein
Biological evaluation
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 γ-phosphate group of [γ- 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 β-glycerolphosphate) and 10 μl are transferred to assay plates (results in 2% DMSO final concentration in assay). To each well with test compound a 2.4 μl JNK3/ATP enzyme solution (1.18 U/ml JNK3, 20 μM 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. After this, 3.6 μl of a [γ-33P] ATP-solution (0.20 μCi/μl [γ-33P]ATP, 66.6 mM Mg(Ac)2, 1 mM DTT, 50 mM MOPS pH 7.2, 150 mM NaCI, 0.1 mM EGTA) was added to each well followed by 10 μl a ATF2 solution (60 μg/ml biotinylated ATF2 in assay buffer) to start the reaction. The reaction was allowed to proceed for 10 minutes at ambient temperature. After this, the reaction was terminated by the addition of 200 μl 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 microbeta™.
The IC50 values were calculated as the concentration of test compound at which the ATF2 phosphorylation is reduced to 50% of the control value.
Results
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
1000 nM. Further values for Ki are in the range of about 0.001 nM to about 300 nM.

Claims

A compound of the general Formula I
Figure imgf000076_0001
wherein:
R1 is aryl or heteroaryl, each of which is optionally substituted with one or more of
RJ, ORJ, OCORJ, COORJ, CORJ, CONR 3'Rn4, NHCORJ, NR >3JrR>44, NHSO2RJ, SO2RJ, SO2NR3R4, SR3, CN, halogeno and NO2;
R2 is R5, R6, COR5, COR6, CONHR5, CONHR6, CON(R6)2, COOR5, COOR6 SO2R5 or SO2R6;
R3 and R4 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)Cι-6 alkyl, heterocycle, heterocycleC1-6 alkyl, C1-6 fluoroalkyl, C1-6 trifluoroalkoxyl;
R is aryl or heteroaryl, each of which is optionally substituted with one or more of R7, OR7, OCOR7, COOR7, COR7, CONR7R8, CONHOR7, NHCOR7, NR7R8, NHSO2R7, SO2R7, SO2NR7R8, SR7, R7SR8, CN, halogeno, oxygen and NO2;
R6 is hydrogen, C1-6 alkyl, C3-8 cycloalkyl, (C3.8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycle .6 alkyl, heteroarylCι-6 alkyl, arylC1-6 alkyl, Cι-6 alkoxyl, or C2-6 alkenyl, wherein any of C1-6 alkyl, C3-8 cycloalkyl, (C3.8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleC1-6 alkyl, heteroarylC1-6 alkyl, arylC1-6 alkyl, C1-6 alkoxyl and C2-6 alkenyl is optionally substituted with one or more A;
R7 and R8 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, (C3.8 cycloalkyl)C1-6 alkyl, C2-6 alkenyl, aryl, heteroaryl, heteroarylC1-6 alkyl, heterocycle, heterocycleCι-6 alkyl, aryl, C1-6 fluoroalkyl and C1-6 chloroalkyl,wherein any of C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-6 alkyl, C2-6 alkenyl, heteroaryl, heteroarylC1-6 alkyl, heterocycle and heterocycleC1-6 alkyl is optionally substituted with one or more B;
R9 and R10 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-6 alkyl, C2-6 alkenyl, heterocycle, heterocycleCι-6 alkyl, heteroaryl, heteroarylC1-6 alkyl, aryl or arylC1-6 alkyl, wherein any of C1-6 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-6 alkyl, C2-6 alkenyl, heterocycle, heterocycleC1- alkyl, heteroaryl, heteroarylC1-6 alkyl, aryl or arylC1-6 alkyl is optionally substituted with one or more B;
A is R9, OR9, OCOR9, COOR9, COR9, CONR9R10, CONHOR9, NHCOR9, NR9R10, NR9SO2R10, SO2R9, SO2NR9R10, SR9, R9SR10 ,CN or halogeno;
B is C1-6 alkyl, C1-6 alkoxyl, C1-6 alkylamino, di(C1-6 alkyl)amino or halogeno;
as a free base or a salt, solvate or solvate of salt thereof.
A compound according to claim 1, wherein
R1 is aryl or heteroaryl, optionally substituted with one or more of R3, OR3, NR3R4, halogeno or NO2;
R2 is R5, R6, COR5, COR6, CONHR5, CONHR6, COOR6 or SO2R6;
R and R are each independently hydrogen, C1-6 alkyl or C1-6 fluoroalkyl; R5 is aryl or heteroaryl each of which is optionally substituted with one or more of R7, OR7, COOR7, COR7, CONHOR7, NR7R8, SO2R7, SO2NR7R8, SR7, halogeno, oxygen and NO2;
R6 is hydrogen, C1-6 alkyl, (C3.8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleCι-6 alkyl, wherein any of -β alkyl, (C3-8 cycloalkyl)C1-6 alkyl or heterocycle is optionally substituted with one or more A;
R7 and R8 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, aryl, heterocycle, wherein any of C1-6 alkyl is optionally substituted with one or more B;
R9 and R10 are each independently hydrogen, or C1-6 alkyl, wherein any C1-6 alkyl is optionally substituted with one or more B;
A is COOR9, COR9, CONR9R10, NHCOR9, NR9R10, SR9, R9SR10 , or CN;
B is halogeno or di(C1-6 alkyl)amino.
3. A compound according to claim 1 or 2, wherein R1 is aryl optionally substituted with one or more of R3, OR3 and NR3R4.
A compound according to claim 3, wherein said aryl is phenyl.
5. A compound according to claim 3 or 4, wherein R is selected from C1-6 fluoroalkyl, methyl and halogeno.
6. A compound according to any one of claims 1 to 5, wherein R2 is selected from R5,
COR5 and CONHR5.
7. A compound according to claim 6, wherein R5 is aryl, optionally substituted with one or more of R7, OR7, COOR7, COR7, CONHOR7, NR7R8, SO2R7, SO2NR7R8, SR7, halogeno, oxygen and NO2.
8. A compound according to claim 7, wherein R7 and R8 are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, aryl, heterocycle, wherein C1-6 alkyl is optionally substituted with one or more B, said B being halogeno.
9. A compound according to any one of claims 1 to 5, wherein R2 is selected from R6, COR6, CONHR6 and SO2R6.
10. A compound according to claim 9, wherein R6 is selected from hydrogen, C1-6 alkyl, (C3..8 cycloalkyl)C1-6 alkyl, heterocycle, heterocycleC1-6 alkyl, wherein any of C1-6 alkyl, (C3-8 cycloalkyl)C1-6 alkyl and heterocycle is optionally substituted with one or more A.
11. A compound according to claim 9, wherein said A is selected from COOR9, COR9, CCOONNRR99RR1100,, NNHHCCOORR99,, NNRR99RR1100,, SSRR99,, 1 R9SR10 and CN; and R9 and R10 are each independently hydrogen or C1-6 alkyl.
12. A compound which is
N,N'-Bis[4-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-diamine; NN'-Bis(4-fluorophenyl)-4,4'-bipyridine-2,2'-diamine;
NN'-Bis(3 ,4-difluorophenyl)-4,4' -bipyridine-2,2 ' -diamine;
N,N'-Bis[3-(trifluoromethyl)phenyl]-4,4'-bipyridine-2,2'-diamine;
NN'-Bis[3-(trifluoromethoxy)phenyl]-4,4'-bipyridine-2,2'-di amine;
N,N'-Bis(2-fluorophenyl)-4,4'-bipyridine-2,2'-diamine; NN'-Bis(2-methylphenyl)-4,4' -bipyridine-2,2' -diamine;
N,N'-Bis(2-aminophenyl)-4,4'-bipyridine-2,2'-diamine;
NN'-Bis(2-methoxyphenyl)-4,4' -bipyridine-2,2' -diamine;
N,N'-Bis(2-ethoxyphenyl)-4,4'-bipyridine-2,2'-diamine;
N-(2'-anilino-4,4'-bipyridin-2-yl)-tranj-4-methoxycyclohexanecarboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-cw-4-methoxycyclohexanecarboxamide;
N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}-trαnj,-4-methoxy- cyclohexanecarboxamide; N-{2,-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}-cw-4-methoxy- cyclohexanecarboxamide;
N-(6-methylpyridin-2-yl)-N-phenyl-4,4'-biρyridine-2,2'-diamine;
N-phenyl-N-pyridin-2-yl-4,4'-bipyridine-2,2'-diamine;
N- { 4-[(4-methylpiperazin- 1 -yl)sulfonyl] phenyl } -N-phenyl-4,4'-bipyridine-2,2'- diamine;
Ν-phenyl-Ν'-pyridin-3 -yl-4,4'-bipyridine-2,2 '-diamine ;
N-phenyl-N'-pyrimidin-2-yl-4,4'-bipyridine-2,2'-diamine;
N-phenyl-N,-pyrimidin-5-yl-4,4'-bipyridme-2,2'-di amine;
(2E)- 1 - {4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]phenyl } -3-(dimethylamino)prop-2- en-l-one;
4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-N-(2-pyrrolidin- 1 - ylethyl)benzenesulfonamide;
4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-N-(2-morpholin-4- ylethyl)benzenesulfonamide;
N- { 4-[(4-ethylpiperazin- 1 -yl)sulfonyl]phenyl } -N'-phenyl-4,4'-bipyridine-2,2'- diamine;
N-phenyl-N'-pyridin-4-yl-4,4'-bipyridine-2,2'-diamine;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-piperidin-l-ylpropanamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)nicotinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-(dimethylamino)benzamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-2,6-dimethoxynicotinamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-lH-indole-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)pyridine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridm-2-yl)-3-furamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-l,2,3-thiadiazole-4-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)isoxazole-5-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methylisoxazole-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)pyrazine-2-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)- 1 -methyl- lH-imidazole-4-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-furamide;
N-(2'-anilino-4,4,-bipyridin-2-yl)-4-methoxybenzamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-bromo-2-fur amide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-2-(methylthio)nicotinamide;
Methyl 4-{ [(2'-anilino-4,4'-bipyridin-2-yl)amino]carbonyl}benzoate;
3-(acetylamino)-N-(2'-anilino-4,4'-bipyridin-2-yl)benzamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-l-benzofuran-3- carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-5-[(pyridin-2-ylthio)methyl]-2-fur amide; N-(2'-anilino-4,4'-bipyridin-2-yl)nicotinamide 1 -oxide; N-(2'-anilino-4,4'-bipyridin-2-yl)-3-hydroxypyridine-2-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-6-bromopyridine-2-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)isonicotinamide 1 -oxide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-hydroxynicotinamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-6-hydroxypyridine-2-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-3-benzoylpyridine-2-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-6-methylpyridine-2-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-3,5-dimethylisoxazole-4-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-methoxynicotinamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-4-methyl-l,2,3-thiadiazole-5-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-chloroisonicotinamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methylisoxazole-4-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-3-methylisoxazole-4-carboxamide; N-(2'-anilino-4,4'-biρyridin-2-yl)-l -methyl- lH-pyrrole-2-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-chloronicotinamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-5-chloro-lH-indole-2-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-4-chloro-lH-pyrazole-3-carboxamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-5-methyl-lH-pyrazole-3-carboxamide; (2E)-N-(2'-anilino-4,4'-bipyridm-2-yl)-3-(3-furyl)acrylamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(2-oxo-l,3-benzoxazol-3(2H)-yl)propan amide; N'-(2'-anilino-4,4'-bipyridin-2-yl)-N,N-dimethylsuccinamide; N-(2'-anilino-4,4'-bipyridin-2-yl)-2-[(4-chlorophenyl)sulfonyl]acetamide; -bipyrid Iiin-2-yl)-5-oxoprolinamide; ■bipyrid ϊiin-2-yl)-3-methoxypropanamide; -bipyridin-2-yl)-4-methoxycyclohexanecarboxamide;
-bipyridin-2-yl)-3-methoxypropanamide;
-bipyridin-2-yl)tetrahydrofuran-3 -carboxamide ;
-bipyridin-2-yl)-4-(dimethylamino)butanamide;
-bipyridin-2-yl)nicotinamide;
-bipyridin-2-yl)-4-(dimethylamino)benzamide;
-bipyridin-2-yl)-2,6-dimethoxynicotinamide;
-bipyridin-2-yl)- 1 H-indole-2-carboxamide;
-bipyridin-2-yl)-5-methylpyrazine-2-carboxamide;
-bipyridin-2-yl)pyridine-2-carboxamide;
-bipyridin-2-yl)-3-furamide; •bipyridin-2-yl)-N-phenylurea;
-bipyridin-2-yl)-Ν'-phenylurea;
-bipyridin-2-yl)-N'-[ 1 -(4-bromophenyl)ethyl]urea;
-bipyridin-2-yl)-N'-thien-3-ylurea;
-bipyridin-2-yl)-N'-(2-methylphenyl)urea;
-bipyridin-2-yl)-N'-(4-methylphenyl)urea;
-bipyridin-2-yl)-N'-(3-fluorophenyl)urea;
-bipyridin-2-yl)-N'-(2-fluorophenyl)urea;
•bipyridin-2-yl)-N'-(4-fluorophenyl)urea;
■bipyridin-2-yl)-N'-[4-(chloromethyl)phenyl]urea;
■bipyridin-2-yl)-N'-(3-cyanophenyl)urea;
•bipyridin-2-yl)-N'-(4-cyanophenyl)urea;
■bipyridin-2-yl)-N'-(2-cyanophenyl)urea;
•bipyridin-2-yl)-N'-(2,3-dimethylphenyl)urea;
■bipyridin-2-yl)-N'-(2,5-dimethylphenyl)urea;
•bipyridin-2-yl)-N'-(4-ethylphenyl)urea;
■bipyridin-2-yl)-N'-(3-ethylphenyl)urea;
Figure imgf000082_0001
■bipyridin-2-yl)-N'-(4-methoxyphenyl)urea; N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-methoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-fluoro-2-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-fluorobenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-fluoro-5-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-fluorobenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorophenyl)urea;
N-(2,-anilino-4,4'-bipyridin-2-yl)-N'-(3-chlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chlorobenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,5-difluorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2,4-difluorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3,4-dichlorobenzyl)urea;
N-(4-acetylphenyl)-N'-(2'-anilino-4,4'-bipyridin-2-yl)urea;
N-(3-acetylphenyl)-N'-(2'-anilino-4,4'-bipyridin-2-yl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-isopropylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-isopropylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-ethyl-6-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-mesitylurea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-propylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(dimethylamino)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-l,3-benzodioxol-5-ylurea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methoxy-2-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methoxy-5-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-ethoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-methoxybenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(4-nitrophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(3-nitrophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[3-(methylthio)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-[4-(methylthio)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-methylbenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(5-chloro-2-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'-(2-chloro-5-methylphenyl)urea; N-(2'-anilino-4,4"-biρyridin-2-yl)-N'- (2-chlorobenzyl)urea;
N-(2,-anilino-4,4'-bipyridin-2-yl)-N' (3-chloro-4-fluorophenyl)urea;
N-(2,-anilino-4,4'-biρyridin-2-yl)-N' (2,3 ,4-trifluorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (4-butylρhenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (2-isopropyl-6-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (2-tert-butylphenyl)urea; methyl 4-({ [(2'-anilino-4,4'-bipyridin -2-yl)amino]carbonyl } amino)benzoate;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (3 ,4-dimethoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (3 ,5-dimethoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (3 -chloro-4-methoxyphenyl)urea;
N-(2'-anilino-4,4'-biρyridin-2-yl)-N'' [4-(difluoromethoxy)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' [2-(trifluoromethyl)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- [3-(trifluoromethyl)phenyl]urea;
N-(2'-anilino-4,4,-bipyridin-2-yl)-N' [4-(trifluoromethyl)phenyl]urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (2,5-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (3,5-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (3 ,4-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (2,3-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (2,4-dichlorophenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (4-bromo-3 -methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (2,6-dichloropyridin-4-yl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (4-butyl-2-methylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- [5-methyl-2-(trifluoromethyl)-3-furyl]urea; ethyl 3-({ [(2'-anilino-4,4'-bipyridin-2 yl)amino]carbonyl } amino)benzoate;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' (4-butoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (2,6-diisopropylphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N (4-methylbenzyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N'- (5-chloro-2,4-dimethoxyphenyl)urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' { 4- [(trifluoromethyl)thio]phenyl } urea;
N-(2'-anilino-4,4'-bipyridin-2-yl)-N' [3,5-bis(trifluoromethyl)phenyl]urea; l-acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-4-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-5-oxoprolinamide; N3-acetyl-N1-(2'-anilino-4,4'-bipyridin-2-yl)-β-alaninamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-4-carboxamide;
3-amino-N-(2'-anilino-4,4'-bipyridin-2-yl)butanamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)-L-prolinamide; N-(2'-anilino-4,4'-bipyridin-2-yl)acetamide;
Methyl 2'-anilino-4,4'-bipyridin-2-ylcarbamate;
N-(2'-anilino-4,4'-bipyridin-2-yl)methanesulfonamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)cyclohexanecarboxamide; l-Acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-2-carboxamide; l-Acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-3-carboxamide;
Ethyl 4-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-4-oxobutanoate;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-2-carboxamide;
(5)-3 N2-acetyl-Nl-(2'-anilino-4,4'-bipyridin-2-yl)methioninamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; Ethyl 3-[(2'-anilino-4,4'-bipyridin-2-yl)amino]-3-oxopropanoate;
N-(2'-anilino-4,4'-bipyridin-2-yl)-3-(methylthio)propan amide; (±)N-(2'-anilino-4,4'-bipyridin-2-yl)-2-pyrrolidin-2-ylacetamide; (3S)-3-amino-N-(2'-anilino-4,4'-bipyridin-2-yl)-4-cyanobutanamide;
Nl-(2'-anilino-4,4'-bipyridin-2-yl)cyclopropane-l,l-dicarboxamide; (35)-l-acetyl-N-(2'-anilino-4,4'-bipyridin-2-yl)piperidine-3-carboxamide;
N-(2'-anilino-4,4'-bipyridin-2-yl)tetrahydrofuran-3-carboxamide (+) and (-);
N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}tetrahydrofuran-3-carboxamide;
N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl }tetrahydro-2H-pyran-4- carboxamide; Ethyl 4-({2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}amino)-4-oxobutanoate;
4-( { 2'-[(4-Fluorophenyl)amino]-4,4'-bipyridin-2-yl } amino)-4-oxobutanoic acid;
N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl } -3-(methylthio)propanamide;
(£)- 1 -Acetyl-N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl }piperidine-3- carboxamide; (3R)-l-Acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3- carboxamide; (35)-l-acetyl-N-{2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl}piperidine-3- carboxamide;
1 -Acetyl-N- { 2'-[(4-fluoroρhenyl)amino]-4,4'-bipyridin-2-yl }pyrrolidine-3- carboxamide;
3-(Aminosulfonyl)-N- { 2'-[(4-fluorophenyl)amino]-4,4'-bipyridin-2-yl Jbenzamide;
Ethyl 2-{[(2'-anilino-4,4'-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylate;
2-{[(2'-Anilino-4,4'-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylic acid;
N-phenyl-N-(tetrahydro-277-pyran-4-ylmethyl)-4,4'-bipyridine-2,2'-diamine;
N-phenyl-N-(tetrahydrofuran-3-ylmethyl)-4,4'-bipyridine-2,2'-diamine;
as a free base or a salt, solvate or solvate of salt thereof.
13. A compound according to any one of claims 1 to 12, in the form of a pharmaceutically acceptable salt.
14. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1 to 13 in association with pharmaceutically acceptable carriers or diluents.
15. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1 to 13 for use in the prevention and/or treatment of conditions associated with JΝK activation.
16. A compound according to any one of claims 1 to 13 for use in therapy.
17. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the prevention and or treatment of conditions associated with JΝK activation.
18. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the prevention and/or treatment of conditions selected from: 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, HLV 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-, colorectal, pancreatic, prostate cancer.
19. The use according to claim 18 wherein said condition is Alzheimer's disease.
20. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the prevention and/or treatment of conditions associated with inhibiting the expression of inducible pro-inflammatory proteins.
21. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the prevention and/or treatment of conditions selected from edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.
22. 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 according to any one of claims 1 to 13 to a mammal in need thereof.
23. A method of treating or preventing conditions selected from 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,
HLV 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-, colorectal, pancreatic, prostate cancer comprising the administration of a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 13 to a mammal in need thereof.
24. The method according to claim 23, wherein said condition is Alzheimer's disease.
25. A method of treating or preventing associated with inhibiting the expression of inducible pro-inflammatory proteins comprising the administration of a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 13 to a mammal in need thereof.
26. The method according to claim 25, wherein the condition is selected from edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.
27. A process for the preparation of a compound of formula la, wherein R1 and R5 are as defined in claim 1 ;
Figure imgf000088_0001
la comprising the steps: 88
reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R!-I) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and
reacting a compound of Formula II in a second arylation reaction with an arylhalide ( (RR55--BBrr)) aanndd wwiitthh aa ttrraannssiittiioonn mmeettaall a catalyst or a palladium catalyst ("Pd-catalyst") to obtain a compound of formula la.
28. A process for the preparation of a compound of formula lb, lc or Id, wherein R1, R and R are as defined in claim 1 ;
Figure imgf000089_0001
comprising the steps: reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R1-! and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and reacting said compound of Formula II with a carboxylic acid ("R5COOH alt R COOH") in the presence of a amide coupling reagent and a base in an inert solvent to obtain a compound according to formula lb; or
reacting said compound of Formula II with a carboxylic acid chloride ("R5OCOCl a alltt RR66OOCCOOCCll"")) iinn aann iinneerrtt ssoollvveenntt iinn tthhe presence of a base in a solvent to obtain a compound according to formula lc; or
reacting said compound of Formula II with a chlorocarbonate or sulfonylchloride ("R5SO2Cl or R6SO2Cl") to obtain a compound according to formula Id.
29. A process for the preparation of a compound of formula le, wherein R1, R5 and R6 are as defined in claim 1 ;
Figure imgf000090_0001
comprising the steps: reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R!-I) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and reacting said compound of Formula II with a carboxylic acid ("R COOH alt R R66CCOOOOHH"")) ffoolllloowweedd bbyy rreedduuccttiioonn ttoo tthhee aammiinnee with a reducing agent in a solvent to obtain a compound according to formula le; or
reacting said compound of Formula II with a carboxaldehyde ("R5CHO alt
R6CHO") in the presence of a reducing agent to obtain a compound according to formula le.
30. A process for the preparation of a compound of formula If, wherein R1, R5 and R6 are as defined in claim 1 ;
Figure imgf000091_0001
comprising the steps: reacting 4.4'-bipyridine-2,2'-diamine with an arylhalide (R1-!) and with a transition metal catalyst or a palladium catalyst ("Pd-catalyst") in the presence of a base in an ether or hydrocarbon solvent to give a compound according to Formula II; and
reacting said compound of Formula II with an isocyanate ("R5NCO alt R6NCO") in a solvent, to obtain a compound according to Formula If.
31. A compound according to formula LT
Figure imgf000092_0001
wherein is R1 is aryl or heteroaryl each of which is optionally substituted with one or more of the following R3, OR3, OCOR3, COOR3, COR3, CONR3R4, NHCOR3,
NR3R4, NHSO2R3, SO2R3, SO2NR3R4, SR3, CN, halogeno or NO2;
R3 and R4 are each independently hydrogen, halogeno, C1-6 alkyl, C1-6 alkyl optionally substituted by NR3R4, C3-8 cycloalkyl, C3-6 alkenyl, C3-6 alkenyl optionally substituted by NR3R4, (C3-8 cycloalkyl)C1-6 alkyl, heterocycle, hetrocycleC1-6 alkyl, C1-6 fluoroalkyl, or alternatively NR3R4 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 Cι-6 alkyl or halogeno; as a free base or a salt, solvate or solvate of salt thereof.
32. A compound which is
N-Phenyl-4,4'-bipyridine-2,2'-diamine;
N~(4-Fluorophenyl)-4,4'-bipyridine-2,2'-diamine; as a free base or a salt, solvate or solvate of salt thereof.
33. The use compound according to Formula LT in claim 31 for the preparation of a compound of formula I as defined in any one of claims 1 to 13.
34. The use of a compound according to claim 32 for the preparation of a compound of formula I as defined in any one of claims 1 to 13.
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