WO2009034390A1 - Dérivés hétérocycliques et leur utilisation dans le traitement de l'hépatite c - Google Patents

Dérivés hétérocycliques et leur utilisation dans le traitement de l'hépatite c Download PDF

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WO2009034390A1
WO2009034390A1 PCT/GB2008/050817 GB2008050817W WO2009034390A1 WO 2009034390 A1 WO2009034390 A1 WO 2009034390A1 GB 2008050817 W GB2008050817 W GB 2008050817W WO 2009034390 A1 WO2009034390 A1 WO 2009034390A1
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phenyl
alkyl
unsubstituted
moiety
different
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PCT/GB2008/050817
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Malcolm Clive Carter
Stuart Cockerill
Stephen Sean Flack
Christopher James Wheelhouse
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Arrow Therapeutics Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • 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
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

Definitions

  • the present invention relates to a series of compounds which are useful in treating or preventing a hepatitis C viral (HCV) infection.
  • the present invention provides, in a first embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or alleviating HCV
  • Ri is a moiety -A 1 , -Li-Ai, -A 1 -A/, -Li-Ai-A/ or -Ai-Li-A/;
  • a and B are the same or different and each represent a -CO-NR 7 -, -NR -CO-, -NR 7 - CO-NR 77 -, -NR 7 - or -(C 1 -C 2 alkylene)-NR 7 - moiety, wherein R 7 and R 77 are the same or different and each represent hydrogen or C 1 -C 4 alkyl;
  • R 2 represents H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy or halogen;
  • R 4 is a moiety -A 4 , -L 4 -A 4 , -A 4 -A 4 7 , -L 4 -A 4 -A 4 7 or -A 4 -L 4 -A 4 7 ;
  • W represents ethynyl or a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -Cs carbocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -Cs carbocyclyl moiety being unsubstituted or substituted by Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy or halogen; Y 1 , Y 2 and Y 3 each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y 2 and Y 3 represents N;
  • each A 1 , A 4 , A/ and A 4 7 are the same or different and represent a phenyl, 5- to 10- 5 membered heteroaryl, 5- to 10- membered heterocyclyl or C 3 -Cs carbocyclyl moiety;
  • each Li and L 4 is the same or different and represents a C 1 -C 4 alkylene or a Ci-C 4 hydroxy alky lene group; o the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and
  • Ri and R 4 beings unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(Ci-C 4 alkyl)-Xi, -CO 2 R 7 , -SO 2 NRV, -S(O) 2 -R 7 , -CONR 7 R 77 , -NR 7 -CO-R 777 , -NR 7 -S(O) 2 -R 777 , -CO- NR 7 -(Ci-C 4 alkyl)-NR 7 R 77 and -CO-O-(Ci-C 4 alkyl)-NR 7 R 77 and/or (b) 1, 2 or 3 unsubstituted substituents selected from -(Ci-C 4 alkyl)-X 2 , halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 4 halo
  • a Ci-C 4 alkyl moiety is a linear or branched alkyl moiety containing from 1 to 4 carbon atoms, such as a Ci-C 3 or Ci-C 2 alkyl moiety.
  • Examples of Ci-C 4 alkyl moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.
  • the alkyl moieties may be the same or different.
  • Ci-C 4 alkylene or Ci-C 2 alkylene group is any divalent linear or branched Ci-C 4 or Ci-C 2 alkyl moiety.
  • Linear Ci-C 4 alkylene groups are methylene, ethylene, n-propylene and n-butylene groups.
  • Branched C 1 -C 4 alkylene groups include -CH(CH 3 )-, -CH(CH 3 )-CH 2 - and -CH 2 -CH(CH 3 )-.
  • a C1-C4 hydroxyalkylene group is a said C1-C4 alkylene group which is substituted by a single hydroxy group.
  • Particular C1-C4 hydroxyalkylene groups are branched C1-C4 alkylene groups carrying a hydroxy substituent, which is preferably located on a terminal carbon atom.
  • a halogen is chlorine, fluorine, bromine or iodine.
  • a halogen is typically fluorine, chlorine or bromine.
  • a C1-C4 alkoxy moiety is a said C1-C4 alkyl moiety attached to an oxygen atom.
  • a preferred Ci -C 4 alkoxy moiety is me thoxy.
  • a Ci-C 4 hydroxyalkyl moiety is a said C1-C4 alkyl moiety substituted by a single hydroxyl moiety.
  • Preferred hydroxyalkyl moieties are Ci-C 2 hydroxyalkyl moieties, for example -CH(OH)-CH 3 and -CH 2 OH.
  • a C1-C4 haloalkyl or C1-C4 haloalkoxy moiety is a said C1-C4 alkyl or C1-C4 alkoxy moiety substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkyl and haloalkoxy moieties are perhaloalkyl and perhaloalkoxy moieties such as -CX 3 and -OCX 3 wherein X is a said halogen atom, for example chlorine or fluorine.
  • a particular haloalkyl moiety is -CF 3 .
  • a particular haloalkoxy moiety is -OCF 3 .
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(Ci-C 2 alkyl)-Xi, -CO 2 R 777 , -SO 2 R 777 , -SO 2 NR 7 R 777 , -CONR 7 R 777 , -NR 7 -CO-R 777 , -NR 7 -SO 2 -R 777 and -CO-NR 7 -(Ci-C 2 alkyl)-NR 7 R 777 and/or (b) 1, 2 or 3 unsubstituted substituents selected from -(Ci-C 2 alkyl)-X 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH 2 -Xi, -CO 2 -R 777 , -SO 2 R 777 , -SO 2 NR 7 R 777 , -CONR 7 R 777 , -NR 7 -C0- R 777 , -NR 7 -SO 2 -R 777 and -CO-NR 7 -(Ci-C 2 alkyl)-NR 7 R 777 and/or (b) 1 or 2 unsubstituted substituents selected from -CH 2 -X 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH 2 -Xi, -CO 2 -R 777 , -SO 2 NR 7 R 777 , -CONR 7 R 777 , -NR 7 -CO-R 777 , -NR 7 - SO 2 -R 777 and -CO-NR 7 -(Ci-C 2 alkyl)-NR 7 R 777 and/or (b) 1 or 2 unsubstituted substituents selected from -CH 2 -X 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 77 ,
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R4 are unsubstituted or substituted by SO 2 -R 777 , halogen or C1-C4 alkoxy wherein R 777 represents C 1 -C 4 alkyl.
  • a 5- to 10-membered heteroaryl moiety is a monocyclic 5- to 10- membered aromatic ring, containing at least one heteroatom, for example 1 , 2 or 3 heteroatoms, selected from O, S and N.
  • a 5- to 10-membered heteroaryl moiety is a 5- to 6-membered heteroaryl moiety.
  • a 5- to 10- membered heteroaryl moiety is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused or fused to a phenyl ring. In another embodiment, it is a non-fused 5- to 6- membered ring as defined above.
  • a said fused or non-fused heteroaryl moiety is unsubstituted or substituted as set out above. In one embodiment, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH 2 -X 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C 1 -C 4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 77 , wherein each X 2 is the same or different and is cyano or -NR 7 R 77 , and each R 7 and R 77 is the same or different and represents hydrogen or C 1 -C 4 alkyl.
  • it is a saturated Cs-Cioring (preferably a Cs-C 6 ring) in which 1, 2 or 3 of the carbon atoms in the ring are replaced with a moiety selected from O, S, SO 2 and NH and incorporating up to two CO moieties.
  • a heterocyclyl moiety is a 5- to 6- membered ring.
  • examples include azetidinyl, pyrazolidinyl, piperidyl, piperidin-2,6-dionyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl, S, S- dioxothiomorpholinyl, 1,3-dioxolanyl, 1 ,4-dioxanyl, pyrrolidinyl, imidazolidinyl, imidazol-2-onyl, pyrrolidin-2-onyl, tetrahydrofuranyl, tetrahydrothienyl, dithiolanyl, thiazolidinyl, oxazolidinyl, tetrahydropyranyl and pyrazolinyl moieties.
  • heterocyclyl moieties are selected from piperidyl, piperidin-2,6-dionyl, piperidin-2-onyl, azetidinyl, piperazinyl, morpholinyl, thiomorpholinyl, S, S- dioxothiomorpholinyl, 1,3-dioxolanyl, pyrrolidinyl, imidazol-2-onyl, pyrrolidin-2-onyl, tetrahydrofuranyl and tetrahydropyranyl.
  • a 5- to 10- membered heterocyclyl moiety is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused or fused to a phenyl ring. In another embodiment, it is a non-fused 5- to 6- membered ring as defined above.
  • a said fused or non- fused heterocyclyl moiety is unsubstituted or substituted as set out above. In one embodiment, it is unsubstituted or substituted by (a) an unsubstituted -SO 2 R 777 or -SO 2 -NR 7 R 77 substituent and/or (b) 1 or 2 unsubstituted substituents selected from -CH 2 -X 2 , halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci -C 2 haloalkyl, Ci-C 2 haloalkoxy, C 1 - C4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 77 , wherein each X 2 is the same or different and is cyano or -NR 7 R 77 , each R 7 and R 77 is the same or different and represents hydrogen or Q- C 4 alkyl and each R 777 is C 1 -C 4 alkyl.
  • it is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(C 1 -C 4 alkyl) or -SO 2 -NR 7 R 77 substituent, wherein R 7 and R 77 are the same or different and each represent hydrogen or C 1 -C 4 alkyl and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy and hydroxy.
  • it is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(Ci-C4 alkyl) or -SO 2 -N(Ci-C4 alkyl) 2 substituent and/or (b) 1 or 2 unsubstituted substituents selected from C1-C4 alkyl and hydroxy substituents.
  • a said fused or non- fused heterocyclyl moiety is unsubstituted or substituted by (a) an unsubstituted -SO 2 R 777 substituent and/or (b) 1 or 2 unsubstituted substituents selected from -CH 2 -X 2 , halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and NR 7 R 77 , wherein each X 2 is the same or different and is cyano or -NR 7 R 77 , each R 7 and R 77 is the same or different and represents hydrogen or C 1 -C 4 alkyl and each R 777 is C 1 -C 4 alkyl.
  • it is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(C 1-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy and hydroxy.
  • it is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(C 1-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from C1-C4 alkyl and hydroxy substituents.
  • a said fused or non- fused heterocyclyl moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from - CH 2 -X 2 , halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, Ci-C 4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 77 , wherein each X 2 is the same or different and is cyano or -NR 7 R 77 , and each R 7 and R 77 is the same or different and represents hydrogen or Ci-C 4 alkyl.
  • it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy and hydroxy.
  • substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy and hydroxy.
  • said preferred substituents are selected from C 1 - C 4 alkyl and hydroxy substituents.
  • heteroaryl and heterocyclyl groups refer to an "N" moiety which can be present in the ring, as will be evident to a skilled chemist the N atom will be protonated (or will carry a substituent as defined above) if it is attached to each of the adjacent ring atoms via a single bond.
  • a said phenyl group is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused or fused to a 5- to 6- membered heteroaryl or heterocyclyl ring.
  • a said fused or non- fused phenyl group is unsubstituted or substituted as set out above.
  • the fused moiety is typically unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C 2 haloalkyl, Ci-C 2 alkyl and hydroxy groups.
  • the fused moiety is unsubstituted or substituted by a halogen or Ci-C 2 haloalkyl substituent.
  • a C 3 -Cs carbocyclic moiety is a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 8 carbon atoms. In one embodiment, it is a saturated hydrocarbon ring (i.e. a cycloalkyl moiety) having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In another embodiment, it is a C 3 -C 6 carbocyclic moiety. A C 3 -Cs carbocyclyl group is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused.
  • a said fused or non- fused carbocyclyl moiety is unsubstituted or substituted as set out above. In one embodiment, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH 2 -X 2 , halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C 1 -C 4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 77 , wherein each X 2 is the same or different and is cyano or -NR 7 R 77 , and each R 7 and R 77 is the same or different and represents hydrogen or C 1 -C 4 alkyl.
  • the Ai moiety represents a non-fused 5- to 6- membered heterocyclyl or C 3 -Cs carbocyclyl group, or a phenyl or 5- to 6- membered heteroaryl group which is optionally fused to a phenyl ring or to a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
  • it is a non-fused group or an indazolyl, indolyl, benzimidazolyl, benzo[l,3]dioxolanyl, lH-benzo[d]imidazol-2(3H)- onyl, benzothiazolyl or quinoxalinyl group.
  • it is a phenyl, pyrrolidinyl, indazolyl, pyridyl, indolyl, benzimidazolyl, piperidinyl, thienyl, imidazolyl, furanyl, benzo[l,3]dioxolanyl, piperazinyl, benzothiazolyl, S,S-dioxo-thiomorpholinyl, lH-benzo[d]imidazol-2(3H)-onyl, cyclopropyl or quinoxalinyl group.
  • Ai is substituted or unsubstituted as set out above. However, when Ai is other than a non-fused phenyl ring, it is typically unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH 2 -X 2 , halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C 1-C 4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 77 , wherein each X 2 is the same or different and is cyano or -NR 7 R 77 , and each R 7 and R 77 is the same or different and represents hydrogen or C1-C4 alkyl.
  • it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C 1 - C 2 haloalkyl, Ci-C 2 haloalkoxy and hydroxy.
  • the A/ moiety represents a non-fused phenyl, C 3 -Cs carbocyclyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
  • the A/ moiety represents a phenyl, oxazolyl, piperazinyl, triazolyl, piperidinyl, piperidin-2- onyl, piperidin-2,6-dionyl, morpholinyl, pyrrolidinyl, pyrazolyl, isoxazolyl, cyclohexyl, thiomorpholinyl or S,S-dioxothiomorpholinyl group.
  • the A/ moiety represents a morpholino, piperazinyl or S, S- dioxothiomorpholinyl group.
  • A/ is a piperazinyl moiety.
  • A/ is a S, S- dioxothiomorpholinyl moiety.
  • the A/ moiety is unsubstituted or substituted by (a) an unsubstituted -SO 2 -R 777 or -SO 2 NR 7 R 77 substitutent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C1-C4 hydroxyalkyl, hydroxy and -NR 7 R 77 , wherein each R 7 and R 77 are the same or different and are selected from hydrogen and C1-C4 alkyl and R /// represents Ci-C alkyl.
  • the Ai moiety is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(Ci-C 4 alkyl) or -SO 2 -NR 7 R 77 substituent, wherein R 7 and R 77 are the same or different and each represent hydrogen or C 1 -C 4 alkyl, and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, Ci-C 2 alkyl, Ci-C 2 haloalkyl and Ci-C 2 hydroxyalkyl.
  • the A/ moiety is unsubstituted or substituted by (a) an unsubstituted -SO 2 -R 777 substitutent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, Ci-C 4 hydroxyalkyl, hydroxy and -NR 7 R 77 , wherein each R 7 and R 77 are the same or different and are selected from hydrogen and C 1 -C 4 alkyl and each R 777 represents C 1 -C 4 alkyl.
  • the A/ moiety is unsubstituted or substituted by (a) an unsubstituted -SC>2-(Ci-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C 1 -C 2 alkyl, Ci-C2 haloalkyl and C 1 -C 2 5 hydroxy alkyl.
  • the A/ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, Ci-C 4 hydroxyalkyl, hydroxy and -NR 7 R 77 , wherein each R 7 and R 77 are the same or different and are selected from hydrogen and Ci-C 4 0 alkyl.
  • the A/ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, Ci-C 2 alkyl, Ci-C 2 haloalkyl and Ci-C 2 hydroxyalkyl.
  • the A/ moiety represents a group
  • R is Ci-C 4 alkyl, -S(O) 2 -R 7 or -S(O) 2 -NR 7 R 77 wherein R 7 and R 77 are the same or different and each represent hydrogen or Ci-C 4 alkyl.
  • R is Ci-C 4 alkyl or -SO 2 -(Ci-C 4 alkyl).
  • the A 4 moiety is a non-fused 5- to 6- membered heterocyclyl or C3-C8 carbocyclyl group, or a phenyl or 5- to 6- membered heteroaryl group which is optionally fused to a phenyl ring or to a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
  • the A 4 moiety represents a non-fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3 -Cs carbocyclyl group, or a5 phenyl group which is optionally fused to a 5- to 6- membered heteroaryl group.
  • the A 4 moiety represents phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C 3 -Cs cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S, S- dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl.
  • the A 4 moiety represents phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, cyclopropyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl.
  • the A4 moiety is unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CO 2 R 777 and -CONR 7 R 777 and/or (b) 1, 2 or 3 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, -NR 7 R 777 , C 1 - C4 haloalkyl, C1-C4 haloalkoxy and cyano, wherein R 7 represents hydrogen or C1-C4 alkyl and R 777 represents C 1 -C 4 alkyl.
  • the A 4 moiety is unsubstituted or substituted by (a) a single unsubstituted -CONR 7 R 777 substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, -NR 7 R 777 , C1-C4 alkyl, C 1 -C 2 alkoxy, C1-C2 haloalkyl and cyano, wherein R 7 is hydrogen or C1-C4 alkyl and R 777 represents C1-C4 alkyl.
  • the A4 moiety is unsubstituted.
  • the A 4 7 moiety represents a non- fused phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3 -C 6 carbocyclyl group. In one embodiment, the A4 7 moiety represents a non- fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3 -C 6 cycloalkyl group.
  • the A4 7 moiety is a morpholinyl, piperazinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo- piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group.
  • the A 4 7 moiety is a morpholinyl, isoxazolyl, pyrrolidinyl, S, S- dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group.
  • the A 4 7 moiety is a morpholinyl group.
  • the A4 7 moiety is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(C 1-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C 1 - C 4 hydroxyalkyl, hydroxy and -NR 7 R 77 , wherein each R 7 and R 77 are the same or different and are selected from hydrogen and C 1 -C 4 alkyl.
  • the A 4 7 moiety is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(Ci-C 2 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, Ci-C 2 alkyl and Ci-C 2 haloalkyl.
  • the A 4 7 moiety is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(Ci-C 2 alkyl) substituent and/or (b) 1 or 2 unsubstituted Ci-C 2 alkyl groups.
  • the A 4 7 moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci -C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, Ci-C 4 hydroxyalkyl, hydroxy and -NR 7 R 77 , wherein each R 7 and R 77 are the same or different and are selected from hydrogen and Ci-C 4 alkyl.
  • the A 4 7 moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, Ci-C 2 alkyl and Ci-C 2 haloalkyl. In another embodiment, the A 4 7 moiety is unsubstituted or substituted by 1 or 2 unsubstituted Ci-C 2 alkyl groups.
  • Li is a Ci -C 3 alkylene group or a Ci-C 3 hydroxyalkylene group. In another embodiment, Li is a Ci-C 2 alkylene group. In another embodiment, Li is a methylene group.
  • L 4 is a Ci-C 3 alkylene group or a Ci-C 3 hydroxyalkylene group. In another embodiment, L 4 is a Ci-C 2 alkylene group. In another embodiment, L 4 is a methylene group.
  • Ai is a non- fused unsubstituted phenyl or piperazinyl group and A/ is a non-fused morpholinyl, pyrazolyl, isoxazolyl, triazolyl, piperidin-2-onyl or phenyl group, which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen, hydroxy, Ci-C 2 alkyl and Ci-C 2 haloalkyl groups.
  • Ri is -A 1 -A/, it is an unsubstituted non- fused - phenyl-morpholino group.
  • R 1 is -Ai-Li-A/.
  • Ri is -Ai-Li-A/
  • Ai is typically a non-fused unsubstituted phenyl group.
  • Li is typically -CH 2 - or -CH 2 -CH 2 -, more typically -CH 2 -.
  • A/ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(Ci-C 4 alkyl) or -SO 2 -NR 7 R 77 group, wherein R 7 and R 77 are the same or different and each represent hydrogen or Ci-C 4 alkyl and/or (b) 1 or 2 unsubstituted substituents selected from halogen, hydroxy, Ci-C 2 alkyl and Ci-C 2 alkoxy groups.
  • A/ is a non- fused unsubstituted morpholinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl group or A/ is a piperazinyl group which is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(Ci-C 4 alkyl) or -SO 2 -NR 7 R 77 substituent, wherein R 7 and R 77 are the same or different and each represent hydrogen or Ci- C 4 alkyl, and/or (b) 1 or 2 unsubstituted Ci-C 2 alkyl groups.
  • a 7 is a piperazinyl group which is unsubstituted or substituted by (a) an unsubstituted -SC>2-(Ci-C4 alkyl) or -SO 2 -NR 7 R 77 substituent, wherein R 7 and R 77 are the same or different and each represent hydrogen or C1-C4 alkyl, and/or (b) 1 or 2 unsubstituted Ci-C 2 alkyl groups.
  • Ri is -Ai-Li-A/
  • Ai is typically a non-fused unsubstituted phenyl group.
  • Li is typically -CH 2 -.
  • A/ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) an unsubstituted -SO 2 -(Ci-C 4 alkyl) group and/or (b) 1 or 2 unsubstituted substituents selected from halogen, hydroxy, Ci-C 2 alkyl and Ci-C 2 alkoxy groups.
  • A/ is a non-fused unsubstituted morpholinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl group or A/ is a piperazinyl group which carries a single unsubstituted -S(O) 2 -(Ci-C 4 alkyl) substituent.
  • Li is typically -CH 2 -.
  • Ai is typically a non-fused unsubstituted phenyl group.
  • A/ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C 2 alkyl groups.
  • A/ is a morpholinyl or piperazinyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C 2 alkyl groups.
  • A represents a -(C r C 2 alkylene)-NR 7 -, -CO-NR 7 - or -NR 7 -CO- group, in which R 7 is hydrogen or Ci-C 2 alkyl, preferably hydrogen.
  • R 7 is hydrogen or Ci-C 2 alkyl, preferably hydrogen.
  • A represents a -CO-NH- group.
  • the right hand side of these groups is bonded to Ri and the left hand side is bonded to W.
  • B represents a -CO-NR 7 -, -NR 7 -C0-, -(Ci-C 2 alkylene)-NR 7 -, -NR 7 - or - NR 7 -CO-NR 77 - group, wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 2 alkyl. For the avoidance of doubt, the left hand side is of these groups is bonded to R 4 .
  • B represents a -CO-NH-, -NH-CO-, -(Ci-C 2 alkylene)-NH-, - NH- or -NH-CO-NH- group.
  • R 2 represents H, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy or halogen.
  • R 2 is present on a carbon atom ortho to the group W.
  • R 2 is chlorine, trifluoromethoxy or C 1 -C 4 alkyl, typically Ci-C 2 alkyl such as methyl.
  • W represents a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -Cs carbocyclyl moiety. In another embodiment, W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety. In another embodiment, W represents a 5- or 6- membered heterocyclyl moiety. In another embodiment, W represents a piperazinyl moiety.
  • group W represents a cyclic moiety it is typically unsubstituted or substituted by C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy or halogen. In one embodiment, it is unsubstituted or substituted by chlorine, trifluoromethoxy or C1-C4 alkyl, typically Ci-C 2 alkyl such as methyl. In another embodiment, it is unsubstituted.
  • Y 1 , Y 2 and Y 3 each represent CH; provided that at the same time, W is not phenyl.
  • Yi and Y 2 represent N and Y 3 represents CH. In one embodiment, Y 2 and Y 3 represent N and Yi represents CH.
  • R 4 is a moiety -A 4 , -A 4 -A 4 7 , -L 4 -A 4 or -A 4 -L 4 -A 4 7 wherein A 4 , A 4 7 , L 4 and
  • L ⁇ 44 are as defined above.
  • R 4 is -A 4 or -A 4 -A 4 7 .
  • a 4 is typically a non-fused phenyl or 5- to 6- membered heteroaryl moiety which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C 2 alkyl, halogen and Ci-C 2 haloalkyl substituents.
  • a 4 is a non-fused phenyl, pyridyl or oxadiazolyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C 2 alkyl, halogen and C 1 - C 2 haloalkyl substituents.
  • a 4 7 is typically a non-fused 5- to 6- membered heteroaryl or heterocyclyl group, or a non-fused C 3 -C 6 cycloalkyl group, and is unsubstituted or substituted by 1 or 2 unsubstituted Ci-C 2 alkyl groups.
  • a 4 7 is a non- fused morpholinyl, piperazinyl, isoxazolyl, triazolyl, piperidin-2,2-dionyl, cyclopropyl or cyclohexyl group, which is unsubstituted or substituted by an unsubstituted Ci-C 2 alkyl group.
  • a 4 is typically a non- fused unsubstituted phenyl or 5- to 6- membered heteroaryl moiety.
  • a 4 is a non- fused unsubstituted phenyl, pyridyl or oxadiazolyl group.
  • a 4 7 is typically a non- fused 5- to 6- membered heteroaryl or heterocyclyl group, or a non-fused C 3 -C 6 cycloalkyl group, and is unsubstituted or substituted by 1 or 2 unsubstituted Ci-C 2 alkyl groups.
  • a 4 7 is a non-fused morpholinyl, isoxazolyl, triazolyl, piperidin-2,2- dionyl, cyclopropyl or cyclohexyl group, which is unsubstituted or substituted by an unsubstituted Ci-C 2 alkyl group.
  • R 4 when R 4 is -A 4 -A 4 7 , it is a non- fused unsubstituted -phenyl- morpholino group.
  • a 4 is typically a non- fused unsubstituted phenyl group.
  • L 4 is typically -CH 2 -.
  • a 4 7 is typically a non-fused 5- to 6- membered heterocyclyl group, preferably a piperazinyl group or a S,S-dioxo-thiomorpholinyl group, which is unsubstituted or substituted by an unsubstituted -SO 2 -(Ci-C 2 alkyl) substituent. More typically, A 4 7 is a non-fused unsubstituted 5- to 6- membered heterocyclyl group, preferably a S,S-dioxo-thiomorpholinyl group.
  • R 4 when R 4 is -A 4 -L 4 -A 4 7 it is -phenyl-CH 2 -(S,S- dioxothiomorpholino), wherein the cyclic moieties are non-fused and unsubstituted, or - phenyl-CH 2 -piperazinyl-SO 2 -(Ci-C 2 alkyl).
  • R 4 when R 4 is -A 4 -L 4 -A 4 7 it is -phenyl-CH 2 -(S,S- dioxothiomorpholino), wherein the cyclic moieties are non-fused and unsubstituted, or - phenyl-CH 2 -piperazinyl-SO 2 -(Ci-C 2 alkyl).
  • Ri is a moiety -A 1 , -Li-Ai, -A 1 -A/ or -Ai-Li-A/;
  • a and B are the same or different and each represent a -CO-NR 7 -, -NR 7 -CO-, -NR 7 - or -(C 1 - C 2 alkylene)-NR 7 - moiety, wherein R 7 and R 77 are the same or different and each represent hydrogen or Ci-C 4 alkyl; R 2 represents H, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy or halogen; R 4 is a moiety -A 4 , -L 4 -A 4 , -A 4 -A 4 7 or -A 4 -L 4 -A 4 7 ;
  • W represents a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -Cs carbocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -Cs carbocyclyl moiety being unsubstituted or substituted by Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy or halogen;
  • Y 1 , Y 2 and Y 3 each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y 2 and Y 3 represents N; each A 1 , A 4 , A/ and A 4 7 are the same or different and represent a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C 3 -Cs carbocyclyl moiety; each Li and L 4 is the same or different and represents a Ci-C 4 alkylene or a Ci-C 4 hydroxy alky lene group; 5 the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by (a)
  • each X 2 is the same or different and is cyano, nitro or -NR 7 R 77
  • each R 7 and R 77 is thes same or different and represents hydrogen or Ci-C 4 alkyl
  • each R 777 is the same or different and represents Ci-C 4 alkyl.
  • Ri is a moiety -A 1 , -Li-Ai, -A 1 -A/ or -Ai-Li-A/;
  • a and B are the same or different and each represent a -CO-NR 7 -, -NR 7 -C0-, -NR 7 - or -(C 1 -o C 2 alkylene)-NR 7 - moiety, wherein R 7 and R 77 are the same or different and each represent hydrogen or Ci-C 4 alkyl;
  • R 2 represents H, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy or halogen;
  • R 4 is a moiety -A 4 , -L 4 -A 4 , -A 4 -A 4 7 or -A 4 -L 4 -A 4 7 ;
  • W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl5 moiety; said phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl,
  • Y 1 , Y 2 and Y 3 each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y 2 and Y 3 represents N; o each A 1 , A 4 , A/ and A 4 7 are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -C 6 carbocyclyl moiety; each Li and L 4 is the same or different and represents a Ci-C 4 alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by (a) a single unsubstituted substituent selected from
  • Xi is -CO 2 R 7 , -SO 2 -R 7 , -NR 7 -CO 2 -R 77 , -NR 7 -S(O) 2 -R 777 , -CONR 7 R 77 or -SO 2 -o NR 7 R 77
  • each X 2 is the same or different and is cyano, nitro or -NR 7 R 77
  • each R 7 and R 77 is the same or different and represents hydrogen or Ci-C 4 alkyl
  • each R 777 is the same or different and represents Ci-C 4 alkyl.
  • Ri is a moiety -Ai, -Li-Ai, -A 1 -A/ or -Ai-Li-A/; s A and B are the same or different and each represent a -CO-NH-, -NH-CO-, -NH- or -(C 1 -
  • R 2 represents H, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy or halogen;
  • R 4 is a moiety -A 4 , -L 4 -A 4 , -A 4 -A 4 7 or -A 4 -L 4 -A 4 7 ;
  • W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclylo moiety; said phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl,
  • Y 1 , Y 2 and Y 3 each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y 2 and Y 3 represents N; 5 each A 1 , A 4 , A/ and A 4 7 are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -C 6 carbocyclyl moiety; each Li and L 4 is the same or different and represents a Ci-C 2 alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring;o and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by (a) a single unsubstituted substituent selected from
  • X 2 halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 777 , wherein Xi is -CO 2 R 777 , -NR 7 -CO 2 -R 777 or -SO 2 -
  • each X 2 is the same or different and is cyano or -NR 7 R 77
  • each R 7 and R 77 is the same or different and represents hydrogen or C 1 -C 4 alkyl
  • each R 777 is the same or different and represents C1-C4 alkyl.
  • Ri is a moiety -A 1 , -L 1 -A 1 , -A 1 -A/ or -Ai-Li-A/;
  • a and B are the same or different and each represent a -CO-NH-, -NH-CO-, -NH- or -CH 2 - NH- moiety;
  • R 2 represents H, Ci-C 2 alkyl, Ci-C 2 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy or halogen;
  • R 4 is a moiety -A 4 , -L 4 -A 4 , -A 4 -A 4 7 or -A 4 -L 4 -A 4 7 ;
  • W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C 2 alkyl, Ci-C 2 alkoxy, Ci-C 2 haloalkyl,
  • Y 1 , Y 2 and Y 3 each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y 2 and Y3 represents N; each A 1 , A 4 , A/ and A 4 7 are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -C 6 carbocyclyl moiety; each Li and L 4 is the same or different and represents a Ci-C 2 alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -
  • X 2 halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy, Ci-C 4 hydroxyalkyl, hydroxy, cyano and -NR 7 R 777 , wherein Xi is -CO 2 R 777 , -NR 7 -CO 2 -R 777 or -SO 2 - NR 7 R 777 , each X 2 is the same or different and is cyano or -NR 7 R 77 , each R 7 and R 77 is the same or different and represents hydrogen or Ci-C 4 alkyl and each R 777 is the same or different and represents Ci-C 4 alkyl.
  • Xi is -CO 2 R 777 , -NR 7 -CO 2 -R 777 or -SO 2 - NR 7 R 777
  • each X 2 is the same or different and is cyano or -NR 7 R 77
  • Ri is a moiety -A 1 -A/ or -Ai-Li-A/;
  • a and B are the same or different and each represent a -CO-NH-, -NH-CO-, -NH- or -CH 2 -
  • R 2 represents H, Ci-C 2 alkyl, Ci-C 2 haloalkoxy or halogen
  • R 4 is a moiety -A 4 or -A 4 -A 4 7 ;
  • W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C 2 alkyl, Ci-C 2 alkoxy, Ci-C 2 haloalkyl, Ci-C 2 o haloalkoxy or halogen;
  • Y 1 , Y 2 and Y 3 each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y 2 and Y 3 represents N; each A 1 , A 4 , A/ and A 4 7 are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C 3 -C 6 carbocyclyl moiety; s each Li and L 4 is the same or different and represents a Ci-C 2 alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by -S(O) 2 -R 777 , hal
  • the medicaments of the present invention are for use in treating or preventing a hepatitis C viral infection in the human or animal body.
  • the medicaments are for use in humans.
  • Compounds of formula (I) containing one or more chiral centre may be used in5 enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers.
  • the compounds of formula (I) can, if desired, be used in the form of solvates. Further, for the avoidance of doubt, the compounds of the invention may be used in any tautomeric form.
  • a pharmaceutically acceptable salt is a salt with a o pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines. Examples of compounds of the invention include:
  • the compounds of formula (I) may be prepared by analogy with known methods. See, for example, the processes disclosed in WO 2007/031791.
  • the present invention further provides an analogy process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which comprises,
  • R2, R4, Yi, Y2, Y3, B and W are as defined above; with an amine of formula HNR'-RI wherein R 7 and Ri are as defined above; or (b) when the group A represents -CO-NH-, reacting a compound of formula (III)
  • R2, R4, Yi, Y2, Y3, B and W are as defined above and H represents an acidic hydrogen such as a hydrogen attached to nitrogen or an alkyne; with an isocyanate of formula OCN-Ri wherein Ri is as defined above; or
  • Ri, R2, Yi, Y2, Y3, A and W are as defined above; with a carboxylic acid (or an activated derivative thereof) of formula R4-COOH wherein
  • R4 is as defined above; and optionally after (a), (b) or (c) carrying out one or more of the following: • converting the compound obtained to a further compound of the invention • forming a pharmaceutically acceptable salt of the compound.
  • the amide coupling reactions referred to above may be carried out by reaction of amines with acid chlorides, or by reaction with carboxylic acids and a suitable coupling reagent e.g. HBTU or EDAC/HOBT.
  • a suitable coupling reagent e.g. HBTU or EDAC/HOBT.
  • the compounds of the invention are potentially useful as pharmaceuticals since they show activity against hepatitis C virus.
  • the present invention therefore provides a method for treating a patient suffering from or susceptible to a hepatitis C infection, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof.
  • Also provided is a method for alleviating or reducing the incidence of a hepatitis C infection in a patient comprises administering to said patient an effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof.
  • the present invention further provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for the treatment of the human or animal body.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention.
  • Preferred pharmaceutical compositions are sterile and pyrogen free.
  • the compounds of the invention may be administered in a variety of dosage forms.
  • the compounds of the invention can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrroli
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • compositions comprising:
  • Also provided is a product comprising:
  • interferon and/or ribavirin for separate, simultaneous or sequential use in the treatment of the human or animal body.
  • a therapeutically effective amount of a compound of the invention is administered to a patient.
  • a typical dose is from about 0.01 to 100 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 0.05 to 16 mg per kg of body weight, more preferably, from 0.05 to 1.25 mg per kg of body weight.
  • BINAP 2,2 '-Bis(diphenylphosphino)- 1 , 1 '-binaphthyl TBME: tert-Butyl methyl ether
  • Step 2 4-Methyl-N-(4-morpholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl-ri,3,21dioxaborolan-
  • Step 1 6-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-nicotinic acid ethyl ester
  • Step 2 6-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamov ⁇ -phenyll-nicotinic acid 6- [2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl] -nicotinic acid ethyl ester from Step 1 (249 mg) was treated with sodium hydroxide (22 mg) in methanol (10 ml) and heated to reflux for 1Oh. It was then cooled, concentrated to dryness and triturated with acetone (5 ml). The solid formed was collected and dried in vacuo to afford the title compound (184 mg, 75%).
  • Step 2 5-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-thiophene-2- carboxylic acid ethyl ester
  • Intermediate 2 (422 mg) and 5-bromo-thiophene-2-carboxylic acid ethyl ester (352 mg) were dissolved in isopropanol (10 ml) and treated with IM sodium bicarbonate (5 ml), palladium tetrakis(triphenylphosphine) (58 mg, 5 %mol) and heated to 90 0 C overnight.
  • Step 3 5-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-thiophene-2- carboxylic acid
  • Step 1 5-Bromo-thiophene-2-carboxylic acid [4-0 J-dioxo-llambda-*6*-thiomorpholin- 4-ylmethyl)-phenyll-amide
  • Step 3 5-(5-Amino-2-methyl-phenv ⁇ -thiophene-2-carboxylic acid [4-d.l-dioxo-llambda- * 6 * -thiomorpholm-4-ylmethvO-phenyl] -amide
  • Step 1 4-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-piperazine-l- carboxylic acid tert-butyl ester A solution of 3-bromo-4-methyl-N-(4-morpholin-4-yl-phenyl)-benzamide (Intermediate 2)
  • Step 1) (918 mg), and Boc piperazine (500 mg) in dry dioxane (50 ml) was treated with sodium tert-butoxide (492 mg), tris(dibenzylideneacetone)dipalladium(0) (67 mg) and
  • Step 2 4-Methyl-N-(4-morpholin-4-yl-phenyl)-3-piperazin- 1 -yl-benzamide
  • Step 1 4-(Propane-l-sulfonyl)-piperazine-l-carboxylic acid ethyl ester Piperazine-1-carboxylic acid ethyl ester (18 g) was dissolved in TBME (50 ml) and triethylamine (15.9 ml) added. The stirred TBME solution was cooled to 0 0 C prior to dropwise addition of n-propylsulfonyl chloride (12.8 ml). The stirred reaction mixture was allowed to warm to RT over 2h before being partitioned between IM HCl and DCM. The DCM was dried and the solvent was removed under vacuum to give the expected product as a solid (22.73 g, 76%).
  • Step 2 1 -(Propane- 1-sulfonvD-piperazine
  • Step 4 4-[4-(Propane- 1 -sulfonvD-piperazin- 1 -ylmethyll-phenylamine l-(4-Nitro-benzyl)-4-(propane-l-sulfonyl)-piperazine (5.5 g) in methanol (250 ml) was hydrogenated at atmospheric pressure over 5% Pt/C (550 mg). The catalyst was filtered off and the bulk of the methanol removed under vacuum, a further filtration through celite removed any remaining catalyst. The methanol was removed under vacuum to give the title compound as a yellow powder (5.11 g, 100%).
  • Step 1 5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-furan-2-carboxylic acid ethyl ester
  • Step 3 5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-furan-2-carboxylic acid [4-(l.l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyll-amide
  • This material was prepared as for Example 2 except that p-anisidine (8.4 mg) was used. Yield (10 mg, 28%).
  • This material was prepared as for Example 2 except that 6-aminoindazole (9 mg) was used.
  • Step 2 4-r3-(4-Morpholin-4-yl-phenylcarbamoyl)-phenyll-piperazine-l-carboxylic acid tert-butyl ester
  • a solution of the above intermediate (1 g), and N-Boc piperazine (565 mg) in dry dioxane (35 ml) was treated with sodium tert-butoxide (830 mg), tris(dibenzylideneacetone)dipalladium(0) (210 mg) and BINAP (277 mg) and was heated to 110 0 C, under nitrogen, for 5 days. The mixture was cooled, diluted with acetone and filtered through celite. The solution was evaporated and the residue purified via column chromatography. Elution with (2:1 petrol/ethyl acetate up to 1:1 petrol/ethyl acetate) gave the title compound (365 mg, 27%).
  • Step 3 N-(4-Morpholin-4-yl-phenyl)-3-piperazin-l-yl-benzamide
  • TFA 7 ml
  • THF 10 ml
  • Step 4 4-r3-(4-Morpholin-4-yl-phenylcarbamoyl)-phenyll-piperazine-l-carboxylic acid 2- chloro-benzylamide
  • Example 17 4- [2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl] -piperazine-1-carboxylic acid (3-bromo-phenyl)-amide To Intermediate 7 (44 mg) in THF (2.5 ml) and triethylamine (0.042 ml) was added 3- bromophenylisocyanate (0.024 ml) and the resulting solution was stirred for 2h at RT. The mixture was evaporated in vacuo and the residue purified via preparative HPLC to give the title compound as a light brown solid (26 mg, 37%).
  • the title compound was prepared according to the procedure described in Example 20 except that m-anisoyl chloride (75 mg) was used.
  • Example 22 lH-Pyrazole-4-carboxylic acid (3- ⁇ 5-[4-(l,l-dioxo-llambda-6-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-thiophen-2-yl ⁇ -4-methyl-phenyl)-amide
  • the title compound was prepared according to the procedure described as in Example 1 , Step 3 except that 4-pyrazole carboxylic acid (49 mg) and Intermediate 6 were used. Yield (35 mg, 34%).
  • Step 3 except that thiophene-2-carboxylic acid (56 mg) and Intermediate 6 were used.
  • Step 2 A mixture of the above intermediate (827 mg) and trimethylsilylacetylene (0.3 ml) in DMF
  • Step 1 4-(6-Chloro-pyrimidin-4-vD-benzoic acid methyl ester
  • Step 2 446-(Cvclopropylmethyl-amino)-pyrimidin-4-yl "
  • Step 3 446-(Cvclopropylmethyl-amino)-pyrimidin-4-yl "
  • Step 1 4-(2-Chloro-pyrimidin-4-yl)-benzoic acid tert-butyl ester
  • 2,4-dichloropyrimidine 0.45 g
  • 4-tert butoxycarbonylphenyl boronic acid 0.83 g
  • palladium tetrakis triphenylphosphine 0.29 g
  • caesium carbonate 1.625 g
  • DME 60 ml
  • water 60 ml
  • Water and ethyl acetate were added and the organic phase was washed with 2M hydrochloric acid, saturated sodium carbonate, dried over sodium sulphate and concentrated in vacuo.
  • Step 2 4-r2-(Cvclopropylmethyl-amino)-pyrimidin-4-vH-benzoic acid tert-butyl ester
  • a mixture of 4-(2-chloro-pyrimidin-4-yl)-benzoic acid tert-butyl ester (0.1 g) and cyclopropylmethylamine (0.048 g) in ethanol (1.7 ml) were heated in a microwave at 130 0 C for 75 min.
  • Step 3 4-[2[(Cvclopropylmethyl-amino)-pyrimidin-4-yll-N- (4-[4-(propane- 1 -sulfonvO- piperazin- 1 -ylmethyl] -phenyl I -benzamide
  • HCV replicon cells Huh 9B (ReBlikon), containing the firefly luciferase - ubiquitin - neomycin phosphotransferase fusion protein and EMCV-IRES driven HCV polyprotein with cell culture adaptive mutations.
  • Assay procedure A flask of cells was trypsinised and a cell count carried out. Cells were diluted to
  • the cells in the white plate were harvested by washing 23.5mM beetle luciferin (Promega E 1603), 26mM ATP (Sigma O-2060) in 10OnM Tris buffer pH 7.8 aliquoted and stored at -80 0 C was thawed and diluted 1 :50 in luciferase assay buffer (2OmM Tricine (Sigma T-0377), 1.07mM magnesium carbonate hydroxide (Sigma M-5671), O.lmM EDTA (Sigma E-5134), 2.67mM MgSO 4 (BDH 101514Y), 33.3mM dithiothreitol (Sigma 150460) pH 7.8).
  • the M injector of the microplate luminometer (Lmax, Molecular Devices) was primed with 5 x 300 ⁇ l injections of the diluted substrate. After 5-60 min incubation in lysis buffer at room temperature, a plate was inserted into the luminometer and 100 ⁇ l luciferase assay reagent was added by the injector on the luminometer. The signal was measured using a 1 second delay followed by a 4 second measurement programme.
  • the IC 50 the concentration of the drug required for reducing the replicon level by 50% in relation to the untreated cell control value, can be calculated from the plot of the percentage reduction of the luciferase activity vs. drug concentration.
  • the clear plate was stained with 100 ⁇ l 0.5% methylene blue in 50% ethanol at room temperature for Ih, followed by solvation of the absorbed methylene blue in lOO ⁇ l per well of 1% lauroylsarcosine. Absorbance of the plate was measured on a microplate spectrophotometer (Molecular Devices) and the absorbance for each concentration of compound expressed as a proportion of the relative DMSO control.
  • the TD50 the concentration of drug required to reduce the total cell area by 50% relative to the DMSO controls, can be calculated by plotting the absorbance at 620 nm minus background against drug concentration.

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Abstract

L'invention concerne un l'utilisation d'un composé de formule (I) ou d'un sel de qualité pharmaceutique de ce composé, pour la fabrication d'un médicament permettant de traiter ou d'atténuer l'hépatite C. Formule (I): dans laquelle R1, R2, R4, Y1, Y2, Y3, A, B et W sont comme définis dans le descriptif.
PCT/GB2008/050817 2007-09-14 2008-09-12 Dérivés hétérocycliques et leur utilisation dans le traitement de l'hépatite c WO2009034390A1 (fr)

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WO2010099527A1 (fr) 2009-02-27 2010-09-02 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
WO2011081918A1 (fr) 2009-12-14 2011-07-07 Enanta Pharmaceuticals, Inc Inhibiteurs du virus de l'hépatite c
US8008303B2 (en) 2005-09-16 2011-08-30 Astrazeneca Ab Biphenyl derivatives and their use in treating hepatitis C
JP2013501745A (ja) * 2009-08-12 2013-01-17 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト 殺微生物複素環
WO2013030750A1 (fr) 2011-09-01 2013-03-07 Lupin Limited Composés antiviraux
WO2013118102A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction hétérotricycle
US9328096B2 (en) 2014-05-07 2016-05-03 Pfizer Inc. Tropomyosin-related kinase inhibitors
WO2020117849A1 (fr) 2018-12-04 2020-06-11 Bristol-Myers Squibb Company Procédés d'analyse utilisant une courbe d'étalonnage dans un échantillon par surveillance de réaction d'isotopologues multiples
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
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
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
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

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8008303B2 (en) 2005-09-16 2011-08-30 Astrazeneca Ab Biphenyl derivatives and their use in treating hepatitis C
WO2010099527A1 (fr) 2009-02-27 2010-09-02 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
JP2013501745A (ja) * 2009-08-12 2013-01-17 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト 殺微生物複素環
WO2011081918A1 (fr) 2009-12-14 2011-07-07 Enanta Pharmaceuticals, Inc Inhibiteurs du virus de l'hépatite c
WO2013030750A1 (fr) 2011-09-01 2013-03-07 Lupin Limited Composés antiviraux
WO2013118102A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction hétérotricycle
WO2013118097A1 (fr) 2012-02-10 2013-08-15 Lupin Limited Composés antiviraux avec une fraction dibenzooxahétérocycle
US9073942B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a heterotricycle moiety
US9073943B2 (en) 2012-02-10 2015-07-07 Lupin Limited Antiviral compounds with a dibenzooxaheterocycle moiety
US9328096B2 (en) 2014-05-07 2016-05-03 Pfizer Inc. Tropomyosin-related kinase inhibitors
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
WO2020117849A1 (fr) 2018-12-04 2020-06-11 Bristol-Myers Squibb Company Procédés d'analyse utilisant une courbe d'étalonnage dans un échantillon par surveillance de réaction d'isotopologues multiples
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
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
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors

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