[go: up one dir, main page]

WO2006038001A1 - Derives d’aminopyrimidine en tant qu’inhibiteurs de la jnk - Google Patents

Derives d’aminopyrimidine en tant qu’inhibiteurs de la jnk Download PDF

Info

Publication number
WO2006038001A1
WO2006038001A1 PCT/GB2005/003827 GB2005003827W WO2006038001A1 WO 2006038001 A1 WO2006038001 A1 WO 2006038001A1 GB 2005003827 W GB2005003827 W GB 2005003827W WO 2006038001 A1 WO2006038001 A1 WO 2006038001A1
Authority
WO
WIPO (PCT)
Prior art keywords
lcms
chloro
indol
pyrimidin
vacuo
Prior art date
Application number
PCT/GB2005/003827
Other languages
English (en)
Inventor
Andrew James Ratcliffe
Mahbub Alam
Rebekah Elisabeth Beevers
Richard John Davenport
Natasha Davies
Alan Findlay Haughan
Mark William Jones
Christopher Lowe
Benjamin Garfield Perry
David Jonathan Phillips
William Ross Pitt
Andrew Sharpe
Original Assignee
Celltech R & D Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0422284A external-priority patent/GB0422284D0/en
Priority claimed from GB0509642A external-priority patent/GB0509642D0/en
Application filed by Celltech R & D Limited filed Critical Celltech R & D Limited
Publication of WO2006038001A1 publication Critical patent/WO2006038001A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of substituted arainopyrimidine derivatives and to their use in therapy. More particularly, the invention provides 2-aminopyrimidine derivatives which are substituted in the 4-position by a fused bicyclic heteroaromatic moiety. These compounds are selective inhibitors of c- Jun NH 2 -terminal kinase (INK) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, vascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.
  • INK c- Jun NH 2 -terminal kinase
  • the JNK pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases (cf. A.M. Manning & RJ. Davis, Nature Reviews: Drug Discovery, 2003, 2, 554-565).
  • the compounds in accordance with the present invention are therefore of use in the treatment and/or prevention of various human ailments.
  • autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; vascular disorders; neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, colon, prostate and ovary; pain and nociceptive disorders; and ophthalmic disorders including age-related macular degeneration (ARMD).
  • AMD age-related macular degeneration
  • the compounds according to the present invention may be used as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds according to this invention may be useful as radioligands in assays for detecting compounds capable of binding to human JNK enzymes.
  • the compounds according to the present invention are potent and selective JNK inhibitors having a binding affinity (IC 5 o) for the human JNKl and/or JNK2 and/or JNK3 enzyme of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 2OnM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
  • IC 5 o binding affinity for the human JNKl and/or JNK2 and/or JNK3 enzyme of 5 ⁇ M or less, typically of 1 ⁇ M or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 2OnM or less
  • the compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human JNKl and/or JNK2 and/or JNK3 polypeptide relative to other human kinases.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate or iV-oxide thereof:
  • A represents a pyrrole, pyrazole, imidazole or triazole ring
  • B represents a benzene, pyridine or pyrimidine ring
  • M represents the residue of an azetidine, pyrrolidine or piperidine ring
  • E represents a covalent bond or an optionally substituted straight or branched alkylene chain containing from 1 to 4 carbon atoms; wherein the optional substituents are selected from cyano, aminocarbonyl, C 1-6 alkylaminocarbonyl and di(C 1- 6 )alkylaminocarbonyl;
  • Z represents hydrogen, -COR a , -CO 2 R b , -CONR c R d , -CONR c OR b , -COCO 2 R b , - COCONR c R d , -COCH 2 NR c R d , -COCH 2 NR°CONR 0 R 11 , -COCH 2 NR c CO 2 R b , -NR c COR a , - NR c CO 2 R b , -NR c CONR c R d , -SO 2 R e , -SO 2 NR c R d or -SO 2 NR c CO 2 R b ; or Z represents an optionally substituted phenyl, heteroaryl or C 3-7 heterocycloalkyl group;
  • R and R independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, aminocarbonyl or C 2-6 alkoxycarbonyl;
  • R 3 represents hydrogen, Ci -6 alkyl, -CH 2 CONR c R d or -SO 2 R 6 ;
  • R 4 represents hydrogen, C 1-6 alkoxy, oxo, -CO 2 R b or -CONR c R d ;
  • R a represents hydrogen; or Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(Ci -6 )alkyl, aryl, aryl(Ci -6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(Ci -6 )alkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R b represents hydrogen or Ci -6 alkyl
  • R c is as defined above for R a , and R represents hydrogen, Ci -6 alkyl or hydroxy(Ci -6 )alkyl; or R c and R d , when taken together with the nitrogen atom to which they are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, any of which groups may be optionally substituted by Ci -6 alkyl or hydroxy; and
  • R e is as defined above for R a .
  • One group of compounds of the invention has the formula (I), wherein: B represents a benzene or pyridine ring;
  • E represents a covalent bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms
  • Z represents hydrogen, -COR a , -CO 2 R b , -CONR c R d , -CONR c OR b , -NR c COR a , - NR c CO 2 R b , -NR c CONR c R d , -SO 2 R 6 , -SO 2 NR c R d or -SO 2 NR c CO 2 R b ; or Z represents an optionally substituted heteroaryl group;
  • R d represents hydrogen or Ci -6 alkyl
  • A, M, R 1 , R 2 , R 3 , R 4 , R a , R b , R c and R e are as defined above.
  • Another group of compounds of the invention has the formula (I) wherein R 3 represents hydrogen, -CH 2 CONR c R d or -SO 2 R 6 ; R c and R d , when taken together with the nitrogen atom to which they are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl, morphorinyl, thiomorpholinyl or piperazinyl, any of which groups may be optionally substituted by C 1-6 alkyl; and A, B, E, Z, M, R 1 , R 2 , R 4 , R a , R b and R e are as defined above.
  • Z in the compounds of formula (I) above represents a phenyl, heteroaryl or C 3-7 heterocycloalkyl group
  • this group may be unsubstituted, or substituted by one or more substituents.
  • the phenyl, heteroaryl or C 3-7 heterocycloalkyl group Z will be unsubstituted, or substituted by one or two substituents.
  • the phenyl, heteroaryl or C 3-7 heterocycloalkyl group Z will be unsubstituted or monosubstituted.
  • Typical substituents on the phenyl, heteroaryl or C 3-7 heterocycloalkyl group Z include halogen, cyano, nitro, oxo, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1- 6 )alkylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl and C 2-6 alkoxycarbonyl.
  • the heteroaryl group Z may be substituted by one or more, typically one or two substituents selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl and C 2-6 alkoxycarbonyl.
  • Suitable substituents on the heteroaryl group Z include halogen, C 1-6 alkyl, cyano, amino and nitro.
  • Particular substituents on the heteroaryl group Z include halogen and C 1-6 alkyl. Particular substituents on the C 3-7 heterocycloalkyl group Z include oxo and C 2-6 alkoxycarbonyl. Typically the phenyl group Z is unsubstituted.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • a pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
  • Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
  • Suitable alkyl groups which may be present on the compounds according to the invention include straight-chained and branched C 1-6 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "C 1-6 alkoxy", "Ci -6 alkylamino" and "Ci -6 alkylsulphonyl" are to be construed accordingly.
  • C 3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci -6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • Suitable heterocycloalkyl groups include azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Further suitable examples include tetrahydrothienyl, oxazolidinyl and dihydropyridazinyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl and pyrazinyl groups.
  • heteroaryl groups include naphthyridinyl, cinnolinyl and benzotriazolyl.
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, especially fluoro or chloro.
  • compounds of formula (I) may accordingly exist as enantiomers.
  • compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers.
  • the invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • ring A represents a pyrrole ring. In an additional embodiment, ring A represents a pyrazole ring. In another embodiment, ring A represents an imidazole ring. In a further embodiment, ring A represents a triazole ring, especially a 1,2,4-triazole ring. Suitably, A represents a pyrrole, imidazole or triazole ring.
  • ring B represents a benzene ring. In another embodiment, ring B represents a pyridine ring. In a further embodiment B represents a pyrimidine ring.
  • B represents a benzene or pyridine ring.
  • fused bicyclic ring systems represented by the moiety A/B include lH-indol-1-yl, lH-indol-3-yl, lH-indazol-1-yl, lH-indazol-3-yl, pyrazolo[l,5-a]pyridin-3- yl, lH-benzimidazol-1-yl, imidazo[l,2- ⁇ ]pyridin-3-yl, pyrrolo[3,2-&]pyridm-3-yl, pyrrolo [3 ,2-c]pyridm-3 -yl, pyrrolo [2,3 -c]pyridin-3 -yl, pyrrolo [2,3 -&]pyridin-3 -yl, imidazo[4,5-b]pyridm-l-yl, imidazo[4,5-Z?]pyrid
  • a further example of a fused bicyclic ring system represented by the moiety A/B includes imidazo[l,2- a]pyrirnidin-3-yl.
  • Further examples of fused bicyclic ring systems represented by the moiety A/B include lH-pyrrolo[3,2-b]pyridin-l-yl, lH-pyrrolo[2,3-b]pyridin-l-yl and pyrazolo[ 1 ,5-a]pyridin-3-yl.
  • Particular A/B ring systems include lH-indol-3-yl, lH-indol-1-yl, IH- benzimidazol-1-yl, imidazo[l,2- ⁇ ]pyridin-3-yl, pyrrolo[2,3-&]pyridin-3-yl, pyrrolo[3,2- c]pyridin-3-yl, [l,2,4]triazolo[4,3- ⁇ ]pyridin-3-yl and imidazo[l,2-a]pyrimidin-3-yl.
  • the A/B ring systems include lH-indol-3-yl, IH- benzimidazol-1-yl, imidazo[l,2- ⁇ ]pyridm-3-yl, pyrrolo[2,3- ⁇ ]pyridin-3-yl and [l,2,4]triazolo[4,3- ⁇ ] ⁇ yridin ⁇ 3-yl.
  • A/B ring systems include IH- ⁇ yrrolo[3,2-b]pyridin-l-yl, lH-pyrrolo[2,3-b]pyridin-l-yl and pyrazolo[l,5-a]pyridin-3-yl.
  • the A/B ring system represents lH-indol-3-yl. In another embodiment, the A/B ring system represents lH-indol-1-yl. In yet another embodiment, the A/B ring system represents lH-benzimidazol-1-yl. In an additional embodiment, the A/B ring system represents imidazo[l,2- ⁇ ]pridin-3-yl. In a further embodiment, the A/B ring system represents pyrrolo[2,3-£]pyridin-3-yl. In a yet further embodiment, the A/B ring system represents pyrrolo[3 5 2-c]pyridin-3-yl.
  • the A/B ring system represents [l,2,4]triazolo[4,3- ⁇ ]pyridin-3-yl. In another embodiment, the A/B ring system represents imidazo[l,2-a]pyrimidin-3-yl. In a further embodiment, the A/B ring system represents lH-pyrrolo[3,2-b]pyridin-l-yl. In another embodiment, the A/B ring system represents lH-pyrrolo[2,3-b]pyridin-l-yl. In another embodiment, the A/B ring system represents pyrazolo[l,5 ⁇ a]pyridin-3-yl.
  • M represents the residue of an azetidine ring, especially an azetidin-3-yl ring.
  • M represents the residue of a pyrrolidine ring, especially a pyrrolidin-3-yl ring.
  • M represents the residue of a piperidine ring, suitably a piperidin-3-yl or piperidin-4-yl ring, especially a piperidin-4-yl ring.
  • E represents a straight or branched alkylene chain, this may be, for example, methylene, ethylmethylene, ethylene, 1-methylethylene, propylene, 2- methylpropylene or butylene. E may also represent methylmethylene.
  • E substituents that may be present on E include cyano, aminocarbonyl and methylaniinocarbonyl.
  • E may represent a covalent bond. Where E represents a covalent bond, the moiety Z is attached directly to the heterocyclic ring of which M is the residue.
  • E represents a covalent bond or an unsubstituted straight or branched alkylene chain containing from 1 to 4 carbon atoms.
  • E represents a covalent bond, or a methylene, ethylmethylene or ethylene linkage.
  • E represents a covalent bond, or a methylene linkage.
  • E represents a covalent bond.
  • E represents a methylene linkage.
  • E represents an ethylmethylene linkage.
  • E represents an ethylene linkage.
  • E represents a methylmethylene linkage.
  • Z does not represent -NR c COR a , -NR c CO 2 R b or -NR c CONR c R d .
  • Selected values of R 1 include hydrogen, fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl- sulphonyl, amino, methylamino, dimethylamino, aminocarbonyl, methoxycarbonyl and ethoxycarbonyl.
  • R 1 represents hydrogen, halogen, cyano or C 1-6 alkyl.
  • R 1 also suitably represents C 1-6 alkoxy.
  • Particular values of R 1 include hydrogen, fluoro, chloro, cyano, methoxy and methyl.
  • particular values of R 1 include hydrogen, fluoro, chloro, cyano and methyl.
  • R 1 represents hydrogen, hi another embodiment, R 1 represents halogen, in particular fluoro or chloro, especially chloro. In an additional embodiment, R 1 represents cyano. hi a further embodiment, R 1 represents C 1-6 alkyl, in particular methyl or ethyl, especially methyl. In another embodiment, R 1 represents C 1-6 alkoxy, in particular methoxy.
  • Selected values of R 2 include hydrogen, fluoro, chloro, cyano, nitro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl- sulphonyl, amino, methylamino, dimethylamino, aminocarbonyl, methoxycarbonyl and ethoxycarbonyl.
  • R represents hydrogen, cyano or halogen.
  • R also suitably represents C 1- ⁇ alkoxy, amino, C 1-6 dialkylamino or aminocarbonyl.
  • Particular values of R 2 include hydrogen, cyano, fluoro and chloro. Further particular values of R 2 include bromo, amino, methoxy, dimethylamino and aminocarbonyl.
  • R 2 represents hydrogen or halogen, typically hydrogen, fluoro and chloro.
  • R 2 represents hydrogen, hi another embodiment, R 2 represents halogen, in particular fluoro or chloro or R 2 represents bromo. In a further embodiment, R 2 represents cyano. hi another embodiment, R 2 represents amino. In a yet further embodiment, R 2 represents C 1-6 alkoxy, in particular methoxy. hi an additional embodiment, R 2 represents C 1-6 dialkylamino, in particular dimethylamino. hi a further embodiment, R 2 represents aminocarbonyl.
  • R a represents hydrogen; or C 1-6 alkyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(Ci -6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a examples include C 1-6 alkyl, C 1-6 alkoxy, hydroxy, hydroxy(C 1-6 )alkyl, halogen, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, di(C 1- 6 )alkylhydrazinylcarbonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, aminocarbonylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylsulfonyl and C 1-6 alkylaminocarbonyl(C 1-6 )alkyl.
  • suitable substituents that may be present on R a include
  • R a examples include methyl, methoxy, oxo, acetyl, carboxy, ethoxycarbonyl, dimethylhydrazinylcarbonyl, dimethylamino, acetylamino and aminocarbonylamino.
  • substituents on R a include hydroxy, hydroxymethyl, 2-hydroxyethyl, fluoro, methoxycarbonyl, tert-butoxycarbonyl, amino, methylamino, 1,3-dimethylbutylamino, aminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, aminosulfonyl, methylsulfonyl and methylaminocarbonylmethyl.
  • Even further examples include isopropylamino, methylaminocarbonyl, dimethylaminocarbonyl and methylcarbonylamino.
  • R a Typical values of R a include methyl, ethyl, isopropyl, tert-bntyl, methoxymethyl, acetylaminomethyl, dimethylhydrazinylcarbonylethyl, aminocarbonylaminoethyl, 1- (methoxycarbonylmethyl)ethyl, 1 -(carboxymethyl)ethyl, 3-hydroxy(l -methyl)propyl, aminocarbonylethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, (1,3- dimethylbutyl)aminomethyl, l-(methylamino)ethyl, phenyl, methylphenyl, phenyl(methylamino)methyl, phenyl(methyl)methyl, dimethylaminophenyl, acetylaminophenyl, tetrahydrofuranyl, oxopyrrolidinyl, tetrahydropyranyl,
  • 2-aminocarbonyl-l-methylethyl 2- (dimethylaminocarbonyl)-l-methylethyl, 2-(methylaminocarbonyl)-l-methylethyl, 1- methylcarbonylamino-2-hydroxyetliyl, isopropylaminomethyl, isobutyl, methylpiperidinyl, dioxotetrahydrothienylmethyl, acetylpyrrolidinyl, tert-butoxycarbonylazetidinyl, azetidinyl, tert-butoxycarbonylpyrrolidinyl, pyrrolidinyl, acetylpyrrolidinyl, aminocarbonylpyrrolidinylmethyl, oxopiperazinylmethyl, hydroxy( 1 -acetylpyrrolidinyl, hydroxyazetidinylmethyl, methylaminocarbonylmethylazetidinyl
  • typical values of R a include methyl, methoxymethyl, acetylaminomethyl, dimethylhydrazinylcarbonylethyl, aminocarbonylaminoethyl, dimethylaminophenyl, acetylaminophenyl, tetrahydrofuranyl, oxopyrrolidinyl, tetrahydropyranyl, acetylpiperidinyl, dioxoimidazolidinyhnethyl, furyl, methylpyrrolyl, pyridinyl, methylpyrazinyl and methylisoxazolylmethyl.
  • R b represents hydrogen. In another embodiment, R b represents C 1-6 alkyl, especially methyl, ethyl or tert-butyl.
  • R Q suitably represents hydrogen; or C 1-6 alkyl or C 3-7 heterocycloalkyl(C 1-6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • Examples of typical substituents on R c include C 1-6 alkyl, carboxy, C 2-6 alkoxycarbonyl and di(C 1-6 )alkylamino. Further typical examples include oxo, halogen, hydroxy, hydroxy(C 1 . 6 )alkyl and aminosulfonyl. More typical examples include C 2-6 alkylcarbonylamino, aminocarbonyl and phenyl. Examples of particular substituents on R c include methyl, carboxy, ethoxycarbonyl and dimethylamino. More examples of particular substituents on R c include oxo, fluoro, hydroxy, hydroxymethyl and aminosulfonyl. Further examples of particular substituents on R c include methoxycarbonyl, tez-t-butoxycarbonyl, acetylamino, aminocarbonyl and phenyl.
  • R c examples include hydrogen, methyl, carboxymethyl, ethoxycarbonyl- methyl, ethyl, ethoxycarbonylethyl, dimethylaminoethyl and methylpiperazinylpropyl, acetyl, tetrahydropyranylcarbonyl, piperidinyl, piperidinylethyl, pyrrolidinylmethyl, methylpyrrolidinylmethyl, morpholinylethyl, morpholinyl(dimethyl)ethyl, 1,1- dioxidotetrahydrothienyl, 1,1-dioxidothiomo ⁇ holinylethyl, aminosulfonylphenyl, fluorophenyl, phenyl(hydroxy)ethyl, thiazolyl, pyridinyl, pyrimidinyl, methylimidazolylmethyl, imidazolylpropyl, pyridinylmethyl,
  • R c examples include isopropyl, tert-butyl, 2- methylbutyl, acetylaminoethyl, 1-carboxypropyl, phenyl(hydroxy)propyl, aminocarbonylmethyl, 2-hydroxy- 1 -methoxycarbonylethyl, methylpiperidinyl, cyclopropyl, tetrahydrofuranyl, oxotetrahydrofuranyl, tetrahydropyranyl, tert- butoxycarbonylazetidinyl, azetidinyl, fert-butoxycarbonylpiperidinyl, thienyl, methyltriazolylmethyl and dimethylpyrazolylmethyl.
  • typical values of R c include hydrogen, methyl, carboxymethyl, ethoxycarbonyl-methyl, ethyl, ethoxycarbonylethyl, dimethylaminoethyl and methylpiperazinylpropyl.
  • R d represents hydrogen. In another embodiment, R d represents C 1-6 alkyl, especially methyl. In another embodiment, R d represents hydroxy(C 1-6 )alkyl.
  • Representative hydroxy(C 1-6 )alkyl groups include 2-hydroxyethyl, 2- hydroxyprop-1-yl, 3-hydroxypropyl, 4-hydroxybutyl, l-hydroxyprop-2-yl, l-hydroxy-4- methylpent-2-yl, l-hydroxybut-2-yl, l-hydroxy-2-methylprop-2-yl, l-hydroxy-3- methylbut-2-yl, 2-hydroxybut-l-yl and 3-hydroxy-2-dimethylprop-l-yl.
  • Further representative hydroxy(C 1-6 )alkyl groups include 4-hydroxypentyl, l-hydroxy-3- methylpent-2-yl and 6-hydroxyhexyl.
  • the moiety -NR c R d may suitably represent azetidin-1-yl, pyrrolidin- 1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl or piperazin-1-yl, any of which groups maybe optionally substituted by C 1-6 alkyl (e.g. methyl).
  • the moiety -NR c R d may also be substituted by hydroxy.
  • Particular values of -NR c R d include morpholin-4-yl and A- methylpiperazin-1-yl. Further values include azetidin-1-yl and hydroxy-pyrrolidin-1-yl.
  • R e represents C 1-6 alkyl; or R 6 represents aryl, optionally substituted by C 1-6 alkyl. R e also suitably represents heteroaryl or heteroaryl(C 1-6 )alkyl. In one embodiment, R e represents C 1-6 alkyl, typically methyl, isopropyl or n- propyl, especially n-propyl. In another embodiment, R e represents aryl, optionally substituted by C 1-6 alkyl; examples include phenyl and methylphenyl (especially A- methylphenyl).
  • R e represents heteroaryl, optionally substituted by C 1-6 alkyl, typically methylimidazolyl (especially l-methylimidazol-4-yl).
  • R e represents heteroaryl(C 1-6 )alkyl, typically pyridinylmethyl, especially pyridin-2-ylmethyl or pyridin-4-ylmethyl.
  • Z represents hydrogen, -COR a , -CO 2 R b , -CONR c R d , -CONR c OR b , - COCO 2 R b , -COCONR c R d , -COCH 2 NR c R d , -COCHzNR'CONR ⁇ , -COCH 2 NR c CO 2 R b , - NR c COR a , -SO 2 R 6 or -SO 2 NHCO 2 R b ; or Z represents an optionally substituted phenyl, heteroaryl or C 3-7 heterocycloalkyl group.
  • Z typically represents hydrogen, -COR a , -CO 2 R b , - CONR c R d , -CONR c OR b , -NR c C0R a , -SO 2 R 6 or -SO 2 NHCO 2 R b ; or Z represents an optionally substituted heteroaryl group.
  • Suitable heteroaryl groups that may represent the group Z include imidazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl and isoxazolyl, more suitably imidazolyl (especially lH-imidazol-2-yl or lH-imidazol-4-yl).
  • Typical substituents that may be present on the Z heteroaryl group include methyl, cyano, amino and nitro.
  • Illustrative examples include l/J-imidazol-2-yl, lH-imidazol-4-yl, oxadiazol-3-yl, pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, 5-aminopyridin-2-yl, 5-cyanopyridin-2-yl, 5- methylisoxazol-3-yl, pyrimidin-2-yl, pyrazin-2-yl and 5-nitrothiazol-2-yl.
  • a further example includes pyridin-2-yl-N-oxide.
  • Z is an optionally substituted C 3-7 heterocycloalkyl group
  • suitable examples include optionally substituted tetrahydrofuranyl and piperidinyl.
  • Typical substituents include tert-butoxycarbonyl and oxo.
  • Representative examples for C 3-7 heterocycloalkyl group that may represent Z include tetrahydrofuran-3-yl, 2-oxotetrahydrofuran-3-yl, piperidin-4-yl and l-tert-butoxycarbonylpiperidin-4-yl.
  • Z represents -COR a , -CO 2 R b , -CONR c R d , -CONR c OR b , -SO 2 NHCO 2 R b or -COCH 2 NR c R d .
  • Z represents -COR a , -CO 2 R b , -CONR c R d , - CONR c OR b or -SO 2 NHCO 2 R b .
  • Z represents -CONR c R d or -COCH 2 NR c R d .
  • Selected values of Z include hydrogen, acetyl, methoxyacetyl, acetylamino- methylcarbonyl, dimethylhydrazinylcarbonylethylcarbonyl, aminocarbonylamino- ethylcarbonyl, ethylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, 1-
  • Z include 2- aminocarbonyl- 1 -methylethylcarbonyl, 2-(dimethylaminocarbonyl)- 1 - methylethylcarbonyl, 2-(methylaminocarbonyl)- 1 -methylethylcarbonyl, 1 - methylcarbonylamino-2-hydroxyethylcarbonyl, isopropylaminomethylcarbonyl, isobutylcarbonyl, methylpiperidinylcarbonyl, azetidin-1 -ylcarbonyl, hydroxy-pyrrolidin-1- ylcarbonyl, dioxotetrahydrothienylmethylcarbonyl, acetylpyrrolidinylcarbonyl, tert- butoxycarbonylazetidinylcarbonyl, azetidinylcarbonyl, tert-butoxycarbonyl- pyrrolidinylcarbonyl, pyrrolidinylcarbonyl, ace
  • selected values of Z include hydrogen, acetyl, methoxyacetyl, acetylamino-methylcarbonyl, dimethymydrazinylcarbonylethylcarbonyl, aminocarbonylamino-ethylcarbonyl, dimethylaminophenylcarbonyl, acetylaminophenylcarbonyl, tetrahydrofuranylcarbonyl, oxopyrrolidinylcarbonyl, tetrahydropyranylcarbonyl, acetylpiperidinylcarbonyl, dioxoimidazolidinylmethylcarbonyl, furylcarbonyl, methylpyrrolylcarbonyl, pyridinylcarbonyl, methylpyrazinylcarbonyl, methylisoxazolyl-methylcarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylamino-carbonyl, carboxy
  • R 3 examples include hydrogen, methylaminocarbonylmethyl, phenylsulphonyl and methylphenylsulphonyl (especially 4-methylphenylsulphonyl).
  • R 3 may also suitably represent C 1-6 alkyl, typically methyl.
  • R 3 is hydrogen.
  • Typical values of R 4 include hydrogen, methoxy, oxo, methoxycarbonyl, aminocarbonyl and dimethylaminocarbonyl.
  • R 4 represents hydrogen or C 1-6 alkoxy. Particular values of R 4 include hydrogen and methoxy. Preferably, R 4 is hydrogen.
  • a typical sub-class of compounds in accordance with the invention is represented by the compounds of formula (IA), (IB) and (IC) and (ICi), especially (IC) and (ICi):
  • a typical sub-class in accordance with the invention is represented by the compounds of formula (IA), (IB) and (IC) especially (IC).
  • Another sub-class of compounds in accordance with the invention is represented by the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), especially (ID):
  • X represents CH or N
  • Y represents CH or N
  • R 1 , R 2 , R 3 , R 4 , M 3 E and Z are as defined above.
  • X is CH. In another embodiment, X is N. hi one embodiment, Y is CH. In another embodiment, Y is N.
  • One sub-class of compounds in accordance with the invention is represented by the compounds of formula (ID), (IE), (IF), (IG), (IH), (O), (IK) and (IL).
  • Another sub-class of compounds in accordance with the invention is represented by the compounds of formula (ID), (IE), (IF), (IG), (IH), (IJ), especially (ID).
  • Another sub-class of compounds in accordance with the invention is represented by the compounds of formula (ID), (IE) and (IF).
  • One particular sub-class is represented by a compound of formula (ID).
  • Another particular sub-class is represented by a compound of formula (IF), especially when Y is CH.
  • R 11 represents hydrogen, halogen, cyano or C 1-6 alkyl
  • R 21 represents hydrogen, halogen or cyano
  • E 1 represents a covalent bond or a methylene linkage
  • Z 1 represents -COR a , -CO 2 R b , -CONR c R d , -CONR c OR b , -SO 2 NHCO 2 R 13 or - COCH 2 NR c R d ;
  • R a , R b , R c , R d and X are as defined above.
  • R 11 include hydrogen, fluoro, chloro, cyano and methyl.
  • R 11 represents hydrogen, halogen or C 1-6 alkyl, especially hydrogen or halogen.
  • R 11 represents halogen or cyano.
  • R 11 represents hydrogen.
  • R 11 represents halogen, in particular fluoro or chloro, especially chloro.
  • R 11 represents cyano.
  • R 11 represents C 1-6 alkyl, in particular methyl or ethyl, especially methyl.
  • R 21 represents hydrogen or halogen.
  • Particular values of R 21 include hydrogen and fluoro. Further, R 21 may also in particular represent chloro.
  • R 21 represents hydrogen. In another embodiment, R 21 represents halogen, in particular fluoro or chloro. In one embodiment R 21 represents fluoro. In one embodiment, E 1 represents a covalent bond. In another embodiment, E 1 represents a methylene linkage.
  • Z 1 represents -COR a , -CO 2 R b , - CONR c R d , -CONROR b or -SO 2 NHCO 2 R b .
  • Z 1 represents -COR a , -CO 2 R b , -CONR c R d , -CONR c OR b or -COCH 2 NR c R d .
  • Z 1 represents -CONR c R d or -COCH 2 NR c R d .
  • Z 1 Particular values include acetyl, methoxyacetyl, acetylamino- methylcarbonyl, dimethylhydrazinylcarbonylethylcarbonyl, aminocarbonylamino- ethylcarbonyl, ethylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, 1- (methoxycarbonylmethyl)ethyl- 1 -carbonyl, 1 -(carboxymethyl)ethyl- 1 -carbonyl, 3- hydroxy(l-methyl)propyl-l -carbonyl, aminocarbonylethylcarbonyl, aminomethylcarbonyl, methylaminomethylcarbonyl, dimethylaminomethylcarbonyl, (1,3- dimethylbutyl)aminomethylcarbonyl, 1 -(methylamino)ethyl- 1 -carbonyl, dimethylaminophenylcarbonyl, acetylaminopheny
  • Z 1 examples include 2-aminocarbonyl- 1 -methylethylcarbonyl, 2-(dimethylaminocarbonyl)- 1 - methylethylcarbonyl, 2-(methylaminocarbonyl)- 1 -methylethylcarbonyl, 1 - methylcarbonylamino-2-hydroxyethylcarbonyl, isopropylaminomethylcarbonyl, isobutylcarbonyl, methylpiperidinylcarbonyl, azetidin-1-ylcarbonyl, hydroxy-pyrrolidin-1- ylcarbonyl, dioxotetrahydrothienylmethylcarbonyl, acetylpyrrolidinylcarbonyl, tert- butoxycarbonylazetidinylcarbonyl, azetidinylcarbonyl, tert-butoxycarbonyl- pyrrolidinylcarbonyl, pyrrolidinylcarbonyl, pyr
  • selected values of Z 1 include acetyl, methoxyacetyl, acetylaminomethylcarbonyl, dimethylhydrazinylcarbonylethylcarbonyl, aminocarbonylaminoethylcarbonyl, dimethylaminophenylcarbonyl, acetylaminophenylcarbonyl, tetrahydrofuranylcarbonyl, oxopyrrolidinylcarbonyl, tetrahydropyranylcarbonyl, acetylpiperidinylcarbonyl, dioxoimidazolidinylmethylcarbonyl, furylcarbonyl, niethylpyrrolylcarbonyl, pyridinyl- carbonyl, methylpyrazinylcarbonyl,
  • Z 1 represents methylaminomethylcarbonyl, dimethylaminomethylcarbonyl, (dimethylamino)ethyl- aminocarbonyl or piperidinylaminocarbonyl, typically piperidin-3-ylaminocarbonyl.
  • R 12 represents hydrogen, halogen or C 1-6 alkyl
  • R 22 represents hydrogen or halogen
  • E 2 represents a covalent bond or a methylene linkage
  • Z 2 represents -COR a , -CO 2 R b , -CONR c R d , SO 2 R 6 or -COCH 2 NR c R d ;
  • R a , R b , R c , R d and R e are as defined above.
  • R 12 include hydrogen, chloro and methyl.
  • R 12 hydrogen or halogen.
  • R represents hydrogen.
  • R represents halogen, in particular fluoro or chloro, especially chloro.
  • R 12 represents C 1-6 alkyl, in particular methyl or ethyl, especially methyl.
  • R 22 represents hydrogen.
  • E 2 represents a covalent bond.
  • E 2 represents a methylene linkage.
  • Z 2 Particular values of Z 2 include tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, oxopyrrolidinylcarbonyl, tert-butoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, methylpiperazinylcarbonyl, methylsulfonyl, isopropylsulfonyl, methylimidazolylcarbonyl and methylcarbonylaminomethylcarbonyl.
  • Z 2 examples include furanylcarbonyl, oxooxazolidinylcarbonyl, mo ⁇ holinylmethylcarbonyl, methylisoxazolylmethylcarbonyl, isobutylcarbonyl, dimethylaminomethylcarbonyl, acetylaminomethylcarbonyl, thienylaminocarbonyl, imidazolylmethylcarbonyl, ethoxycarbonyl and dimethylaminocarbonyl.
  • Z 2 represents methylaminocarbonyl or methylimidazolylcarbonyl.
  • Particularly useful compounds in accordance with the invention include each of the compounds described in the accompanying Examples, and pharmaceutically acceptable salts, solvates and iV-oxides thereof.
  • the present invention also provides a pharmaceutical composition which comprises a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or iV-oxide thereof, in association with one or more pharmaceutically acceptable carriers.
  • Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
  • the compounds according to the present invention may be conveniently formulated as microionized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • compounds may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • the quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
  • the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV): m (IV)
  • L 1 represents a suitable leaving group.
  • the leaving group L 1 is typically a halogen atom, e.g. chloro; or a C 1-6 alkylsulphonyl group, e.g. methylsulphonyl.
  • the reaction between compounds (III) and (FV) is conveniently effected at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as 7V,N-dimethylformamide, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium carbonate or an organic base such as triethylamine or diisopropylethylamine.
  • a suitable solvent e.g. a dipolar aprotic solvent such as 7V,N-dimethylformamide
  • reaction between compounds (III) and (IV) is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol or 2-ethoxyethanol, typically under basic conditions, e.g. in the presence of an organic base such as triethylamine.
  • a suitable solvent e.g. a lower alkanol such as ethanol or 2-ethoxyethanol
  • L 2 represents a suitable leaving group
  • V 1 represents a boronic acid moiety -B(OH) 2
  • V 1 represents -ZnG 1 in which G 1 represents a halogen atom, e.g. bromo; in the presence of a transition metal catalyst.
  • the leaving group L 2 is typically a halogen atom, e.g. chloro.
  • the transition metal catalyst of use in the reaction between compounds (V) and (VI) is suitably tetrakis(triphenylphosphine)palladium(0).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as acetonitrile or tetrahydrofuran, typically in the presence of sodium carbonate.
  • reaction between compounds (V) and (VI) may be effected in the presence of bis(dicyclohexylamino)palladium acetate (DAPCy) (J. Org. Chem., 2004, 69, 4330-4335) and potassium phosphate, typically in a lower alkanol solvent such as ethanol.
  • DAPCy bis(dicyclohexylamino)palladium acetate
  • potassium phosphate typically in a lower alkanol solvent such as ethanol.
  • V 1 represents -B(OH) 2
  • the starting materials of formula (V) wherein V 1 represents -B(OH) 2 may be prepared by the procedure described in J Med. Chem., 2001, 44, 2229-2237, or by methods analogous thereto.
  • the starting materials of formula (V) wherein V 1 represents -ZnG 1 may typically be prepared in situ by sequential treatment of the appropriate compound of formula (V) wherein V 1 represents a halogen atom, e.g. bromo, with a base such as n-butyllithium and a zinc halide, e.g. zinc bromide, following the procedure described in J. Chem. Soc, Perkin Trans. 1, 2002, 1847-1849, or methods analogous thereto.
  • a halogen atom e.g. bromo
  • a base such as n-butyllithium
  • a zinc halide e.g. zinc bromide
  • the intermediates of formula (III) wherein the A/B ring system represents lH-benzimidazol-1-yl or indol-1-yl may be prepared by reacting a compound of formula (VI) as defined above with a compound of formula (VII):
  • R 2 is as defined above and W represents carbon or nitrogen.
  • the reaction is conveniently accomplished in a suitable solvent, e.g. tetrahydrofuran or N,N-dimethylformamide; typically under basic conditions, e.g. in the presence of an inorganic base such as sodium hydride or potassium carbonate.
  • a suitable solvent e.g. tetrahydrofuran or N,N-dimethylformamide
  • an inorganic base such as sodium hydride or potassium carbonate.
  • the intermediates of formula (III) wherein the A/B ring system represents [l,2,4]triazolo[4,3- ⁇ ]pyridin-3-yl maybe prepared by reacting a compound of formula (VIII) with a compound of formula (IX):
  • R 1 , R 2 and L 1 are as defined above, and L represents a suitable leaving group.
  • the leaving group L 3 is typically a halogen atom, e.g. chloro.
  • the reaction is conveniently effected under basic conditions, e.g. triethylamine in dichloromethane; followed by treatment with phosphorus oxychloride at an elevated temperature.
  • the intermediates of formula (III) above wherein L 1 is methylsulphonyl may be prepared from the corresponding compound wherein L 1 represents methylthio by treatment with an oxidising agent such as zneto-chloroperbenzoic acid.
  • the methylthio derivatives may in turn be prepared by reacting a compound of formula (X) with a compound of formula (XI) or a salt thereof, especially the sulphate salt:
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a lower alkanol such as ethanol, typically under basic conditions, e.g. in the presence of sodium ethoxide.
  • a suitable solvent e.g. a lower alkanol such as ethanol
  • the intermediates of formula (III) wherein L 1 represents methylthio may be prepared by heating compound (X) and thiourea with a base such as sodium methoxide in a lower alkanol solvent, e.g. /z-butanol, followed by treatment with methyl iodide, as described by Thomas et al. in Bioorg. Med. Chem. Lett., 2004, 14, 2245-2248.
  • A, B, R 1 , R 2 and R 3 are as defined above; with the diethyl acetal of 7V,iV- dimethylformamide, typically in a solvent such as tetrahydrofuran.
  • compounds of formula (I) may be prepared directly by reacting a compound (X) and a guanidine of formula (XIa):
  • reaction is heated under basic conditions e.g. in the presence of sodium hydride in an appropriate solvent such as iV,N-dimethylformamide.
  • Guanidines of formula (XIa) may be prepared by treatment of the corresponding amines (IV) with a suitable reagent such as 3,5-dimethylpyrazole-l-carboxamidine nitrate. Where they are not commercially available, the starting materials of formula (IV),
  • a compound of formula (I) wherein -E-Z is hydrogen may be converted into the corresponding compound wherein -E-Z represents -CONH 2 by treatment with trimethylsilyl isocyanate.
  • a compound of formula (I) wherein -E-Z is hydrogen may be converted into the corresponding compound wherein -E-Z represents lH-imidazol-2-ylmethyl or lH-imidazol-4-ylmethyl by treatment with imidazole-2- carboxaldehyde or imidazole-4-carboxaldehyde respectively in the presence of a reducing agent, e.g. sodium cyanoborohydride; other compounds of formula (I) wherein Z represents an optionally substituted heteroaryl group may be prepared similarly.
  • a reducing agent e.g. sodium cyanoborohydride
  • a compound of formula (I) wherein -E-Z is hydrogen may be converted into the corresponding compound wherein E represents a C 1-4 straight or branched alkylene chain by reaction with a compound of formula HaI-E-Z (wherein Hal represents a halogen atom, e.g. chloro or bromo), typically in the presence of a base such as sodium carbonate.
  • a compound of formula (I) wherein -E-Z is hydrogen may be converted into the corresponding compound wherein -E-Z represents -CONR°R d by reaction with a compound of formula Hal-CONR°R d (wherein Hal is as defined above), typically in the presence of a base such as triethylamine.
  • a compound of formula (I) wherein -E-Z is hydrogen may be converted into the corresponding compound wherein -E-Z represents -CONR°R d or -CONR c OR b by treatment with the appropriate compound of formula HNR°R d or R b O-NHR c in the presence of a carbonylating agent such as triphosgene or bis(4-nitrophenyl)carbonate 5 typically in the presence of a base such as triethylamine or diisopropylethylamine.
  • a carbonylating agent such as triphosgene or bis(4-nitrophenyl)carbonate 5 typically in the presence of a base
  • a base such as triethylamine or diisopropylethylamine.
  • a compound of formula (I) wherein -E-Z is hydrogen may be converted into the corresponding compound wherein -E-Z represents -COR a by treatment with the appropriate compound of formula R a CO 2 H and a condensing agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, typically in the presence of 1- hydroxybenzotriazole hydrate and l-methyl-2-pyrrolidinone.
  • a condensing agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • a compound of formula (I) wherein -E-Z is hydrogen may be converted into the corresponding compound wherein -E-Z represents -SO 2 NHCO 2 C(CH 3 ) 3 by treatment with iV-(tert-butoxycarbonyl)-iV-[4- (dimethylazaniumylidene)- 1 ,4-dihydropyridin- 1 -ylsulfonyl]azanide.
  • a compound of formula (I) wherein Z contains a carboxy group -CO 2 H may be obtained from the corresponding compound wherein Z contains a C 2-6 alkoxycarbonyl moiety by saponification, which typically involves treatment with an inorganic base such as lithium hydroxide.
  • a compound of formula (I) wherein R 1 is chloro may be converted into the corresponding compound wherein R 1 is hydrogen by treatment with hydrogen in the presence of a hydrogenation catalyst such as palladium on carbon.
  • a compound of formula (ID) wherein R 3 represents -SO 2 R e may be converted into the corresponding compound wherein R 3 is hydrogen by treatment with a base such as potassium hydroxide, typically in methanol.
  • a compound of formula (ID) wherein R 3 is hydrogen may be converted into the corresponding compound wherein R 3 represents -CH 2 CONR c R d by reaction with a compound of formula Hal-CH 2 CONR c R d (wherein Hal is as defined above), typically in the presence of a base such as sodium carbonate.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd edition, 1999.
  • the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
  • the compounds in accordance with this invention potently inhibit the activity of human JNKl and/or JNK2 and/or JNK3.
  • the JNK in-vitro enzyme assay determines the effect of test compounds on phosphorylation of the substrate, GST-c-Jun(l-89), at the Ser73 site using a heterogeneous time-resolved fluorometric assay method, DELFJA ® (dissociation enhanced lanthanide fluorescence immunoassay). Glutathione plates are pre-coated with 100 ⁇ l/well GST-c-Jun (1 ⁇ g/ml) overnight at 4°C.
  • kinase assay buffer is added to all wells [2OmM MOPS, pH 7.2, containing 25 mM ⁇ -glycerolphosphate, 5 mM MgCl 2 , 5 mM EGTA and 1 mM DTT].
  • Test compounds dissolved in 20% DMSO/kinase assay buffer are added at 10 ⁇ l/well, giving a final concentration range of 0.3 nm to 10 ⁇ M.
  • Recombinant human JNK is added in 10 ⁇ l kinase assay buffer, and the kinase reaction is initiated by the addition of ATP in 10 ⁇ l kinase assay buffer. After incubation for 60 minutes at room temperature, assay plates are washed 3 times with DELFIA ® wash buffer (from Perkin-Elmer), to terminate the reaction and to remove assay components. Detection of phosphorylated substrate protein is initiated with the addition of 100 ⁇ l/well primary antibody [rabbit polyclonal anti-phospho Ser73 antibody used at 1/1000 dilution (from Cell Signalling Technology)].
  • the compounds of the accompanying Examples were all found to possess IC 5O values for inhibition of human HStKl and/or JNK2 and/or JNK3 enzyme activity of 5 ⁇ M or better.
  • Typical injection volume 0.5-4.0 ml at 25 mg/ml
  • Typical injection volume 0.5-4.0 ml at 25 mg/ml
  • Typical injection volume 0.5 ml at 25 mg/ml
  • Varian Gradient HPLC system consisting of Varian 9012/9050/9100 Modules and Waters fraction collector.
  • the aqueous phase was re-extracted with EtOAc (100 ml) and the organic layers were combined, washed with saturated Na 2 CO 3 solution (100 ml), separated, dried over MgSO 4 , filtered and concentrated in vacuo.
  • the resulting brown solid was dissolved in 1,4-dioxane (50 ml) and to this solution was added aqueous 2M NaOH solution (50 ml). The mixture was heated at 80°C for 30 min. After cooling, the mixture was partitioned between brine (100 ml) and DCM (250 ml), and the aqueous layer was washed with DCM (2 x 75 ml).
  • INTERMEDIATE 28 1 -CPyridin-2-ylmethyl)piperidin-4-amine tris(hydrochloride)
  • 2-pyridinecarboxaldehyde (0.24 ml)
  • DIPEA 0.44 ml
  • sodium triacetoxyborohydride 635 mg
  • the resulting solid was dissolved in dry THF (10 ml) and to this was added 2N HCl (5 ml). The solution was stirred at room temperature for 24 hours. The pH of the mixture was adjusted to pH7 with 2N NaOH and extracted with DCM (4 x 75 ml). The organic layers were combined, washed with saturated NaCl solution (100 ml), separated, dried over Na 2 SO 4 , filtered and the solvent removed in vacuo. The crude material was partially purified by column chromatography on silica eluting with 80% EtOAc/heptane.
  • Example 4 (183 mg) was stirred as a suspension in a solution of HCl (2M in Et 2 O) (5 ml) at room temperature for 95 min. The reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (150 mg, quantitative). LCMS 314/316 [M+ ⁇ ] + (free base), RT 1.74 min.
  • Example 9 A solution of Example 9 (1.0 g) in DCM (40 ml) and TFA (10 ml) was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue partitioned between DCM (100 ml) and 2N HCl (300 ml). The aqueous phase was separated, basified with 3M aqueous NaOH and extracted with DCM (4 x 200 ml). The combined organic extracts were dried over MgSO 4 , filtered and concentrated in vacuo to afford the title compound as an off-white solid (0.44 g, 57%). LCMS 337 [M+H] + , RT 1.78 min.
  • Example 2 To a suspension/solution of Example 2 (290 mg) in MeO ⁇ /DCM (10 ml/10 ml) was added a solution of HCl (2.0M in Et 2 O, 6.8 ml) and the mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dry DCM (40 ml) under nitrogen. To this was added TEA (0.48 ml) followed by ethyl isocyanate (0.05 ml) dropwise. The mixture was stirred at room temperature for 2 hours. Water (30 ml) was added and the mixture extracted with DCM (100 ml). The organic layer was washed with water (20 ml), separated, dried over MgSO 4 , filtered and concentrated in vacuo.
  • Example 23 Prepared in a similar manner to Example 23 from Example 20 (30 mg) and ethyl 3-isocyanato-propionate (13 ⁇ l) in T ⁇ F (5 ml). Purification by column chromatography on silica eluting with 0-5% MeO ⁇ /DCM afforded the title compound as a white powder (31 mg, 72%). LCMS 480 [M+ ⁇ ] + , RT 3.11 min.
  • Example 23 Prepared in a similar manner to Example 23 from 4 Example 20 (30 mg) and ethyl isocyanatoacetate (11 ⁇ l) in T ⁇ F (5 ml). Purification by column chromatography on silica eluting with 0-5% MeO ⁇ /DCM afforded the title compound as a white powder (26 mg, 62%). LCMS 466 [M+ ⁇ ] + , RT 3.02 min.
  • Example 20 Sodium cyanoborohydride (38 mg) and imidazole-2-carboxaldehyde (35 mg) were added to a suspension of Example 20 (100 mg) in MeOH (20 ml) under nitrogen. The reaction mixture was stirred for 72 hours at room temperature, at which point a further portion of sodium cyanoborohydride (19 mg) was added and stirring was continued for a further 18 hours. Saturated K 2 CO 3 solution (2 ml) was added and the solvent was removed in vacuo. The residue was partitioned between water (60 ml) and EtOAc (60 ml). The aqueous phase was extracted with DCM (50 ml) and more EtOAc (2 x 50 ml).
  • Example 28 Prepared in a similar manner to Example 28 from Example 20 (80 mg), 4(5)- imidazolecarboxaldehyde (28 mg) and sodium cyanoborohydride (30 mg). Purification by ⁇ PLC (Method A) afforded the title compound as a white powder (19 mg, 19%). LCMS 417 [M+ ⁇ ] + , RT 1.57 min.
  • Example 32 (70 mg) was dissolved in DMF (10 ml) before the addition of 2- chloro-iV-methylacetamide (23 mg) and Na 2 CO 3 (121 mg) took place. The reaction was heated at 8O°C under nitrogen for 2 hours before being allowed to cool to room temperature. The solvent was removed in vacuo and the residue purified by prep HPLC (Method A) to afford the title compound as a brown solid (3.5 mg, 5%). LCMS 401/399 [M+H] + , RT 1.79 min.
  • Methoxylamine hydrochloride (10 mg) was dissolved in DCM (5 ml) and cooled to -78°C under nitrogen. TEA (0.05 ml) was added followed by triphosgene (13 mg) and the mixture was stirred at O°C for 30 min. Example 32 (40 mg) and TEA (0.05 ml) were added and the mixture was stirred with warming to room temperature overnight. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3 x 20 ml). The DCM fractions were combined, dried over MgSO 4 , filtered and the solvent removed in vacuo to give a mixture of product and starting material.
  • Example 32 To a solution of Example 32 (50 mg) in DCM (2 ml) was added iV-acetylglycine (27 mg), followed by a solution of EDCHCl (44 mg) in DCM (1 ml) and a solution of HOBt (catalytic amount) in NMP (1 ml). The reaction mixture was stirred overnight at room temperature, then diluted with DCM (50 ml) and washed with water (10 ml). The organic phase was separated, dried over MgSO 4 , filtered and concentrated in vacuo. Purification by column chromatography on silica eluting with 10% MeOH/DCM afforded the title compound as an off-white powder (29 mg, 45%).
  • Examples 38-53 were prepared using parallel synthesis techniques as described below.
  • Example 32 (280 mg) was dissolved in NMP (3.8 ml). Portions of this solution (200 ⁇ l) were dispensed into the first 18 wells of a Whatman 48 deep well plate. Solutions of the appropriate carboxylic acid (0.5 M in NMP, 200 ⁇ l) were added to the individual wells. A solution of EDCHCl (0.2 M in DCM, 500 ⁇ l) and a solution of HOBt (0.2 M in NMP) (50 ⁇ l) were added to each well and the plate shaken overnight. The solvents were removed in vacuo and DMSO (500 ⁇ l) added to each well. The desired products from each well were isolated by prep HPLC Method A) to yield on average 1 mg of the title compounds .
  • Example 63 To a solution of Example 63 (1.0 g) in DCM (20 ml) was added TFA (280 ⁇ l) in one portion and the mixture was stirred at room temperature for 4 hours. The solution was then poured into 10% NaHCO 3 solution (200 ml) and DCM (100 ml) and stirred rapidly for 1 hour. The organic layer was separated, washed with water (75 ml) and brine (75 ml), and dried over MgSO 4 . The mixture was filtered and the solvent removed in vacuo to yield a yellow solid (540 mg).
  • Example 63 To a solution of Example 63 (1.00 g) in DCM (20 ml) was added TFA (280 ⁇ l) in one portion and the mixture was stirred for 4 hours. The solution was then poured into 10% NaHCO 3 solution (200 ml) and DCM (100 ml) and stirred rapidly for 1 hour. The organic layer was separated, washed with water (75 ml) and brine (75 ml), and dried over MgSO 4 . The mixture was filtered and the solvent removed in vacuo to yield the desired product (540 mg).
  • Example 73 Prepared in similar manner to Example 73 from the bis HCl salt of Example 32 (30 mg) and (i?)-(+)-2-pyrrolidone-5-carboxylic acid (13 mg). Purification by column chromatography on silica eluting with 10% MeO ⁇ /DCM afforded the title compound as an off-white solid (12.8 mg, 39%). LCMS 439/441 [M+ ⁇ ] + , RT 2.48 min.
  • Example 73 Prepared in similar manner to Example 73 from Example 32 (50 mg) and tetrahydro-3-furoic acid (16 mg). Purification by column chromatography on silica eluting with 10% MeOH/DCM gave a racemic mixture of the title compounds. Separation of the two enantiomers was achieved using chiral prep HPLC. (Mobile phase: 75% EtOH, 25% heptane, flow rate: 9 ml/min, run time 35 min.) Enantiomer 1 was afforded as a white solid (18 mg, 28%). Chiral HPLC (Mobile phase: 60% EtOH, 40% heptane, flow rate: 1 ml/min, run time: 30 min) RT 8.55 min.
  • Example 73 Prepared in similar manner to Example 73 from Example 32 (100 mg) and 3-oxo- cyclopentane-1-carboxylic acid (77 mg). Purification by column chromatography on silica eluting with 10% MeOHTDCM furnished the title compound as a yellow oil (84 mg, 63%). LCMS 438/440 [M+H] + , RT 2.90 min.
  • Example 73 Prepared in similar manner to Example 73 from the TFA salt of Example 32 (50 mg) and (,S)-(-)-2-pyrrolidone-5-carboxylic acid (15 mg). Purification by column chromatography on silica eluting with 10% MeOH/DCM gave the title compound as an off-white solid (23.8 mg, 48%). LCMS 439/441 [M+H] + , RT 2.49 min.
  • Example 73 Prepared in similar manner to Example 73 from 5-chloro-4-(lH-mdol-3-yl)-iV- (piperidin-4-yl)pyrimidin-2-amine (100 mg) and 4-hydroxycyclohexanecarboxylic acid (45 mg). Purification was achieved by prep ⁇ PLC (Method C). Example 81 was afforded as a white solid (2.4 mg, 2%). LCMS 454/456 [M+ ⁇ ] + , RT 2.66min.
  • Example 82 was afforded as a yellow solid (22.4 mg, 16%): LCMS 454/456 [M+H] + , RT 2.84 min.
  • 1 H NMR 400MHz, d 4 -Me0H) 8.64 (1H, d), 8.49 (1H, s), 8.18 (1H, s), 7.47 (1H, d), 7.27-7.16 (2H, m), 4.59-4.49 (1H, m), 4.25- 4.05 (2H, m), 3.98 (1H, s, br), 3.32-3.20 (1H, m), 2.95-2.82 (1H, m), 2.78-2.69 (1H, m), 2.27-2.09 (2H, m), 2.01-1.79 (4H, m), 1.69-1.41 (6H, m), 1.36-1.27 (1H, m).
  • Example 73 Prepared in similar manner to Example 73 from the bis HCl salt of Example 32 (30 mg) and 4-methoxycyclohexane carboxylic acid (13 mg). Purification by column chromatography on silica eluting with EtO Ac/heptane afforded the title compound as an off-white powder (12.6 mg, 36%). LCMS 468/470 [M+ ⁇ ] + , RT 3.36 min.
  • Examples 86-112 were prepared using parallel synthesis techniques as described below.
  • the bis HCl salt of Example 32 (1.65 g) was dissolved in DCM (55 ml). A portion of this solution (1 ml) was dispensed into the 48 wells of one Whatman 48 deep well plate and 7 wells of another. Solutions of the appropriate carboxylic acid (0.5 M in NMP) (200 ⁇ l) were added to the individual wells.
  • Example 111 was afforded as a white solid (3 mg, 10%).
  • Example 112 was afforded as a white solid (20 mg, 66%): LCMS 440/442 [M+H] + , RT 2.84 min.
  • 1 H NMR 400MHz, (I 4 -MeOH) 8.64 (1H, d), 8.49 (1H, s), 8.19 (1H, s), 7.48 (1H, d), 7.27-7.16 (2H, m), 4.90 (1H, s), 4.59-4.49 (1H, m), 4.29-4.08 (3H, m), 3.37-3.18 (2H, m), 3.00-2.89 (1H, m), 2.28-2.08 (3H, m), 2.01-1.79 (4H, m), 1.78-1.68 (1H, m), 1.62-1.45 (2H, m).
  • Example 84 To a solution of Example 84 in water/THF (5 ml/5 ml) was added LiOH-H 2 O (45.6 mg). The reaction mixture was stirred at r.t. for 2 hours and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 0-10%
  • Example 84 To a solution of Example 84 (227 mg) in dry DCM under nitrogen (5 ml) cooled to -78°C was added slowly over a period of 15 min diisobutylaluminium hydride (1.5 M in toluene) (1 ml). The reaction mixture was stirred for a further hour at -78°C. The solvent was removed in vacuo and the residue purified by prep HPLC (Method A) to afford the title compound as an orange oil (5.2 mg, 2.3%). LCMS 428/430 [M+H] + , RT 2.96 min (pH 5.8).
  • Example 116 To a solution of Example 116 (100 mg) in DCM (10 ml) was added ethyl isocyanate (17.4 ⁇ l). The reaction mixture was stirred overnight at r.t. and the solvent was removed in vacuo. Purification by prep HPLC (Method B) afforded the title compound as a matt gold solid (21.1 mg, 18%). LCMS (pH 5.8) 510/512 [M+H] + , RT 3.04 min.
  • Example 116 (lOOmg) in DCM (10 ml) was added methane sulphonyl chloride (17.02 ⁇ l) and TEA (63.6 ⁇ l). The reaction mixture was stirred at r.t. overnight and the solvent was removed in vacuo. Purification by prep HPLC (Method B) afforded the title compound as a dark orange solid (2.1 mg, 1.8%). LCMS (pH 5.8) 517/519 [M+H] + , RT 3.21 min.
  • N-[(E)-2-imidazo[l,2-a]pyridin-3-ylvinyl]-iV,N- dimethylamine (0.54 g) was added and the reaction mixture was heated at 100°C overnight. The mixture was allowed to cool to r.t, water (50 ml) was added and the mixture extracted with EtOAc (200 ml). The organic layer was washed with water (6 x 30 ml), washed with brine (30ml), separated, dried over MgSO 4 , filtered and the solvent removed in vacuo. Trituration in Et 2 O afforded the title compound as a cream solid (0.58 g, 59%).
  • Example 120 To a solution of Example 120 (75 mg) in MeOH / DCM (10 ml / 5 ml) was added HCl (2.0M in Et20) (3.8 ml). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo to afford the title compound as a yellow solid (90 mg, quantitative). LCMS (pH 5.8) 295 [M+H] + , RT 1.59 min.
  • Example 73 Prepared in similar manner to Example 73 from Example 121 (100 mg) and tetrahydro-2H-pyran-4-carboxylic acid (CAS 5337-03-1) (48 mg). Purification by trituration in DCMZEt 2 O afforded the title compound as a cream solid (51 mg, 51%).
  • Example 73 Prepared in similar manner to Example 73 from Example 121 (100 mg) and (S)-(- )-2-pyrrolidone-5-carboxylic acid (44 mg). Purification by trituration in DCM/Et 2 O afforded the title compound as a lemon yellow solid (48 mg, 52%). LCMS 406 [M+H] + , RT 1.38 min.
  • Example 121 To a solution of Example 121 (100 mg) in DCM (5 ml) and DMF (2ml) was added iV-acetylglycine (32 mg), HBTU (100 mg) and DIPEA (240 ⁇ l). The reaction mixture was stirred at r.t. overnight. The solvent was removed in vacuo and the residue partitioned between water (50 ml) and EtOAc (50 ml). Precipitation was observed and the solvent from the organic layer was removed in vacuo. Purification by prep HPLC (Method B) afforded the title compound as a brown solid (40 mg, 44%). LCMS (pH 5.8) 394 [M+H] + (Free base), RT 2.07 min (pH 5.8).
  • Example 124 Prepared in similar manner to Example 124 from Example 121(175 mg) and tetrahydrofuoric acid (20 ⁇ l). Purification by column chromatography on reverse phase silica eluting with 0-60% (MeOH + 0.04% formic acid)/(H 2 O + 0.04% formic acid) afforded the title compound as a brown solid (48 mg, 64%). LCMS 393 [M+H] + , RT 1.55 min.
  • Example 73 Prepared in similar manner to Example 73 from Example 126 (50 mg) and N- acetylglycine (13.4 mg). Precipitation from EtO Ac/aqueous sodium bicarbonate solution afforded the title compound as a yellow solid (25 mg, 51%). LCMS 428/430 [M+H] + , RT 1.72 min.
  • Example 73 Prepared in similar manner to Example 73 from Example 126 (50 mg) and tetrahydro-2H " -pyran-4-carboxylic acid (CAS 5337-03-1) (15 mg). Precipitation from EtOAc/Et 2 O afforded the title compound as a yellow solid (50 mg, 95%).
  • Example 32 To a solution of Example 32 (100 mg) in dry MeCN (10 ml) under nitrogen was added (2-pyridylmethyl)sulfonyl chloride Inflate (115 mg) and TEA (0.134 ml). The mixture was stirred at r.t. overnight. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 20% EtO Ac/heptane to afford the title compound as an ivory powder (8.5 mg 5 5.8%). LCMS 483/485 [M+H] + , RT 3.19 min.
  • Example 129 Prepared in similar manner to Example 129 from the bis HCl salt of Example 32 (150 mg) and (4-pyridylmethyl)sulfonyl chloride triflate (128 mg). Purification by prep HPLC (Method A) afforded the title compound as a gold solid (13 mg, 7%). LCMS 483/485 [M+H] + , RT 3.33 min.
  • Example 121 To a suspension/solution of Example 121 (100 mg) in dry DCM/DMF (10 ml/5 ml) under nitrogen was added TEA (0.16 ml). Isopropylsulphonyl chloride (0.04 ml) was then added and the reaction mixture was stirred at r.t. overnight. LCMS showed a mixture of product and starting material. The solvent was removed in vacuo and the residues dissolved in dry DCM/DMF (10 ml/5 ml) under nitrogen and to this added DIPEA (0.2 ml) and isopropylsulphonyl chloride (0.04 ml). The reaction mixture was stirred for 3 days and the solvent was removed in vacuo.
  • Example 134 Prepared in a similar manner to Example 134 from Example 121 (75 mg) and 1- methylimidazole-4-sulphonyl chloride (37 mg). Purification by trituration in DMSO afforded the title compound as a white solid (62 mg, 76%). LCMS 439 [M+H] + , RT 1.69 min.
  • Example 126 To a solution of Example 126 (50 mg) in dry DCM/DMF (3 ml/3 ml) under nitrogen was added isopropylsulfonyl chloride (16 mg) and TEA (70 ⁇ l). The reaction mixture was stirred at r.t. overnight and partitioned between EtOAc (100 ml) and sodium hydrogencarbonate solution (50 ml). The organic layer was washed with brine (20 ml), separated, dried over MgSO 4 , filtered and the solvent removed in vacuo. Trituration in EtOAc/Et 2 O afforded the title compound as a yellow solid (50 mg, quantitative). LCMS 435/437 [M+H] + , RT 2.49 min.
  • EXAMPLE 137 EthvU4-([5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino ⁇ piperidin-1-yl)(oxo)acetate
  • ethyl oxalyl chloride 0.025 ml
  • TEA 0.114 ml
  • the mixture was stirred at r.t. for 2 days. More ethyl oxalyl chloride (0.03 ml) and DMF (1 ml) were added and the mixture heated in a microwave at 7O°C for 10 min.
  • Example 143 Prepared in a similar manner to Example 143 from Example 139 (80 mg) and dimethylamine hydrochloride (18 mg). Purification by prep HPLC (Method A) afforded the title compound as yellow solid (21 mg, 27%). LCMS 427/429 [M+H] + , RT 2.75 min.
  • Example 144 Prepared in similar manner to Example 144 from the TFA salt of Example 32 (100 mg) and l,l-dioxidotetrahydro-thien-3-ylamine hydrochloride (39 mg). Purification by prep HPLC (Method B) afforded the title compound as a white solid (7.9 mg, 8%).
  • Example 32 To a suspension of Example 32 (80 mg) in dry THF (12 ml) under nitrogen was added 4-isocyanato-l-trifluoroacetyl piperidine (60 mg) and the mixture stirred at r.t. overnight. The solvent was removed in vacuo and the residue triturated with Et 2 O to give a yellow solid (90 mg). A portion of this solid (75 mg) was dissolved in MeOH/water (4 ml/1 ml) and K 2 CO 3 (38mg) was added. The reaction mixture was stirred at r.t. overnight. The mixture was diluted with water (10 ml) and extracted sequentially with DCM (50 ml), EtOAc (50 ml) and DCM (50 ml).
  • Example 21 To a solution of Example 21 (82 mg) in MeOH (10ml) was added NaOH (lOmg) followed by palladium on carbon (50 mg). The reaction mixture was stirred under an atmosphere of hydrogen for 3 hours, after which the solution was neutralised with IM HCl and filtered through a pad of celite. The solvent was removed in vacuo to give a yellow gum, which was purified by column chromatography on reverse phase silica eluting with 0-100% (MeOH + 0.04% formic acid)/(H 2 O with 0.04% formic acid) to give the title compound as a yellow solid (44 mg, 59%). LCMS 365 [M+H] + (Free base) RT 1.83 min.
  • Example 150 Prepared in similar manner to Example 150 from Example 32 (40 mg) and N- methylpiperazine (55 ⁇ l) to give the title compound as an off-white solid (12.8 mg, 22%).
  • HCl was added to the test sample to aid solubility in DMSO.
  • Example 150 Prepared in similar manner to Example 150 from Example 32 (40 mg) and aqueous ammonia (19 ⁇ l) to give the title compound as a glass (10 mg, 16%).
  • Morpholme-4-carboxylic acid (2- ⁇ 4-[5-chloro-4-(1H-indol-3-yl)-pyrimidin-2-ylamino]- piperidin- 1 -yl ⁇ -2-oxo-ethyl)-amide
  • Example 156 Prepared in similar manner to Example 156 from the bis HCl salt of Example 32 (80 mg) and morpholine carbonyl chloride (50 ⁇ l). Purification by column chromatography on silica eluting with 0-100% MeO ⁇ /DCM followed by prep ⁇ PLC (Method A) afforded the title compound as a brown solid (5.5 mg, 6%). LCMS 498/500 [M+ ⁇ ] + , RT 2.54 min.
  • Examples 160-198 were prepared using parallel synthesis techniques as described below.
  • the bis HCl salt of Example 32 (3.6 g) was dissolved in DMF (117 ml).
  • the reaction mixture was then dispensed (1 ml per tube) into 118 tubes, which had been pre-prepared with the appropriate amines (1 mmol per tube). The tubes were shaken for 72 hours. LCMS analysis of four tubes at random showed that some conversions were incomplete.
  • Example 150 Prepared in similar manner to Example 150 from Example 32 (50 mg), 2- chloroproionyly chloride (14 ⁇ l) and methylamine (2M in T ⁇ F) (0.3 ml). Purification by prep ⁇ PLC (Method A) afforded the title compound as a white solid (26.1 mg, 41%).
  • Example 150 Prepared in similar manner to Example 150 from Example 32 (100 mg) and 2- chloro-2-phenyl-acetyl chloride (48 ⁇ l) and methylamine (2M in THF) (0.6 ml) Purification by prep HPLC (Method A) afforded the title compound as a yellow solid (12.6mg, 8%). LCMS 475/477 [M+H] + , RT 2.19 min.
  • Example 32 To a suspension of Example 32 (400 mg), (tert-butoxycarbonyl-mefhyl-amino)- acetic acid (CAS 13734-36-6) (208 mg) and HATU (418 mg) in DMF (10 ml) was added DIPEA (0.871 ml). The resulting solution was stirred overnight at r.t. The reaction mixture was concentrated in vacuo and redissolved in DCM (50 ml). The organic layer was washed with saturated aqueous NaHCO 3 solution (3 x 20 ml), washed with brine (20 ml), separated, dried over MgSO 4 , filtered and the solvent removed in vacuo.
  • DIPEA 0.871 ml
  • Tetrahydro-pyran-4-carboxylic acid (2- ⁇ 4-[5-chloro-4-(1H-indol-3-yl)-pyrimidin-2- ylamino]-piperidin- 1 -yl> -2-oxo-ethyl)-amide
  • a solution of tetrahydro-2H-pyran-4-carbonyl chloride (CAS 40191-32-0) (223 mg) in dry DCM (20 ml) was added glycine methyl ester HCl (207 mg) and TEA (0.42 ml). The reaction mixture was stirred at room temperature overnight.
  • Example 32 To a solution of Example 32 (50 mg) and 3-picolyl chloride HCl (30 mg) in DMF (10 ml) was added Na 2 CO 3 (32 mg). The reaction was stirred at 95°C for 3 hours and the solvent removed in vacuo. Purification by prep HPLC (Method B) afforded the title compound as a white solid (26 mg, 41%). LCMS (pH 5.8) 419/421 [M+H] + , RT 3.14 min.
  • Example 32 To a solution of Example 32 (460 mg) and tert-butyl bromoacetate (0.25 ml) in DMF (20 ml) was added Na 2 CO 3 (164 mg). The reaction was stirred at r.t. overnight and the solvent removed in vacuo. The residue was dissolved in EtOAc (100 ml) and washed with water (50 ml). The organic layer was separated, dried over MgSO 4 , filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica eluting with 50-100% EtOAc/heptane. The resulting ester was dissolved in DCM (10 ml) and TFA (1.3 ml) added.
  • Examples 212-223 were prepared using parallel synthesis techniques as described below.
  • a stock solution of Example 211 (0.5 M in NMP) (200 ⁇ l) was dispensed into each of the used wells of a Whatman 48 deep well plate. Solutions of the appropriate amines (0.5 M in NMP) (200 ⁇ l) were added to the individual wells.
  • a solution of EDCHCl (0.2 M in DCM) (500 ⁇ l) and a solution of HOBt (0.2 M in NMP) (50 ⁇ l) were added to each well and the plate shaken for 18 hours. The solvents were removed in vacuo and DMSO (500 ⁇ l) added to each well.
  • the desired products from each well were isolated by prep HPLC (Method A) to yield on average 1 mg of the title compounds.
  • Example 33 Prepared in similar manner to Example 33 from the bis HCl salt of Example 32 (68 mg) and 2-chloro-N-methyl-2- ⁇ henylacetamide (CAS 7899-96-4) (42 mg).

Landscapes

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

Abstract

La présente invention concerne un composé de formule (I) ou un sel, un solvate ou un N-oxyde pharmaceutiquement acceptables de celui-ci. Dans ladite formule, A représente un cycle pyrrole, pyrazole, imidazole ou triazole ; B représente un cycle benzène, pyridine ou pyrimidine ; M représente le résidu d’un cycle azétidine, pyrrolidine ou pipéridine ; E représente une liaison covalente ou une chaîne alkylénique droite ou ramifiée facultativement substituée contenant de 1 à 4 atomes de carbone ; Z représente l’hydrogène, -CORa, -C02Rb, -CONKc Rd, -CONRcORb, -COCO2Rb, - COCONRcRd, -COCH2NRcRd, -COCH2NRcCONKcRd, COCH2NRcCO2Rb, -NRcCORa, - NRcCO2Rb, -NRcCONRcRd, -S02Re, -SO2NRcRd ou -SO2NRcC02Rb ; ou bien Z représente un groupe phényle, hétéroaryle ou hétérocycloalkyle en C3-7 facultativement substitué ; R1 et R2 représentent indépendamment l’hydrogène, un halogène, un groupe cyano, nitro, alkyle en C1-6, trifluorométhyle, hydroxyle, alcoxy en C1-6, difluorométhoxy, trifluorométhoxy, alkylsulphonyle en C1-6, amino, alkylamino en C1-6, dialkylamino en C1-6, aminocarbonyle ou alcoxycarbonyle en C2-6 ; R3 représente l’hydrogène, un alkyle en C1-6, -CH2CONRcRd ou -SO2Re ; R4 représente l’hydrogène, un alcoxy en C1-6, un groupe oxo, -CO2Rb ou -CONKcRd. Les composés de la présente invention sont des inhibiteurs puissants de la JNK.
PCT/GB2005/003827 2004-10-06 2005-10-04 Derives d’aminopyrimidine en tant qu’inhibiteurs de la jnk WO2006038001A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0422284A GB0422284D0 (en) 2004-10-06 2004-10-06 Therapeutic agents
GB0422284.0 2004-10-06
GB0509642.5 2005-05-11
GB0509642A GB0509642D0 (en) 2005-05-11 2005-05-11 Therapeutics agents

Publications (1)

Publication Number Publication Date
WO2006038001A1 true WO2006038001A1 (fr) 2006-04-13

Family

ID=35219477

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2005/003827 WO2006038001A1 (fr) 2004-10-06 2005-10-04 Derives d’aminopyrimidine en tant qu’inhibiteurs de la jnk

Country Status (1)

Country Link
WO (1) WO2006038001A1 (fr)

Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007107221A1 (fr) * 2006-03-20 2007-09-27 Merck Patent Gmbh Derive de 4-(pyrrolopyridinyl)-pyrimidinyl-2-amine
EP1698375A4 (fr) * 2003-12-25 2007-11-07 Ono Pharmaceutical Co Composes cycliques d'azetidine et medicaments les renfermant
WO2008101587A1 (fr) * 2007-02-21 2008-08-28 Merck Patent Gmbh Dérivés de 4-(pyrrolopyridinyl)-pyrimidin-2-yl-amine
WO2008078100A3 (fr) * 2006-12-22 2008-11-13 Astex Therapeutics Ltd Nouveaux composés
US7507826B2 (en) 2004-03-30 2009-03-24 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
WO2008118626A3 (fr) * 2007-03-08 2009-05-07 Burnham Inst Medical Research Inhibiteurs de jnk et procédés pour identifier des inhibiteurs de jnk
WO2009114950A1 (fr) * 2008-03-21 2009-09-24 Chlorion Pharma, Inc. Composés de pyrrolidine et de pipéridine substitués, leurs dérivés et procédés de traitement de la douleur
WO2009138340A1 (fr) * 2008-05-16 2009-11-19 F. Hoffmann-La Roche Ag Inhibiteurs de la jnk
JP2009542604A (ja) * 2006-07-06 2009-12-03 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４−ヘテロシクロアルキルピリミジン、それらの調製方法及び医薬としての使用
FR2933982A1 (fr) * 2008-07-18 2010-01-22 Sanofi Aventis Nouveaux derives imidazo°1,2-a!pyrimidine, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de met
US7767816B2 (en) 2006-01-17 2010-08-03 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of janus kinases
WO2010097335A1 (fr) * 2009-02-24 2010-09-02 F. Hoffmann-La Roche Ag Imidazo[1,2-a]pyridines comme modulateurs de la jnk
WO2010144416A1 (fr) * 2009-06-08 2010-12-16 Gaeta Federico C A Composés de pyrazolo[1,5‑a]pyridine substitués à activité multiciblée
EP2338888A1 (fr) * 2009-12-24 2011-06-29 Almirall, S.A. Dérivés d'imidazopyridine en tant qu'inhibiteurs JAK
US8071614B2 (en) 2007-10-12 2011-12-06 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
WO2011151357A1 (fr) * 2010-06-04 2011-12-08 F. Hoffmann-La Roche Ag Inhibiteurs de la jnk
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8247421B2 (en) 2006-12-21 2012-08-21 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
EP2548864A1 (fr) 2011-07-22 2013-01-23 Université Joseph Fourier Nouveaux dérivés bis-indoliques, leur procédé de préparation et leurs utilisations en tant que médicament
US8410089B2 (en) 2009-02-18 2013-04-02 Takeda Pharmaceutical Company Limited Fused heterocyclic ring compound
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use
EP2563774A4 (fr) * 2010-04-27 2013-07-10 Hutchison Medipharma Ltd Pyrimidinylindoles
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8829007B2 (en) 2009-06-17 2014-09-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
JP5586234B2 (ja) * 2007-12-27 2014-09-10 第一三共株式会社 イミダゾールカルボニル化合物
US8871774B2 (en) 2010-12-16 2014-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US8895745B2 (en) 2006-12-22 2014-11-25 Astex Therapeutics Limited Bicyclic heterocyclic compounds as FGFR inhibitors
US8962622B2 (en) 2006-09-08 2015-02-24 Roche Palo Alto Llc Benzotriazole kinase modulators
US9034311B2 (en) 2011-08-01 2015-05-19 Almirall, S.A. Pyridin-2(1 H)-one derivatives as JAK inhibitors
US9051319B2 (en) 2011-08-01 2015-06-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
CN104803981A (zh) * 2015-04-22 2015-07-29 复旦大学 一种哌啶-4-胺基二芳基嘧啶衍生物及其制备方法和用途
US9133200B2 (en) 2010-11-26 2015-09-15 Almirall, S.A. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine derivatives as JAK inhibitors
US9145387B2 (en) 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9206183B2 (en) 2010-02-18 2015-12-08 Almirall, S.A. Substituted pyrazolo[1,5-a]pyridines as JAK inhibitors
RU2572247C2 (ru) * 2010-06-04 2016-01-10 Ф. Хоффманн-Ля Рош Аг Производные 2-амино-пиримидина в качестве ингибиторов jnk
JP2017002067A (ja) * 2011-07-05 2017-01-05 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ アザインドールを作製するための方法および中間体
KR20170091516A (ko) * 2016-01-29 2017-08-09 한양대학교 에리카산학협력단 Jnk 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
WO2017204626A1 (fr) 2016-05-24 2017-11-30 Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Polythérapie combinant map2k4/map3k1 et une inhibition de mek/erk
WO2018013867A1 (fr) * 2016-07-13 2018-01-18 Marineau Jason J Inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10047071B1 (en) 2018-01-15 2018-08-14 King Saud University Dihydropyrimidinone derivatives
WO2018141002A3 (fr) * 2017-02-01 2018-11-22 University Of South Australia Dérivés de n-cycloalkyl/hétérocycloalkyle-4-(imidazo[1,2-a]pyridine)pyrimidin-2-amine en tant qu'agents thérapeutiques
US10266530B2 (en) 2016-09-09 2019-04-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
WO2019143730A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
WO2019143719A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
US10533004B2 (en) 2015-05-13 2020-01-14 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
WO2020093006A1 (fr) * 2018-11-01 2020-05-07 Syros Pharmaceuticals, Inc. Méthodes de traitement du cancer chez des patients identifiés par biomarqueurs avec des inhibiteurs non covalents de la kinase cycline-dépendante 7 (cdk7)
CN111393415A (zh) * 2020-04-30 2020-07-10 苏州信诺维医药科技有限公司 一种杂芳腈类化合物及其应用
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US10766884B2 (en) 2018-04-26 2020-09-08 Pfizer Inc. Cyclin dependent kinase inhibitors
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US11306070B2 (en) * 2016-11-22 2022-04-19 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof
WO2022134641A1 (fr) * 2020-12-24 2022-06-30 湃隆生物科技有限公司（香港） Composé hétérocyclique aromatique, composition pharmaceutique et utilisation de celui-ci
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
WO2023049691A1 (fr) * 2021-09-23 2023-03-30 Zeno Management, Inc. Inhibiteurs de cdk7 et méthodes de traitement du cancer
WO2023116761A1 (fr) * 2021-12-22 2023-06-29 英矽智能科技知识产权有限公司 Composé hétérocyclique de pyrimidine, son procédé de préparation et son utilisation en médecine
JP2023538326A (ja) * 2020-08-11 2023-09-07 ボード オブ トラスティーズ オブ ミシガン ステイト ユニバーシティ プロテアソームエンハンサ及びその使用
JP2023539690A (ja) * 2020-09-03 2023-09-15 エフ． ホフマン－ラ ロシュ アーゲー 複素環式化合物
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors
EP4186895A4 (fr) * 2020-07-24 2024-09-11 TYK Medicines Inc. Composé utile en tant qu'inhibiteur de kinase cdk7 et son utilisation
US12168663B2 (en) 2014-12-23 2024-12-17 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
WO2024260325A1 (fr) * 2023-06-19 2024-12-26 英矽智能科技知识产权有限公司 Synthèse d'un composé macrocyclique et utilisation médicale d'un composé macrocyclique
US12441731B2 (en) 2021-08-04 2025-10-14 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000207A1 (fr) * 1999-06-30 2001-01-04 Merck & Co., Inc. Composes inhibiteurs de la src kinase
WO2003106455A1 (fr) * 2002-06-14 2003-12-24 Applied Research Systems Ars Holding N.V. Derives de cyanure d'azole methylidene et leur utilisation comme modulateurs de proteine kinase
US20040053942A1 (en) * 2000-08-22 2004-03-18 Alberti Michael John Fused pyrazole derivatives bieng protein kinase inhibitors
WO2004089913A1 (fr) * 2003-04-11 2004-10-21 Novartis Ag Derives de 2-aminopyrimidine et leur application en medecine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000207A1 (fr) * 1999-06-30 2001-01-04 Merck & Co., Inc. Composes inhibiteurs de la src kinase
US20040053942A1 (en) * 2000-08-22 2004-03-18 Alberti Michael John Fused pyrazole derivatives bieng protein kinase inhibitors
WO2003106455A1 (fr) * 2002-06-14 2003-12-24 Applied Research Systems Ars Holding N.V. Derives de cyanure d'azole methylidene et leur utilisation comme modulateurs de proteine kinase
WO2004089913A1 (fr) * 2003-04-11 2004-10-21 Novartis Ag Derives de 2-aminopyrimidine et leur application en medecine

Cited By (186)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7511159B2 (en) 2003-12-25 2009-03-31 Ono Pharmaceutical Co., Ltd. Azetidine ring compounds and drugs comprising the same
EP1698375A4 (fr) * 2003-12-25 2007-11-07 Ono Pharmaceutical Co Composes cycliques d'azetidine et medicaments les renfermant
US8987454B2 (en) 2004-03-30 2015-03-24 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US7507826B2 (en) 2004-03-30 2009-03-24 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8188281B2 (en) 2004-03-30 2012-05-29 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8501446B2 (en) 2004-03-30 2013-08-06 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8722889B2 (en) 2004-03-30 2014-05-13 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
US8450489B2 (en) 2006-01-17 2013-05-28 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of janus kinases
US8163917B2 (en) 2006-01-17 2012-04-24 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of Janus kinases
US9120790B2 (en) 2006-01-17 2015-09-01 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of Janus kinases
US8822681B2 (en) 2006-01-17 2014-09-02 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of janus kinases
US7767816B2 (en) 2006-01-17 2010-08-03 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of janus kinases
WO2007107221A1 (fr) * 2006-03-20 2007-09-27 Merck Patent Gmbh Derive de 4-(pyrrolopyridinyl)-pyrimidinyl-2-amine
US8258129B2 (en) * 2006-07-06 2012-09-04 Boehringer Ingelheim International Gmbh 4-heterocycloalkylpyri(mi)dines, process for the preparation thereof and their use as medicaments
JP2009542604A (ja) * 2006-07-06 2009-12-03 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４−ヘテロシクロアルキルピリミジン、それらの調製方法及び医薬としての使用
US8962622B2 (en) 2006-09-08 2015-02-24 Roche Palo Alto Llc Benzotriazole kinase modulators
US8962642B2 (en) 2006-12-21 2015-02-24 Vertex Pharmaceuticals Incorporated 5-cyano-4- (pyrrolo [2,3B] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
US8530489B2 (en) 2006-12-21 2013-09-10 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
JP2014051516A (ja) * 2006-12-21 2014-03-20 Vertex Pharmaceuticals Inc タンパク質キナーゼ阻害剤として有用な５−シアノ−４−（ピロロ［２，３ｂ］ピリジン−３−イル）−ピリミジン誘導体
US8247421B2 (en) 2006-12-21 2012-08-21 Vertex Pharmaceuticals Incorporated 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
US8895745B2 (en) 2006-12-22 2014-11-25 Astex Therapeutics Limited Bicyclic heterocyclic compounds as FGFR inhibitors
AU2007337895C1 (en) * 2006-12-22 2014-07-31 Astex Therapeutics Limited Tricyclic amine derivatives as protein tyrosine kinase inhibitors
JP2010513448A (ja) * 2006-12-22 2010-04-30 アステックス、セラピューティックス、リミテッド 新規化合物
US8513276B2 (en) 2006-12-22 2013-08-20 Astex Therapeutics Limited Imidazo[1,2-a]pyridine compounds for use in treating cancer
AU2007337895B2 (en) * 2006-12-22 2014-01-30 Astex Therapeutics Limited Tricyclic amine derivatives as protein tyrosine kinase inhibitors
WO2008078100A3 (fr) * 2006-12-22 2008-11-13 Astex Therapeutics Ltd Nouveaux composés
AU2008217297B2 (en) * 2007-02-21 2013-01-17 Merck Patent Gmbh 4-(pyrrolopyridinyl)pyrimidin-2-ylamine derivatives
US8557977B2 (en) 2007-02-21 2013-10-15 Merck Patent Gmbh 4 (pyrrolopyridinyl)pyrimidin-2-ylamine derivatives
JP2010519230A (ja) * 2007-02-21 2010-06-03 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ４−（ピロロピリジニル）ピリミジン−２−イルアミン誘導体
US8293891B2 (en) 2007-02-21 2012-10-23 Merck Patent Gesellschaft Mit Beschrankter Haftung 4 (pyrrolopyridinyl)pyrimidin-2-ylamine derivatives
WO2008101587A1 (fr) * 2007-02-21 2008-08-28 Merck Patent Gmbh Dérivés de 4-(pyrrolopyridinyl)-pyrimidin-2-yl-amine
WO2008118626A3 (fr) * 2007-03-08 2009-05-07 Burnham Inst Medical Research Inhibiteurs de jnk et procédés pour identifier des inhibiteurs de jnk
US8076354B2 (en) 2007-10-12 2011-12-13 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8071614B2 (en) 2007-10-12 2011-12-06 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8859582B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
US8859583B2 (en) 2007-10-12 2014-10-14 Astex Therapeutics Limited Bicyclic heterocyclic compounds as protein tyrosine kinase inhibitors
JP5586234B2 (ja) * 2007-12-27 2014-09-10 第一三共株式会社 イミダゾールカルボニル化合物
WO2009114950A1 (fr) * 2008-03-21 2009-09-24 Chlorion Pharma, Inc. Composés de pyrrolidine et de pipéridine substitués, leurs dérivés et procédés de traitement de la douleur
KR101368079B1 (ko) 2008-05-16 2014-03-14 에프. 호프만-라 로슈 아게 Ｊｎｋ 의 억제제
US8183254B2 (en) 2008-05-16 2012-05-22 Roche Palo Alto Llc Inhibitors of JNK
RU2504545C2 (ru) * 2008-05-16 2014-01-20 Ф. Хоффманн-Ля Рош Аг Ингибиторы jnk
CN102015689A (zh) * 2008-05-16 2011-04-13 霍夫曼-拉罗奇有限公司 Jnk的抑制剂
WO2009138340A1 (fr) * 2008-05-16 2009-11-19 F. Hoffmann-La Roche Ag Inhibiteurs de la jnk
US8796244B2 (en) 2008-06-13 2014-08-05 Astex Therapeutics Ltd Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
FR2933982A1 (fr) * 2008-07-18 2010-01-22 Sanofi Aventis Nouveaux derives imidazo°1,2-a!pyrimidine, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation notamment comme inhibiteurs de met
WO2010007318A3 (fr) * 2008-07-18 2010-04-08 Sanofi-Aventis NOUVEAUX DERIVES IMIDAZO[1,2-a]PYRIMIDINE, LEUR PROCEDE DE PREPARATION, LEUR APPLICATION A TITRE DE MEDICAMENTS, COMPOSITIONS PHARMACEUTIQUES ET NOUVELLE UTILISATION NOTAMMENT COMME INHIBITEURS DE MET
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8410089B2 (en) 2009-02-18 2013-04-02 Takeda Pharmaceutical Company Limited Fused heterocyclic ring compound
US8569306B2 (en) 2009-02-24 2013-10-29 Hoffmann-La Roche, Inc. JNK modulators
JP2012518668A (ja) * 2009-02-24 2012-08-16 エフ．ホフマン−ラ ロシュ アーゲー ＪＮＫモジュレーターとしてのイミダゾ［１，２−ａ］ピリジン
WO2010097335A1 (fr) * 2009-02-24 2010-09-02 F. Hoffmann-La Roche Ag Imidazo[1,2-a]pyridines comme modulateurs de la jnk
CN102325771B (zh) * 2009-02-24 2014-10-29 霍夫曼-拉罗奇有限公司 作为jnk调节剂的咪唑并[1,2-a]吡啶类
CN102325771A (zh) * 2009-02-24 2012-01-18 霍夫曼-拉罗奇有限公司 作为jnk调节剂的咪唑并[1,2-a]吡啶类
US8722687B2 (en) 2009-04-15 2014-05-13 Astex Therapeutics Ltd Imidazo [1,2-A]pyridine derivatives as FGFR kinase inhibitors for use in therapy
US8481531B2 (en) 2009-04-15 2013-07-09 Astex Therapeutics Ltd Bicyclic heterocyclyl derivatives as FGFR kinase inhibitors for therapeutic use
WO2010144416A1 (fr) * 2009-06-08 2010-12-16 Gaeta Federico C A Composés de pyrazolo[1,5‑a]pyridine substitués à activité multiciblée
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US10039762B2 (en) 2009-06-17 2018-08-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9808459B2 (en) 2009-06-17 2017-11-07 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9345708B2 (en) 2009-06-17 2016-05-24 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US8829007B2 (en) 2009-06-17 2014-09-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10874673B2 (en) 2009-06-17 2020-12-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9518056B2 (en) 2009-06-17 2016-12-13 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
EP2338888A1 (fr) * 2009-12-24 2011-06-29 Almirall, S.A. Dérivés d'imidazopyridine en tant qu'inhibiteurs JAK
CN102695706A (zh) * 2009-12-24 2012-09-26 阿尔米雷尔有限公司 作为jak抑制剂的咪唑并吡啶衍生物
WO2011076419A1 (fr) * 2009-12-24 2011-06-30 Almirall, S.A. Dérivés de l'imidazopyridine en tant qu'inhibiteurs de jak
JP2013515688A (ja) * 2009-12-24 2013-05-09 アルミラル・ソシエダッド・アノニマ Ｊａｋ阻害剤としてのイミダゾピリジン誘導体
US9206183B2 (en) 2010-02-18 2015-12-08 Almirall, S.A. Substituted pyrazolo[1,5-a]pyridines as JAK inhibitors
AU2010351938B2 (en) * 2010-04-27 2014-10-30 Hutchison Medipharma Limited Pyrimidinyl indole compounds
EP2563774A4 (fr) * 2010-04-27 2013-07-10 Hutchison Medipharma Ltd Pyrimidinylindoles
US8501166B2 (en) 2010-04-27 2013-08-06 Hutchison Medipharma Limited Pyrimidinyl indole compounds
KR101800916B1 (ko) 2010-06-04 2017-11-23 에프. 호프만-라 로슈 아게 Jnk 억제제로서 유용한 2-아미노-피리미딘 유도체
CN102918046A (zh) * 2010-06-04 2013-02-06 霍夫曼-拉罗奇有限公司 Jnk的抑制剂
RU2572247C2 (ru) * 2010-06-04 2016-01-10 Ф. Хоффманн-Ля Рош Аг Производные 2-амино-пиримидина в качестве ингибиторов jnk
WO2011151357A1 (fr) * 2010-06-04 2011-12-08 F. Hoffmann-La Roche Ag Inhibiteurs de la jnk
US9133200B2 (en) 2010-11-26 2015-09-15 Almirall, S.A. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine derivatives as JAK inhibitors
US8871774B2 (en) 2010-12-16 2014-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
JP2017002067A (ja) * 2011-07-05 2017-01-05 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ アザインドールを作製するための方法および中間体
CN106432311A (zh) * 2011-07-05 2017-02-22 沃泰克斯药物股份有限公司 生产氮杂吲哚类的方法和中间体
WO2013014102A1 (fr) 2011-07-22 2013-01-31 Universite Joseph Fourier Dérivés bis-indoliques, procédé pour préparer ceux-ci et leurs utilisations en tant que médicament
EP2548864A1 (fr) 2011-07-22 2013-01-23 Université Joseph Fourier Nouveaux dérivés bis-indoliques, leur procédé de préparation et leurs utilisations en tant que médicament
US9051319B2 (en) 2011-08-01 2015-06-09 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9394302B2 (en) 2011-08-01 2016-07-19 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9034311B2 (en) 2011-08-01 2015-05-19 Almirall, S.A. Pyridin-2(1 H)-one derivatives as JAK inhibitors
US9908878B2 (en) 2011-08-01 2018-03-06 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10875855B2 (en) 2011-08-01 2020-12-29 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US9980964B2 (en) 2013-02-08 2018-05-29 Celgene Car Llc ERK inhibitors and uses thereof
US9561228B2 (en) 2013-02-08 2017-02-07 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9145387B2 (en) 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9504686B2 (en) 2013-02-08 2016-11-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US9796700B2 (en) 2013-02-08 2017-10-24 Celgene Car Llc ERK inhibitors and uses thereof
US9771361B2 (en) 2013-11-13 2017-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US10640501B2 (en) 2013-11-13 2020-05-05 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US11345700B2 (en) 2013-11-13 2022-05-31 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10023569B2 (en) 2013-11-13 2018-07-17 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10202364B2 (en) 2014-08-13 2019-02-12 Celgene Car Llc Forms and compositions of an ERK inhibitor
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
US12168663B2 (en) 2014-12-23 2024-12-17 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
CN104803981A (zh) * 2015-04-22 2015-07-29 复旦大学 一种哌啶-4-胺基二芳基嘧啶衍生物及其制备方法和用途
US10533004B2 (en) 2015-05-13 2020-01-14 Vertex Pharmaceuticals Incorporated Methods of preparing inhibitors of influenza viruses replication
US10273233B2 (en) 2015-05-13 2019-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
KR101894096B1 (ko) 2016-01-29 2018-09-05 삼진제약주식회사 Jnk 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도
KR20170091516A (ko) * 2016-01-29 2017-08-09 한양대학교 에리카산학협력단 Jnk 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도
WO2017204626A1 (fr) 2016-05-24 2017-11-30 Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis Polythérapie combinant map2k4/map3k1 et une inhibition de mek/erk
KR20190038841A (ko) * 2016-07-13 2019-04-09 사이로스 파마수티컬스, 인크. 시클린-의존성 키나제 7 (cdk7)의 억제제
JP2022020860A (ja) * 2016-07-13 2022-02-01 サイロス ファーマシューティカルズ， インコーポレイテッド サイクリン依存性キナーゼ７（ｃｄｋ７）の阻害剤
CN110036004A (zh) * 2016-07-13 2019-07-19 希洛斯医药品股份有限公司 细胞周期蛋白依赖性激酶7(cdk7)的抑制剂
JP7460593B2 (ja) 2016-07-13 2024-04-02 サイロス ファーマシューティカルズ， インコーポレイテッド サイクリン依存性キナーゼ７（ｃｄｋ７）の阻害剤
AU2017295863B2 (en) * 2016-07-13 2022-07-07 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US20230062491A1 (en) * 2016-07-13 2023-03-02 Syros Pharmaceuticals, Inc. Inhibitors of cyclin dependent kinase 7 (cdk7)
WO2018013867A1 (fr) * 2016-07-13 2018-01-18 Marineau Jason J Inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
KR102587758B1 (ko) 2016-07-13 2023-10-12 사이로스 파마수티컬스, 인크. 시클린-의존성 키나제 7 (cdk7)의 억제제
EP4295852A3 (fr) * 2016-07-13 2024-06-12 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase 7 dépendante des cyclines (cdk7)
US12384778B2 (en) 2016-09-09 2025-08-12 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10435405B2 (en) 2016-09-09 2019-10-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11795166B2 (en) 2016-09-09 2023-10-24 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10266530B2 (en) 2016-09-09 2019-04-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11891388B2 (en) 2016-09-09 2024-02-06 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
US11542265B2 (en) 2016-09-09 2023-01-03 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10934288B2 (en) 2016-09-09 2021-03-02 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11306070B2 (en) * 2016-11-22 2022-04-19 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof
US11932625B2 (en) 2016-11-22 2024-03-19 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof
JP2020505419A (ja) * 2017-02-01 2020-02-20 オーセントラ セラピュティクス ピーティーワイ エルティーディーＡｕｃｅｎｔｒａ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｐｔｙ Ｌｔｄ 治療薬としてのＮ−シクロアルキル／ヘテロシクロアルキル−４−（イミダゾ［１，２−ａ］ピリジン）ピリミジン−２−アミン誘導体
AU2018214431B2 (en) * 2017-02-01 2021-07-29 Aucentra Therapeutics Pty Ltd Derivatives of N-cycloalkyl/heterocycloalkyl-4-(imidazo [1,2-a]pyridine)pyrimidin-2-amine as therapeutic agents
US11111245B2 (en) 2017-02-01 2021-09-07 Aucentra Therapeutics Pty Ltd Derivatives of N-cycloalkyl/heterocycloalkyl-4-(imidazo[1,2-a]pyridine)pyrimidin-2-amine as therapeutic agents
WO2018141002A3 (fr) * 2017-02-01 2018-11-22 University Of South Australia Dérivés de n-cycloalkyl/hétérocycloalkyle-4-(imidazo[1,2-a]pyridine)pyrimidin-2-amine en tant qu'agents thérapeutiques
JP7113528B2 (ja) 2017-02-01 2022-08-05 オーセントラ セラピュティクス ピーティーワイ エルティーディー 治療薬としてのＮ－シクロアルキル／ヘテロシクロアルキル－４－（イミダゾ［１，２－ａ］ピリジン）ピリミジン－２－アミン誘導体
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
US10047071B1 (en) 2018-01-15 2018-08-14 King Saud University Dihydropyrimidinone derivatives
US11918592B2 (en) 2018-01-16 2024-03-05 Syros Pharmaceuticals, Inc. Inhibitors of cyclin dependent kinase 7 (CDK7)
US11311542B2 (en) 2018-01-16 2022-04-26 Syros Pharmaceuticals, Inc. Inhibitors of cyclin dependent kinase 7 (CDK7)
WO2019143719A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
WO2019143730A1 (fr) * 2018-01-16 2019-07-25 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
US11731958B2 (en) 2018-02-20 2023-08-22 Incyte Corporation Carboxamide compounds and uses thereof
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US11492354B2 (en) 2018-02-20 2022-11-08 Incyte Corporation Indazole compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US11220494B2 (en) 2018-04-26 2022-01-11 Pfizer Inc. Cyclin dependent kinase inhibitors
US12378232B2 (en) 2018-04-26 2025-08-05 Pfizer Inc. Cyclin dependent kinase inhibitors
US10766884B2 (en) 2018-04-26 2020-09-08 Pfizer Inc. Cyclin dependent kinase inhibitors
US11866426B2 (en) 2018-08-08 2024-01-09 Incyte Corporation Benzothiazole compounds and uses thereof
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
WO2020093006A1 (fr) * 2018-11-01 2020-05-07 Syros Pharmaceuticals, Inc. Méthodes de traitement du cancer chez des patients identifiés par biomarqueurs avec des inhibiteurs non covalents de la kinase cycline-dépendante 7 (cdk7)
US12240869B2 (en) 2018-11-01 2025-03-04 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US10738067B2 (en) 2018-11-01 2020-08-11 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
JP2022515705A (ja) * 2018-11-01 2022-02-22 サイロス ファーマシューティカルズ， インコーポレイテッド サイクリン依存性キナーゼ７（ｃｄｋ７）の非共有結合性阻害剤を用いてバイオマーカーにより特定された患者におけるがんを処置する方法
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11787784B2 (en) 2019-08-06 2023-10-17 Incyte Corporation Solid forms of an HPK1 inhibitor
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US12312331B2 (en) 2019-08-14 2025-05-27 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
CN111393415B (zh) * 2020-04-30 2020-11-20 苏州信诺维医药科技有限公司 一种杂芳腈类化合物及其应用
CN111393415A (zh) * 2020-04-30 2020-07-10 苏州信诺维医药科技有限公司 一种杂芳腈类化合物及其应用
EP4186895A4 (fr) * 2020-07-24 2024-09-11 TYK Medicines Inc. Composé utile en tant qu'inhibiteur de kinase cdk7 et son utilisation
EP4196119A4 (fr) * 2020-08-11 2024-07-31 Board Of Trustees Of Michigan State University Activateurs de protéasome et leurs utilisations
JP2023538326A (ja) * 2020-08-11 2023-09-07 ボード オブ トラスティーズ オブ ミシガン ステイト ユニバーシティ プロテアソームエンハンサ及びその使用
JP2023539690A (ja) * 2020-09-03 2023-09-15 エフ． ホフマン－ラ ロシュ アーゲー 複素環式化合物
WO2022134642A1 (fr) * 2020-12-24 2022-06-30 湃隆生物科技有限公司（香港） Composé hétérocyclique aromatique, et composition pharmaceutique et application de celui-ci
WO2022134641A1 (fr) * 2020-12-24 2022-06-30 湃隆生物科技有限公司（香港） Composé hétérocyclique aromatique, composition pharmaceutique et utilisation de celui-ci
JP2024502301A (ja) * 2020-12-24 2024-01-18 ジーティー アペイロン セラピューティクス リミテッド 芳香族複素環式化合物、薬学的組成物、及びその使用
CN116670123A (zh) * 2020-12-24 2023-08-29 湃隆生物科技有限公司（香港） 芳香杂环类化合物、药物组合物及其应用
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US12441731B2 (en) 2021-08-04 2025-10-14 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
WO2023049691A1 (fr) * 2021-09-23 2023-03-30 Zeno Management, Inc. Inhibiteurs de cdk7 et méthodes de traitement du cancer
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
WO2023116761A1 (fr) * 2021-12-22 2023-06-29 英矽智能科技知识产权有限公司 Composé hétérocyclique de pyrimidine, son procédé de préparation et son utilisation en médecine
WO2024260325A1 (fr) * 2023-06-19 2024-12-26 英矽智能科技知识产权有限公司 Synthèse d'un composé macrocyclique et utilisation médicale d'un composé macrocyclique

Similar Documents

Publication Publication Date Title
WO2006038001A1 (fr) Derives d’aminopyrimidine en tant qu’inhibiteurs de la jnk
EP3356345B1 (fr) Dérivés d'hétéroaryle en tant qu'inhibiteurs de la sepiapterine reductase
US8513284B2 (en) Fused pyridine and pyrazine derivatives as kinase inhibitors
EP2170906B1 (fr) Dérivés de thiazole fusionné comme inhibiteurs de kinase
KR102272792B1 (ko) Ｂｔｋ의 치환된 니코틴이미드 저해제 및 그의 제조 방법 및 암, 염증 및 자가면역 질환에의 용도
EP2872511B1 (fr) Dérivés d'imidazopyrazine en tant que modulateurs de l'activité tnf
US6316444B1 (en) SRC kinase inhibitor compounds
AU2011253057B2 (en) Nitrogen heterocyclic compounds useful as PDE10 inhibitors
KR101421852B1 (ko) 카세인 키나제 억제제로서의 이미다졸 유도체
US6498165B1 (en) Src kinase inhibitor compounds
JP5249787B2 (ja) Ｍｅｋ阻害剤としてのチエノピリジン誘導体
NO174891B (no) Analogifremgangsmåt ved fremstilling av terapeutisk aktive substituerte pyrroler
EP2872508A1 (fr) Dérivés d'imidazopyridine utilisables en tant que modulateurs de l'activité tnf
AU2013347539A1 (en) Purine inhibitors of human phosphatidylinositol 3-kinase delta
EP3833439B1 (fr) Inhibiteurs benzimidazoles d'enzymes pad
TW202342464A (zh) Rna解旋酶dhx9之抑制劑及其用途
JP2025504593A (ja) Ｓｔａｔモジュレーターおよびそれらの使用
CN117321046A (zh) 基于吲唑的化合物和相关使用方法
JP5570981B2 (ja) キナーゼ阻害剤としての縮合チアゾール誘導体
AU2021323245B2 (en) CDK9 inhibitor and use thereof
AU2023267946A1 (en) Pyrrolidinone derivatives as inhibitors of nf kappa b inducing kinase
HK1140756B (en) Fused thiazole derivatives as kinase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05788916

Country of ref document: EP

Kind code of ref document: A1