[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

EP2038253A1 - Dérivés de biphényle et leur utilisation pour le traitement de l'hépatite c - Google Patents

Dérivés de biphényle et leur utilisation pour le traitement de l'hépatite c

Info

Publication number
EP2038253A1
EP2038253A1 EP07712949A EP07712949A EP2038253A1 EP 2038253 A1 EP2038253 A1 EP 2038253A1 EP 07712949 A EP07712949 A EP 07712949A EP 07712949 A EP07712949 A EP 07712949A EP 2038253 A1 EP2038253 A1 EP 2038253A1
Authority
EP
European Patent Office
Prior art keywords
alkylene
alkyl
different
same
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07712949A
Other languages
German (de)
English (en)
Inventor
James Lumley
James Iain Salter
Malcolm Clive Carter
Neil Mathews
Christopher John Pilkington
Alexander James Floyd Thomas
Ian Fraser
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arrow Therapeutics Ltd
Original Assignee
Arrow Therapeutics Ltd
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 GB0610664A external-priority patent/GB0610664D0/en
Priority claimed from GB0610663A external-priority patent/GB0610663D0/en
Priority claimed from PCT/GB2006/003469 external-priority patent/WO2007031791A1/fr
Application filed by Arrow Therapeutics Ltd filed Critical Arrow Therapeutics Ltd
Publication of EP2038253A1 publication Critical patent/EP2038253A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • 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
    • C07D295/22—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 hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a series of biphenyl derivatives which are useful in treating or preventing a hepatitis C viral (HCV) infection. Similar compounds are disclosed in copending application no. PCT/GB06/003469, from which the present application claims priority.
  • the present invention provides, in a first embodiment, the use of a compound which is a biphenyl derivative 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 -Ai-L 1 -A/, -A 1 -Li-AZ-A/ 7 or -AJ-LI-AZ-YI-A/ 7 ; - A and B are the same or different and each represent a direct bond or a -CO-
  • R 2 and R 3 are the same or different and each represent Ci-C 4 alkyl, Ci-C 4 alkoxy, C 1 -C 4 alkylthio, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, halogen, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , -NR 7 -COR 777 or -CO 2 R 777 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Ci-C 4 alkyl; n and m are the same or different and each represent O, 1 or 2; R 4 is a Ci-C 6 alkyl or Cj-C ⁇ haloalkyl group or a moiety -A 4 , -A 4 -A 4 , -L 4 -A 4 , -A 4 -L 4 -A 4 7 , or -L 4 -HeI 4 -L
  • Y 1 represents -CO-NR 7 -, -CO-(Ci-C 4 alkylene)-, -CO-(Ci-C 4 alkylene)-NR 7 -, -NR 7 -CO-, -CO-, -0-CO- or -CO-O-, wherein R 7 is hydrogen or Ci-C 4 alkyl;
  • L 4 7 represents hydrogen or a Ci-C 4 alkyl group
  • Het 4 and Het/ are the same or different and represent -O-, -S- or -NR 7 -, wherein R 7 is hydrogen or a Ci -C 4 alkyl group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CO 2 R 7 , -SO 2 NRV 7 , -S(O) 2 -R 7 , -CONR 77 R 77 , -COR 777 , -CO-CO-OR 777 , -CO-(CI-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-NR 7/ R 77 , -CO-(Ci-C 4 alkylene)-NR 77 -CO-R 777 , -CO- (C-C 4 alkylene)-CO-NR 77
  • R is -Ai-Li-A, 7 -Ai 77 or -Ai-Li-Ai'-Yi-Ai";
  • Ri is -Ai-Li-Ai 7 and A/ is substituted by a -CO 2 R 7 , -SO 2 NR 77 R 77 , -SO 2 -R 7 , -CONR 77 R 77 , -COR 777 , -CO-CO-OR 777 , -CO-(Ci-C 4 alkylene)-OR 77 , -CO-(C 1 -C 4 alkylene)- NR 77 R 77 , -CO-(Ci-C 4 alkylene)-NR 77 -CO-R 777 , -CO-(C 1 -C 4 alkylene)-CO-NR 77 R 77 , -CO- (Ci-C 4 alkylene)-SO 2 -R 777 , -CO-(Ci-C 4 alkylene)-O-(Ci-C 4 alkylene)-OR 7/ , -CO-(Ci-C 4 alkylene)
  • n is 1 and R 2 is C 1 -C 4 alkylthio, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , -NR 7 - COR 777 or -CO 2 R 777 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Ci-C 4 alkyl; or
  • m is 1 and R 3 is C 1 -C 4 alkylthio, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , -NR 7 - C0R 7// or -CO 2 R //7 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents C 1 -C 4 alkyl; or
  • R 4 is -A 4 -HCt 4 -L 4 -HeI 4 -L 4 ' ' .
  • the present invention provides the use of a compound which is a biphenyl derivative of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or alleviating HCV, wherein:
  • -Ri is a moiety -Ai-Li-A/, -AJ-LI-AZ-AZ' or -AI-LJ-AZ-YI-AI";
  • a and B are the same or different and each represent a direct bond or a -CO- NR 7 -, -NR 7 -C0-, -NR 7 -CO-NR 77 -, -NR 7 -S(O) 2 -, -S(O) 2 -NR 7 - or -NR 7 - moiety, wherein R 7 and R are the same or different and each represent hydrogen or Ci-C 4 alkyl;
  • R 2 and R 3 are the same or different and each represent Ci-C 4 alkyl, Ci-C 4 alkoxy, Cj-C 4 alkylthio, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, halogen, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , or -CO 2 R 777 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Ci-C 4 alkyl; - n and m are the same or different and each represent O, 1 or 2;
  • R 4 is a Ci-C 6 alkyl or Ci-C 6 haloalkyl group or a moiety -A 4 , -A 4 -A 4 7 , -A 4 -L 4 - AA , -A 4 -Het 4 -L 4 -Het 4 / -L 4 7 or -L 4 -Het 4 -L 4 ; , each A 1 , A 4 , Ai 7 , Ai 77 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 -C 6 carbocyclyl moiety; each Li and L 4 is the same or different and represents a Cj-C 4 alkylene or a Ci- C 4 hydroxyalkylene group; Yi represents -CO-NR 7 -, -NR 7 -CO-, -0-C0- or -CO-O-, wherein R 7 is hydrogen or Ci-C 4
  • L 4 7 represents hydrogen or a Ci-C 4 alkyl group
  • Het 4 and Het/ are the same or different and represent -0-, -S- or -NR -, wherein R 7 is hydrogen or a C]-C 4 alkyl group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CO 2 R', -SO 2 NRV, -S(O) 2 -R 7 , -CONR 77 R 77 , -COR 777 and -SO 2 -(Ci-C 4 alkylene)-SO 2 -R / and/or (b) 1, 2 or 3 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Cj-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 hydroxyalkyl, hydroxy, cyano,
  • Ri is -Ai-Li-A/ and A/ is substituted by a -CO 2 R 7 , -SO 2 NR 77 R 77 , -SO 2 -R 7 , -CONR 77 R 77 , -C0R 7// or -SO 2 -(Ci-C 4 alkylene)-SO 2 -R / substituent, wherein each R 7 is the same or different and represents hydrogen, Ci-C 4 alkyl or Ci-C 4 haloalkyl, each R 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; or
  • n 1 and R 2 is Ci-C 4 alkylthio, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , or -CO 2 R W , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Cj-C 4 alkyl; or
  • m is 1 and R 3 is Ci-C 4 alkylthio, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 or -CO 2 R 777 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Ci-C 4 alkyl; or
  • R 4 is -A 4 -HCt 4 -L 4 -HeI./-!!,/.
  • a Ci-C 6 alkyl moiety is a linear or branched alkyl moiety containing from 1 to 6 carbon atoms, such as Ci-C 4 alkyl moiety.
  • Examples of Ci-C 6 alkyl moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl moieties.
  • the alkyl moieties may be the same or different.
  • a Ci-C 4 alkylene group is any divalent linear or branched Ci -C 4 or Ci-C 2 alkyl moiety.
  • Ci-C 4 alkylene groups are methylene, ethylene, n- propylene and n-butylene groups. Methylene and ethylene groups are preferred. Branched Ci-C 4 alkylene groups include -CH(CH 3 )-, -CH(CH 3 )-CH 2 - and -CH 2 - CH(CH 3 )-.
  • a Ci-C 4 hydroxyalkylene group is a said Ci-C 4 alkylene group which is substituted by a single hydroxy group.
  • a halogen is chlorine, fluorine, bromine or iodine.
  • a halogen is typically fluorine, chlorine or bromine.
  • a Ci-C 4 alkoxy moiety is a said Ci-C 4 alkyl moiety attached to an oxygen atom.
  • a preferred Ci-C 4 alkoxy moiety is methoxy.
  • a Ci-C 4 hydroxyalkyl moiety is a said Ci-C 4 alkyl moiety substituted by a single hydroxyl moiety.
  • Preferred hydroxyalkyl moieties are Ci-C 2 hydroxyalkyl moieties, for example -C(OH)-CH 3 and -CH 2 OH.
  • a Ci-C 4 haloalkyl or Ci-C 4 haloalkoxy moiety is typically a said C 1 -C 4 alkyl or
  • Ci-C 4 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 and fluorine.
  • a particularly preferred haloalkyl moiety is -CF 3 .
  • a particularly preferred haloalkoxy moiety is -OCF 3 .
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R 1 and R 4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CO 2 R 7 , -S(O) 2 -R 7 , -CONRV, -COR ⁇ , -C0-C0-OR /;/ , -CO-(CI-C 4 alkylene)- 0R ;/ , -CO-(Ci-C 4 alkylene)-NRV, -CO-(Ci-C 4 alkylene)-NR // -CO-R /// , -CO-(Ci-C 4 alkylene)-SO 2 -R /// , -CO-(Ci-C 4 alkylene)-O-(Ci-C 4 alkylene)-OR /; , -SO 2 -(Ci-C 4 alkyleneVOR", -NR ⁇ SO 2
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CO 2 R 7 , -S(O) 2 -R 7 , -CONR 77 R 77 , -COR 777 and -SO 2 -(C 1 -C 4 alkylene)-SO 2 -R / and/or (b) 1, 2 or 3 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl and Ci-C 4 haloalkoxy substituents, wherein each R 7 is the same or different and represents hydrogen, Ci -C 4 alkyl or Ci-C 4 haloalkyl, each R 77 is the same or different and represents hydrogen or Ci-C 4 alkyl and each R 777 is the same or
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -S(O) 2 (Ci-C 4 alkyl), -S(O) 2 -(C 1 -C 4 haloalkyl), -CO-NHR 777 , -COR 7 ", -CO- CO-OR'", -CO-(C-C 2 alkylene)-OR /7 , -CO-(Ci-C 2 alkylene)-NR 7/ R 7/ , -CO-(Ci-C 2 alkylene)-NH-CO-R /7/ , -CO-(Ci-C 2 alkylene)-SO 2 -R 777 , -CO-(C)-C 2 alkylene)-O-(Ci-C 2 alkylene)-OR 77 , -SO 2 -
  • the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -S(O) 2 -R 7 , -CO-NHR 777 , -COR 777 and -SO 2 -(Ci-C 2 alkylene)-SO 2 -R 777 and/or (b) 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl and Ci-C 4 haloalkyl substituents, wherein each R 7 is the same or different and represents Ci-C 4 alkyl or Ci- C 4 haloalkyl and each R 7 is the same or different and represents Ci-C 4 alkyl.
  • a 5- to 10-membered heteroaryl moiety is a 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 hyteroaryl moiety is monocyclic.
  • a 5- to 10-membered heteroaryl moiety is a 5- to 6-membered heteroaryl moiety.
  • Examples include imidazolyl, isoxazolyl, pyrrolyl, thienyl, thiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and triazolyl moieties. Pyridyl and triazolyl moieties are preferred.
  • a said heteroaryl moiety is unsubstituted or substituted as set out above. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl and Ci-C 2 haloalkyl substituents. More preferably, it is unsubstituted.
  • a 5- to 10-membered heterocyclyl moiety is a non-aromatic, saturated or unsaturated C 5 -C10 carbocyclic ring, in which at least one, for example 1, 2 3 or 4, carbon atoms in the ring are replaced with a moiety selected from O, S, SO, SO 2 , CO and N.
  • it is saturated or contains a single double bond within the ring structure.
  • it is a saturated C 5 -C io ring (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 , CO and NH.
  • a heterocyclyl moiety is monocyclic.
  • a heterocyclyl moiety contains up to two CO moieties.
  • a heterocyclyl moiety is a 5- to 6- membered ring.
  • examples include 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, pyrimidin-2,4 (IH, 3H)-dionyl and pyrazolinyl moieties
  • Piperidyl, piperidin-2,6-dionyl, pyrrolidin-2-onyl, imidazolin-2-onyl, pyrimidine-2,4 (IH, 3H)- dionyl, piperazinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl and pyrrolidinyl moieties are preferred.
  • a said heterocyclyl moiety is unsubstituted or substituted as set out above.
  • 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 unsubstituted or substituted as set out above. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy and Ci-C 2 haloalkyl substituents. More preferably, it is unsubstituted.
  • a C 3 -C 6 carbocyclic moiety is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Typically, it is monocyclic. Preferably it is a saturated hydrocarbon ring (i.e. a cycloalkyl moiety) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cycloburyl, cyclopentyl and cyclohexyl. Cyclopropyl and cyclohexyl are preferred.
  • a said carbocyclyl moiety is unsubstituted or substituted as set out above.
  • Ai represents a phenyl group or a 5- to 6- membered heteroaryl group.
  • Ai is a phenyl group.
  • A] is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy and Ci-C 2 haloalkyl substituents. Typically, these substituents are selected from halogen, Ci-C 4 alkyl and Ci-C 2 haloalkyl substituents. More preferably, A] is unsubstituted.
  • Ai is a phenyl group which is unsubstituted or substituted by one or two unsubstituted halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy and Ci-C 2 haloalkyl substituents.
  • Ai is a phenyl group which is unsubstituted or substituted by a Ci-C 2 alkoxy, for example a methoxy, group. Most preferably, A 1 is an unsubstituted phenyl group.
  • the A/ moiety represents a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. More preferably, Ai is a 5- to 6- membered heterocyclyl moiety, such as a piperazinyl, pyrrolidinyl or S,S-dioxothiomorpholinyl group, in particular a piperazinyl or S,S-dioxothiomorpholinyl group. Most preferably, A y is a piperazinyl group.
  • A/ represents an unsubstituted S, S- dioxothiomorpholino group, a pyrrolidinyl group substituted with -NR // -S ⁇ 2 -R //y or a moiety
  • R represents -CO 2 R', -SO 2 KRV, -S(O) 2 -R 7 , -CONR 77 R 77 , -COR 777 , -CO- CO-OR 777 , -CO-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-NR 77 R /7 , -CO-(C 1 -C 4 alkylene)-NR 77 -CO-R 77/ , -CO-(Ci-C 4 -CO-(Ci-C 4 alkylene)-SO 2 - R 77/ , -CO-(Ci-C 4 alkylene)-O-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-O-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-O-(Ci-
  • R represents -CO 2 R 7 , -S(O) 2 -R 7 , -CONR 77 R 77 , -COR 777 , -CO-CO-OR 777 , -CO-(C 1 -C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-NR 77 R 7/ , -CO-(C-C 4 alkylene)- 77 - CO-R 7// , -CO-(Ci-C 4 alkylene)-SO 2 -R 777 , -CO-(Ci-C 4 alkylene)-O-(Ci-C 4 alkylene)-OR 77 , -SO 2 -(CrC 4 alkylene)-OR 77 , -NR 77 -SO 2 -R 777 , -(Ci-C 4 alkylene)-CO-(C r C 4 alkylene)- CO 2 -R 77 ,
  • R represents -S(O) 2 -(Ci-C 4 alkyl), -S(O) 2 -(Ci-C 4 haloalkyl), -CONHR 777 , -COR 777 , -CO-CO-OR 7 ' 7 , -CO-(Ci-C 2 alkylene)-OR 77 , -CO-(Ci-C 2 alkylene)- NR 77 R 77 , -CO-(Ci-C 2 alkylene)-NH-CO-R 777 , -CO-(C 1 -C 2 alkylene)-SO 2 -R 777 , -CO-(Ci-C 2 alkylene)-O-(Ci-C 2 alkylene)-OR 7/ , -SO 2 -(Ci-C 4 ) alkylene)-OH, -NH-SO 2 -R 777 , -(Ci-C 2 alkylene)-CO-(Ci-C 4
  • A/ represents an unsubstituted S,S-dioxothiomorpholino group or a moiety
  • R represents -CO-(CrC 4 alkyl), -SO 2 -(Ci-C 4 alkyl), -SO 2 -(Ci-C 2 haloalkyl) or
  • the Ai 77 moiety is a phenyl, 5- to 6- membered heterocyclyl or C3-C6 carbocyclic group.
  • the A 1 77 moiety is a phenyl, C 3 -C 6 cycloalkyl, morpholino, S,S-dioxothiomorpholino, pyrrolidin-2-onyl, imidazolin-2-onyl or pyrimidin-2,4 (IH, 3H)-dionyl group.
  • the A 1 77 moeity is a C 3 -
  • the A 1 77 moiety is unsubstituted or substituted by 1 or 2 substitutents selected from Ci-C 4 alkyl, halogen and hydroxy substituents.
  • each A 4 moiety is the same or different and is phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3 -C 6 cycloalkyl.
  • each A 4 moiety is the same or different and represents a phenyl, piperidinyl, pyridyl, piperazinyl, pyrrolidinyl, cyclopropyl or cyclohexyl moiety.
  • each A 4 moiety is unsubstituted or substituted by 1, 2 or 3 unsubstituted substituents selected from halogen, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkyl and Ci-C 4 haloalkoxy substituents. More preferably, each A 4 moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci -C 4 alkyl and Ci-C 2 haloalkyl substituents. Most preferably, each A 4 moiety is unsubstituted or substituted with a Ci-C 2 alkyl group.
  • each A 4 ' moiety is the same or different and represents a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
  • each A ⁇ / moiety is the same or different and represents a morpholinyl, phenyl, 2,6-dioxo- piperidinyl or triazolyl group.
  • each A/ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C 1 -C 4 alkyl and Ci-C 4 haloalkyl substituents. More preferably, each A 4 * moiety is unsubstituted or substituted by a Ci- C 2 alkyl group.
  • Li is a Ci-C 4 alkylene group. More preferably, L) is a Ci-C 2 alkylene group. Most preferably, Li is a methylene group (-CH 2 -).
  • L 4 is a Ci-C 4 alkylene group. More preferably, L 4 is a Ci-C 2 alkylene group.
  • Yi represents -CO-(Ci-C 2 alkyl)-, -CO-(Ci-C 2 alkyQ-NR.'-, -CO-,
  • Yi represents -CO-CH 2 -, -CO-CH 2 -NH-, -CO-, -CO-NH- or -NH-CO-.
  • Yi represents -CO-NR 7 - or -NR ⁇ CO-, wherein R 7 is hydrogen or Ci-C 4 alkyl.
  • Yi represents -CO-NH- or -NH-CO-.
  • Y] represents -CO-NH-.
  • L/ is a Ci-C 2 alkyl group. More preferably, L_/ is a methyl group.
  • each Het 4 and Het/ are the same or different and represent -O- or -NR 7 - wherein R 7 is hydrogen or Ci-C 2 alkyl.
  • Het 4 represents -NR'-, more preferably -NH- or -N(CH 3 )-.
  • Hefc/ represents -0-.
  • Ri represents -A 1 -L 1 -A/-A 77
  • it is typically a moiety -phenyl-CH 2 -A/-(C3- Ce cycloalkyl), wherein A/ is as defined above.
  • A/ is a piperazinyl group which is attached to the A 77 moiety and to the -Li-At moiety via N atoms. More typically, A] is unsubstituted. More typically, A/ is an unsubstituted piperazinyl group which is attached to the -A 7/ moiety and to the -Li-Ai moiety via N atoms.
  • Ri represents an unsubstituted -phenyl-CH 2 -(l,4-piperazinyl)-(C3- C 6 cycloalkyl) group.
  • Ri When Ri represents -A 1 -Li-A/- Yi-A/ 7 , it is typically a moiety -phenyl-CH 2 -A/- Yi-Aj 77 , wherein A/, YI and A/ 7 are as defined above.
  • A/ is a piperazinyl group which is attached to the A 77 moiety and to the -L]-Ai moiety via N atoms. More typically, A/ is unsubstituted. More typically, A/ is an unsubstituted piperazinyl group which is attached to the -A 7/ moiety and to the -Li-Ai moiety via N atoms.
  • Yi is -CO-, -CO-CH 2 -, -CO-CH 2 -NH- or -CO-NH-.
  • Ri represents a -phenyl-CH 2 -(l,4-pi ⁇ erazinyl)-Yi-A/ / group, wherein Y and Ai 7/ are as defined above. More preferably, Ri represents an unsubstituted -phenyl-CH 2 -(l,4- piperazinyl)-CO-NH-(C3-C6 cycloalkyl) group.
  • Ri represents a moiety -Aj-Li-A/ or -A 1 -L 1 -A/-Y1-A/ 7 wherein Ai,
  • Li, A/, YI and A/ 7 are as defined above.
  • Ri is a moiety -phenyl-CH 2 -A/ wherein A/ is an unsubstituted S,S-dioxothiomorpholino group or a moiety
  • R represents -CO-(Ci-C 4 alkyl), -SO 2 -(Ci-C 4 alkyl), -SO 2 -(Ci-C 2 haloalkyl) or -SO 2 -(Ci-C 2 alkylene)-SO 2 -(Ci-C 4 alkyl).
  • R is -SO 2 - (Ci-C 4 alkyl).
  • A/ is other than S, S- dioxothiomorpholino.
  • R is -SO 2 -(Ci-C 4 alkyl). More preferably, in this embodiment, the compounds of the invention are not compounds of the formula (I), as set out above, wherein Ri is -phenyl-CH 2 -A/ and A ⁇ is a morpholino or piperazinyl group which is unsubstituted or substituted by a -S(O) 2 - (Ci-C 4 alkyl) substituent.
  • the left hand side of the A and B moieties depicted above are attached to the central biphenyl core.
  • the right hand side of the depicted moieties are attached to Ri or R 4 .
  • a and B are the same or different and each represent -NR / -C0-NR // -, -CO-NR'- or -NR'-CO-, wherein R ; and R ;/ are the same or different and represent hydrogen or Ci-C 4 alkyl.
  • A represents -CO-NR 7 - or -NR'-CO-, wherein R ; is hydrogen or Ci-C 4 alkyl.
  • A represents -C0-NR ; -, more preferably -CO-NH-.
  • B represents -NR'-CO-NR"-, -CO-NR / - or -NR ; -C0- wherein R ; and R /(l are the same or different and represent hydrogen or Cj-C 4 alkyl.
  • B represents -NH-CO-NH, -CO-NH- or -NH-CO-.
  • n and m are the same or different and each represent O or 1.
  • n O or 1.
  • m is 1. More preferably, m is 1 and R 3 is present on a carbon atom ortho to the phenyl ring of the central biphenyl moiety.
  • R 2 and R 3 are the same or different and each represent halogen, Ci- C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, Ci-C 4 haloalkoxy, Ci-C 4 alkylthio, hydroxy, thio, -NR 7 R", -SO 2 R //; , -NR'-COR'" or -CO 2 R" 7 , wherein each R ; and R ;/ are the same or different and represent hydrogen or Ci-C 4 alkyl and R ;// represents Ci-C 4 alkyl.
  • each R 2 is the same or different and represents -NR'R", -NR'-CO-R ⁇ , -SO 2 R //; , -C0 2 R y// , hydroxy or thio, wherein each R f and R ;/ are the same or different and represent hydrogen or Ci-C 4 alkyl and R /;/ is Ci-C 4 alkyl. More typically, in this embodiment, each R 2 is the same or different and represents -SO 2 R //; , -C0 2 R ;// , hydroxy or thio, wherein R u/ is Ci-C 4 alkyl.
  • each R 2 is the same or different and represents -N(R ;// ) 2 , -NH-CO-R /;/ , -SO 2 R 7 V hydroxy, wherein R //; is Ci-C 4 alkyl, preferably CH 3 . More preferably, in this embodiment, each R 2 is the same or different and represents -SO 2 R 77 , in particular -SO 2 -CH 3 , or hydroxy.
  • each R 3 is the same or different and represents Ci-C 4 alkyl, Ci-C 4 alkoxy, halogen, Ci-C 2 haloalkyl, Ci-C 2 haloalkoxy or -NR 7 R 77 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl. More preferably, each R 3 is the same or different and represents Ci-C 2 alkyl, Ci-C 2 alkoxy, halogen, Ci-C 2 haloalkoxy, Ci-C 2 haloalkyl or -NR 7 R 77 , wherein R 7 and R /7 are the same or different and each represent Ci-C 2 alkyl.
  • R 4 is a moiety -A 4 , -A 4 -A/, -L 4 -A 4 , -A 4 -L 4 -A/, -A 4 -HCt 4 -L 4 -HCt 4 -L/ or -L 4 -Het 4 -L/, wherein A 4 , A 4 ', L 4 , ReU, Het/ and L/ are as defined above.
  • R 4 is a moiety -A 4 , -A 4 -A 4 7 , -A 4 -L 4 -A 4 7 , -A 4 -Het 4 -L 4 -Het 4 / -L 4 / or -L 4 -HeI 4 - L 4 7 , wherein A 4 , A 4 7 , L 4 , Het 4 , Het/ and L/ are as defined above.
  • R 4 is -A 4
  • it is typically a C 3 -C ⁇ cycloalkyl or 5- to 6- membered heterocyclyl group.
  • it is a cyclopropyl, cyclohexyl, piperidinyl, piperazinyl or pyrrolidinyl group.
  • the A 4 moiety is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl and Ci-C 4 haloalkyl substitutents.
  • these substituents are selected from Ci-C 2 alkyl groups.
  • a 4 Is typically a phenyl or 5- to 6- membered heteroaryl moiety.
  • a 4 is a phenyl or pyridyl group.
  • a 4 is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl and Ci-C 4 haloalkyl substituents.
  • a 4 is unsubstituted.
  • A/ is typically a 5- to 6- membered heteroaryl or heterocyclyl group.
  • a 4 7 is a morpholinyl, triazolyl or piperidin-2,6-dionyl group.
  • a 4 7 is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen, Ci-C 4 alkyl and CpC 4 haloalkyl substituents.
  • a 4 7 is unsubstituted or substituted by an unsubstituted Ci-C 2 alkyl group.
  • R 4 when R 4 is -A 4 -A/, it is an unsubstituted -pyridyl-morpholino, -phenyl-triazolyl or -phenyl-morpholino group or is a -phenyl-piperidin-2,6-dionyl group which is unsubstituted or substituted by a Ci-C 2 alkyl group.
  • R 4 is -A 4 -L 4 -A 4 7
  • a 4 is typically a 5- to 6- membered heterocyclyl group, in particular a piperidinyl group.
  • L 4 is typically Ci-C 2 alkylene, more preferably -CH 2 -.
  • a 4 is typically a phenyl group.
  • R 4 when R 4 is -A 4 -L 4 -A 4 7 , A 4 and A 4 7 are unsubstituted.
  • a 4 is typically a 5- to 6- membered heterocyclyl group, in particular a pyrrolidinyl group.
  • L 4 is typically CpC 2 alkylene, more preferably -CH 2 -.
  • R 4 when R 4 is -L 4 -A 4 , A 4 is unsubstituted.
  • L 4 is typically Ci-C 2 alkylene, more preferably methylene.
  • Het is typically -NR / -, wherein R 7 is hydrogen or Ci-C 2 alkyl, and is preferably -NH-.
  • L 4 7 is typically Ci-C 2 alkyl, more preferably methyl.
  • R 4 is typically a phenyl group. Typically, A 4 is unsubstituted.
  • Het 4 is typically -NR 7 -, wherein R 7 is hydrogen or Ci-C 2 alkyl, and is preferably -N(CH 3 )-.
  • L 4 is typically Ci-C 2 alkylene.
  • HeU is typically -O-.
  • L 4 7 is typically Ci-C 2 alkyl.
  • R 4 is -A 4 -Het 4 -L 4 -Het / 4 -L 4 / , it is -phenyl- N(CH 3 )-(Ci-C 2 alkylene)-O-(Ci-C 2 alkyl).
  • R 1 is -A 1 -L 1 -AZ-A/ 7 or -A 1 -L 1 -AZ-Y 1 -A 1 77 ;
  • Ri is -Ai-Li-A/ and A/ is substituted by a -CO 2 R 7 , -SO 2 NR 77 R 77 , -SO 2 -R 7 , -CONR 77 R 77 , -COR 777 , -CO-CO-OR.'", -CO-(C 1 -C 4 alkylene)-OR 7/ , -CO-(C 1 -C 4 alkylene)-
  • m is 1 and R 3 is C 1 -C 4 alkylthio, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , -NR 7 - COR 777 or -CO 2 R 777 , wherein R 7 and R 77 are the same or different and represent hydrogen or C 1 -C 4 alkyl and R //; represents C 1 -C 4 alkyl; or
  • R 4 is -A 4 -Het 4 -L 4 -Het 4 7 -L 4 7 .
  • a 1 7 is substituted by a -CO 2 -(Ci-C 4 haloalkyl), -SO 2 (C 1 -C 4 haloalkyl), -COR 777 , -SO 2 -(C 1 -C 4 alkylene)-SO 2 -(Ci-C 4 haloalkyl), -SO 2 -(Ci-C 4 alkylene)-SO 2 -R 777 , -CO-CO-OR 777 , -CO-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-NR // R // , -CO-(Ci-C 4 alkylene)-NR // -CO-R /// , -CO-(Ci-C 4 alkylene)-CO- NEnR.”, -CO-(Ci-C 4 alkylene)-SO 2 -R ;// , -CO-((Ci-C 4 al
  • n is 1 and R 2 is -SO 2 R 777 , -NR 77 R 77 , -NR 77 -COR 7/ , hydroxy, Cj-C 4 alkylthio, thio or -CO 2 R 777 , wherein R 777 is as defined above. More preferably, in option (c), n is 1 and R 2 is -SO 2 R" 7 , -N(R 777 ) 2 , -NH-CO-R 777 or hydroxy.
  • m is 1 and R 3 is -NR 7 R 77 , wherein R 7 and R /7 are as defined above. More preferably, m is 1 and R 3 is -N(CH 3 ) 2 .
  • Ri is -A 1 -L1-A/-A1" or -A 1 -Li-AZ-Y 1 -A 1 77 ; or
  • Ri is -Ai-L 1 -A 7 and A/ is substituted by a -CO 2 -(C 1 -C 4 haloalkyl), -SO 2 -(Ci-C 4 haloalkyl), -COR 777 , -SO 2 -(Ci-C 4 alkylene)-SO 2 -(C,-C 4 haloalkyl), -SO 2 - (Ci-C 4 alkylene)-SO 2 -R /7/ , CO-CO-OR 777 , -CO-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-NR /7 R 77 , -CO-(Ci-C 4 alkylene)-NR 77 -CO-R 777 , -CO-(Ci-C 4 alkylene)-CO- NR /7 R /; , -CO-(Ci-C 4 alkylene)-SO—SO
  • n is 1 and R 2 is C 1 -C 4 alkylthio, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , -NR 7 - COR 777 or -CO 2 R 777 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Ci-C 4 alkyl; or
  • m is 1 and R 3 is Ci-C 4 alkylthio, hydroxy, thio, -NR 7 R 77 , -SO 2 -R 777 , -NR 7 - COR 77 Or -CO 2 R 77 ', wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Ci-C 4 alkyl; or
  • R 4 is -A 4 -Het 4 -L 4 -Het 4 / -L 4 7 .
  • Preferred compounds of formula (I) are those wherein: Ri is -Ai-Li-A/, -AI-LI-AZ-A/ 7 or -AI-LI-AZ-YI-A] 77 ;
  • a and B are the same or different and each represent -NR / -C0-NR // -, -CO-NR 7 - or -NR -CO-, wherein R 7 and R 77 are the same or different and each represent hydrogen or Ci-C 4 alkyl; R 2 and R 3 are the same or different and each represent halogen, Ci-C 4 alkyl, C 1 -
  • each Ai, AA, A ⁇ , AJ 77 and A 4 7 are the same or different and represent a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C 3 -C 6 cycloalkyl moiety; each Li and L 4 is the same or different and represents a Ci-C 4 alkylene group; - Yi represents -CO-(Ci-C 2 alkyl)-, -CO-(Ci-C 2 alkyl)-NR 7 -, -CO-, -CO-NR 7 - or -
  • R 7 is hydrogen or C]-C 4 alkyl
  • L 4 7 represents a Ci-C 2 alkyl group; and each HeI 4 and Het/ are the same or different and represent -O- or -NR 7 - wherein R 7 is hydrogen or Ci -C 2 alkyl; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R 4 being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -S(O) 2 -(Ci-C 4 alkyl), -S(O) 2 -(Ci-C 2 haloalkyl), -CO-NH-R 777 , -CO-R 777 , -CO-CO-OR 777 , -CO-(Ci-C 2 alkylene)-OR 77 , -CO-(Ci-C 2 alkylene)-NR 77 R 77 , -CO-(Ci-C 2 alkylene)-NH- CO-R 777 , -
  • Ri is -A I -L I -AZ-AI 77 or -A 1 -Li-AZ-Yi-Ai 77 ;
  • Ri is -Ai-Li-Ai 7 and AZ is substituted by a -SO 2 -(Ci-C 4 haloalkyl), -COR 777 , -SO 2 -(Ci-C 2 alkylene)-SO 2 -R 777 , -CO-CO-OR 777 , -CO-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-NR -,I" I TR, I' I, -CO-(C 1 -C 4 alkylene)-NR -CO-R III , -CO-(C 1 -C 4 alkylene)-S0 2 -R /// , -CO-(C 1 -C 4 alkylene)-O-(Ci-C 4 alkylene)-OR", -SO 2 -(Ci-C 4 alkylene)-OR // , -(Ci-C 4 alkylene)-CO-CO-
  • n 1 and R 2 is Ci-C 4 alkylthio, hydroxy, thio, -NR'R", -S0 2 R ;// -NR'- CO-R" or -CO 2 R'", wherein R ; and R" are the same or different and represent hydrogen or Ci-C 4 alkyl and R'" represents Ci-C 4 alkyl; or
  • m is 1 and R 3 is Ci-C 4 alkylthio, hydroxy, thio, -NR 7 R", -SO 2 R 7 ", -NR ; - CO-R 7 " or -CO 2 R 777 , wherein R 7 and R 77 are the same or different and represent hydrogen or Ci-C 4 alkyl and R 777 represents Ci-C 4 alkyl; or
  • R 4 is -A 4 -HeU-L 4 -I-W-L 4 '
  • A/ is an unsubstituted S,S-dioxothiomorpholino group, a pyrrolidinyl group substituted with -NH-SO 2 -R /// or is, more preferably, a moiety
  • R represents -S(O) 2 -(C 1 -C 4 alkyl), -S(O) 2 -(Ci-C 4 haloalkyl), -CONHR /// , -COR 777 , -CO-CO-OR 777 , -CO-(C 1 -C 2 alkylene)-0R 7/ , -CO-(C 1 -C 2 alkylene)-NR // R // , -CO- (Ci-C 2 alkylene)-NH-CO-R /// , -CO-(Ci-C 2 alkylene)-S0 2 -R /// , -CO-(C]-C 2 alkylene)-0- (C 1 -C 2 alkylene)-OR 77 , -SO 2 -(Ci-C 4 ) alkylene)-0H, -NH-SO 2 -R 777 , -(Ci-C 2 alkylene)- CO-(Ci-C 2
  • R 2 represents hydroxy, -N(R 777 ) 2 , -NH-CO-R 777 or -SO 2 -R 777 , wherein R 777 represents Ci-C 4 alkyl; - R 3 represents Ci-C 2 alkyl, Cj-C 2 alkoxy, halogen, C 1 -C 2 haloalkoxy, Ci-C 2 haloalkyl or -NR 7 R 77 , wherein R 7 and R 77 are the same or different and each represent Ci- C 2 alkyl;
  • B represents -NH-CO-NH-, -CO-NH- or -NH-CO-;
  • R 4 represents -A 4 , -A 4 -A 4 7 , -L 4 -A 4 , -A 4 -L 4 -A 4 , -A 4 -HBt 4 -L 4 -HCt 4 -L 4 or -L 4 -HeI 4 -L 4 7 ;
  • L 4 is a Ci-C 2 alkylene group; - each Het 4 and Het/ are the same or different and represent -O- or -NR -, wherein
  • R 7 represents hydrogen or Ci-C 2 alkyl
  • L 4 7 is a Ci-C 2 alkyl group.
  • R is -SO 2 -(C 1 -C 4 haloalkyl), -CO-R 777 , -CO-CO-OR 7 ", -CO-(C 1 -C 2 alkylene)- OR", -CO-(Ci-C 2 alkylene)-NR 77 R 77 , -CO-(Ci-C 2 alkylene)-NH-CO-R /// , -CO-(C 1 -C 2 alkylene)-SO 2 -R 777 , -CO-(Ci-C 2 alkylene)-O-(Ci-C 2 alkylene)-OR 77 , -SO 2 -(Ci-C 4 ) alkylene)-OH, -(Ci-C 2 alkylene)-CO-(Ci-C 2 alkylene)-CO 2 -R /// or -SO 2 -(Ci-C 2 alkylene)-SO 2 -R /// , where
  • n 1 ;
  • R 3 is -NR 7 R , wherein R 7 and R 77 are the same or different and each represent Ci-C 2 alkyl; or
  • R 4 represents -A 4 -Het 4 -L 4 -Het 4 7 -L 4 7 .
  • preferred compounds of formula (I) are compounds of formula (Ia 1 ), and pharmaceutically acceptable salts thereof,
  • Ai is an unsubstituted S,S-dioxothiomorpholino group, or is a moiety
  • R represents -CO-(Ci-C 4 alkyl), -SO 2 -(Ci-C 4 alkyl), -SO 2 -(C 1 -C 2 haloalkyl) or ⁇ SO 2 -(Ci-C 2 alkylene)-SO 2 -(Ci-C 2 alkyl);
  • n is O or 1 ;
  • R 2 represents hydroxy or -SO 2 -R 777 , wherein R 777 represents Ci-C 4 alkyl;
  • R 3 represents Ci-C 2 alkyl, Ci-C 2 alkoxy, halogen, Ci-C 2 haloalkoxy, CrC 2 haloalkyl or -NR 7 R 7 , wherein R 7 and R 77 are the same or different and each represent C 1 - C 2 alkyl;
  • each A 4 is a phenyl, 5- to 6- membered heteroaryl or C 3 -C 6 cycloalkyl group (preferably a phenyl, piperidinyl, pyridyl, piperazinyl, pyrrolidinyl, cyclopropyl or cyclohexyl group) which is unsubstituted or substituted by a Ci-C 2 alkyl group; each A 4 moiety is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group (preferably a morpholinyl,
  • L 4 is a Ci-C 2 alkylene group; each Hetj and HeI 4 are the same or different and represent -O- or -NR -, wherein R 7 represents hydrogen or Ci-C 2 alkyl; and - L 4 7 is a Ci-C 2 alkyl group.
  • R is -CO-(Ci-C 4 alkyl), -SO 2 -(Ci-C 2 haloalkyl) or -SO 2 -(Ci-C 2 alkylene)-SO 2 - (Ci-C 2 alkyl),
  • n 1 ;
  • R 3 is -NR 7 R 77 , wherein R 7 and R 77 are the same or different and each represent Ci-C 2 alkyl; or
  • R 4 represents -A 4 -Het 4 -L 4 -Het 4 / -L 4 .
  • R 4 , B, R 3 , n and R 2 are as defined in the formula (I), Yi is -CO-CH 2 -, -CO-CH 2 -NH-, -CO-, -CO-NH- or -NH-CO- and A/ 7 is a phenyl, 5- to 6- memebred heterocyclyl or C 3 -C 6 carbocyclyl group (preferably a phenyl, C 3 -C 6 cycloalkyl, morpholino, S,S-dioxo-thiomorpholino, pyrrolidin-2-onyl, imidazolin-2-onyl or pyrimidin-2,4 (IH, 3H)-dionyl group) which is unsubstituted or substituted by 1 or 2 substituents selected from Ci-C 4 alkyl, halogen and hydroxy substituents.
  • the medicaments of the present invention are for use in treating or preventing a 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 in 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 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 ju-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g.
  • Especially preferred compounds of the invention include: 4-Methyl-piperazine-l-carboxylic acid ⁇ 4'-[4-(4-acetyl-piperazin-l-ylmethyl)- phenylcarbamoyl] -6-methyl-biphenyl-3 -yl ⁇ -amide (S)-Pyrrolidine-2-carboxylic acid ⁇ 4'-[4-(4-acetyl-piperazin-l-ylmethyl)-phenylcarbamoyl]-6- methyl-biphenyl-3 -yl ⁇ -amide (R)-Pyrrolidine-2-carboxylic acid ⁇ 4'-[4-(4-acetyl-piperazm-l-ylmethyl)-phenylcarbamoyl]- 6-methyl-biphenyl-3
  • the compounds of formula (I) may be prepared by analogy with known methods. For example, they can be prepared by the following reactions: scheme (1)
  • R 2 , R 3 , n and m are as defined above, and either X and Y are, respectively, -A-Ri or -B-R 4 , wherein A, B, Ri and R 4 are as defined above, or X and Y represent groups which can be further reacted by standard techniques to yield the moieties -A-Ri or -B-R 4 , for example amino groups or carbocyclic acid groups.
  • schemes (1) and (2) can be effected by known methods, for example cesium carbonate and palladium catalyst in aqueous DMF at reflux.
  • the starting materials used in schemes (1) and (2) are known compounds or can be prepared by analogy with known methods.
  • aryl bromides and boronic acids/esters can be coupled under standard conditions (cesium carbonate and palladium catalyst in aqueous DME at reflux) to provide a number of diverse biphenyl cores. These may have two carbonyl functionalities, two amino functionalities or one of both types. Some products from these reactions are shown below (for the sake of brevity, a substituent on the aromatic ring is either shown as "C” or "N” and the R 2 and R 3 substituents are simply shown as 'R').
  • amide and reverse amide groups may be placed selectively at either end of the biphenyl core.
  • the initial amide coupling reactions 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 hydrolysis of an ester, a deprotection of a protected amine, or a hydrogenation of a nitro-group will then furnish intermediates which are readily coupled as described above to give the final compounds shown below.
  • Analogues in which one of the amides has been replaced by a ring structure may be prepared, for example, via dehydration of a primary amide into a nitrile. Suitable adaptation of the nitrile furnishes compounds with heteroaromatic rings, e.g. 1,2,4- oxadiazoles or 1,2,4-triazoles. Replacement of the amide with aryl, carbocyclyl and heterocyclyl groups may be performed by analogy.
  • the compounds of the invention are active against the hepatitis C virus.
  • the present invention therefore provides a method for ameliorating a hepatitis C infection in a patient, which method comprises administering to said patient an effective amount of a biphenyl derivative 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, 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.
  • the present invention also provides a biphenyl derivative of formula (Ic) or a pharmaceutically acceptable salt thereof, for the treatment of the human or animal body,
  • Ri, R 2 , R 3 , R 4 , A, B, n and m are as defined for formula (I), provided that either (i) when Rj is -Ai-L 1 -A/, the moiety A/ carries a substituent which is other than an alkyl group or (ii) R 3 is other than halogen or alkyl.
  • the substituent on A/ is a single unsubstituted substituent selected from -CO 2 R 7 , -SO 2 NRV, -S(O) 2 -R 7 , -CONR 77 R 77 , -COR 777 , -CO-CO-
  • the substituent on A/ is a single unsubstituted substituent selected from -SO 2 NR 77 R 77 , -S(O) 2 -R', -CONR 77 R 77 , -COR //7 , -CO-CO-OR 777 , - CO-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-NR 77 R 77 , -CO-(Ci-C 4 alkylene)-NR 77 - CO-R 777 , -CO-(C 1 -C 4 alkylene)-CO-NR 7/ R 77 , -CO-(Ci-C 4 allcylene)-SO 2 -R 7// , -CO-(Ci-C 4 alkylene)-O-(Ci-C 4 alkylene)-OR 77 , -CO-(Ci-C 4 alkylene)-O-(Ci-C 4 al
  • the present invention therefore also provides a biphenyl derivative of formula (Ic), as defined above, or a pharmaceutically acceptable salt thereof.
  • a and B are the same or different and each represent -NR- CO-NR"-, -CO-NR ; - or -NR'-CO, wherein R ; and R /; are the same or different and each represent hydrogen or C i -C 4 alkyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a biphenyl derivative of formula (Ic) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable 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 pharmaceutical compositions of the invention typically contain a compound of the invention which is a substantially pure optical isomer.
  • the compounds of the invention may be administered in a variety of dosage forms. Thus, they 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.
  • the compounds of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
  • 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.
  • 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.
  • 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.
  • Compounds of the present invention may be used in conjunction with known anti-viral agents.
  • Preferred known anti-viral agents in this regard are interferon and ribavirin, which are known for the treatment of hepatitis C (Clinical Microbiology Reviews, Jan. 2000, 67-82).
  • the said medicament therefore typically further comprises interferon and/or ribavirin.
  • the present invention provides a pharmaceutical composition 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.
  • Example 3 was prepared as described for Example 2 except that (R)- pyrrolidine-1 ,2-dicarboxylic acid 1 tert-butyl ester was used. The title compound was isolated as a colourless foam (22mg)
  • Example 4 2'-Methyl-5'-(2-methylamino-acetylamino)-biphenyl-4-carboxylic acid[4-(4-acetty- piperazin-l-ylmethyl)-phenyl]-amide
  • Example 4 was prepared as described for Example 2 except that (tert- butoxycarbonyl-methyl-amino)-acetic acid was used. The title compound was isolated as a colourless foam (29mg)
  • Example 13 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyIic acid [4-(4- acetyl-piperazin-l-ylmethyl)-phenyl]-amide.
  • 6-methyl-biphenyl-3,4'-dicarboxylic acid 4'-ethyl ester 200mg
  • 6-morpholin-4-ylpyridin-3-ylamine 163mg
  • HOBt 123mg
  • EDAC 174mg
  • N-methylmorpholine 200 ⁇ l
  • 6-Dimethylamino-4' ⁇ 4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]- phenylcarbamoyl ⁇ -biphenyl-3-carboxylic acid methyl ester (167mg) was dissolved in EtOH (2ml) and 2N NaOH (1ml) and stirred at room temperature overnight.
  • 6-Dimethylamino-4'[4-(4-methanesulfonyl-piperazin-1-ylmethyl)- phenylcarbamoyl]-biphenyl-3-carboxylic acid methyl ester (155mg) was dissolved in EtOH (2ml) and 2N NaOH (1ml) and stirred at room temperature overnight.
  • Example 34 This material was prepared as for Example 34 except that 4-chloro-3-oxo-butyric acid ethyl ester (0.015ml) was used. The title compound was obtained as an orange gum (lOmg)
  • This material was prepared as for Example 39 except that phenylamino-acetic acid (13mg) was used.
  • the title compound was obtained as a colourless glass (14mg)
  • This material was prepared as for Example 39 except that (8)-2-dipropylamino- propionic acid (15mg) was used. The title compound was obtained as an orange foam (35mg)
  • Example 49 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxylic acid [3-chIoro- 4-(4- methanesulfonyl-piperazin-l-ylmethyl)-phenyl]-amide
  • This material was prepared as described for Example 47 except that 3-chloro-4-(4- methanesulfonyl-piperazin-l-ylmethyl)-phenylamine (22.5mg) was used.
  • the title compound was isolated as an off-white solid (20mg).
  • This material was prepared as for Example 39 except that hydroxy-acetic acid (6.5mg) was used.
  • the title compound was obtained as a colourless solid (3 lmg)
  • the commercially available propane sulfonic acid salt (Ig) was sonicated for 20 min in DMF (20 ml) to ensure dissolution.
  • Triethylamine (0.5ml) was added to the stirred solution under N2, followed by acetyl chloride (1. ImI).
  • the resulting mixture was allowed to stir overnight under N 2 before being evaporated to give an orange slurry.
  • DMF (5r ⁇ l) was added and the mixture then filtered through a pad of celite. The pad was washed with DMF (2 x 10ml) and the filtrate then evaporated to give the title compound as an orange oil which was used in the next stage without further purification.
  • Acetic acid 3-[4-(4- ⁇ [5'-(cyclo ⁇ ropanecarbonyl-amino)-2'-methyl-biphenyl-4- carbonyl]-amino ⁇ -benzyl)-piperazine-l-sulfonyl]-propyl ester (69mg) and potassium carbonate (32mg) were stirred for lhr in 1 : 1 aqueous methanol (5ml). The solution was then acidified to pH 3 via the addition of HCl (cone). The reaction mixture was partitioned between aq ammonium chloride and ethyl acetate. The dried extracts were evaporated and the residue purified by prep HPLC giving the title compound as a colourless solid (17mg).
  • HCV replicon cell line o Ib replicon (Huh.7) described in Science 285, 110-113.
  • o Huh-9B liver cell line with persistent bicistronic HCV genotype Ib coding sequence: [I 389 lucubineo_3-3'_ET] includes firefly luciferase-ubiquitin- neomycin phosphotransferase fusion protein and EMCV-IRES driven nonstructural HCV (NS3 to NS5B) coding sequence including cell culture adaptive mutations E1202G, T1280I and K1846T (Lohmann etal, 2001).
  • This assay is set up using all 96 wells of flat-bottomed 96-well plates. Plates are set up one day before addition of compounds. The assay then runs for 4 days with ELISA development taking place on the 5 th day. Day l
  • Exponentialy growing Huh-9B monolayers are washed with sterile PBS to remove serum and treated with trypsin to detach cells from the flask.
  • Cells are suspended in growth media and counted using a haemocytometer.
  • Duplicate 96 well plates are seeded with Huh-9B at a density of 10 4 cells/well in a total volume of 100 ⁇ l/well of growth medium without antibiotics, as depicted below.
  • One of the plates is an opaque white 96-well plate used for IC50 determination based on the luciferase signal (referred as replicon plate), the other one is a clear 96-well plate used for a parallel determination of drug toxicity by methylene blue staining (referred as tox plate).
  • Wells G12 and H12 of the tox plate are left without cells to use as buffer alone background reading.
  • Doubling dilutions of each compound are generated in a separate 96 high volume capacity round bottom plate to twice their initial concentration in the assay using growth medium without antibiotics.
  • Luciferase detection stage on the replicon plate Media is tapped out from wells into Virkon and plates are washed once in warm PBS and tapped dry gently.
  • Luciferase assay buffer is placed it in the luminometer (Lmax, Molecular Devices).
  • the M injector is primed with 4x 300 ⁇ l of luciferase assay buffer.
  • the plate to be analyzed is placed in the luminometer and 100 ⁇ l of luciferase assay buffer injected automatically into one well followed by 4 seconds integration read out. After one second delay a second well is injected with 100 ⁇ l of luciferase assay buffer followed by 4 seconds integration read out and so forth until all 96 wells are analyzed. Once the reading is finished the luminometer injection system is washed with deionised water.
  • the data is acquired using the SOFTmax for Lmax Pro software package.
  • SOFTmax data files are exported as Excel or text files. A standard four parameters nonlinear regression analysis of the data obtained from each compound is then used to calculate the IC50.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés de formule (I) qui se sont révélés actifs contre le HCV. Dans cette formule : R1 est un fragment -A1-L1-A1', -A1-L1-A1'-A1' ou -A1-L1-A1'-Y1-A1'; A et B sont identiques ou différents et chacun représente une liaison directe ou un fragment -CO- NR'-, -NR'-CO-, -NR'-CO-NR'-, -NR'-S(O)2-, -S(O)2-NR'- ou -NR'-, où R' et R' sont identiques ou différents et chacun représente un hydrogène ou un alkyle en C1-C4; R2 et R3 sont identiques ou différents et chacun représente un alkyle en C1-C4, un alcoxy en C1-C4, un alkylthio en C1-C4, un haloalkyle en C1-C4, un haloalcoxy en C1-C4, un halogène, un hydroxy, un thio, -NR'R', -SO2-R'', -NR'-COR'' ou -CO2R'', où R' et R' sont identiques ou différents et représentent un hydrogène ou un alkyle en C1-C4 et R'' représente un alkyle en C1-C4; n et m sont identiques ou différents et chacun représente 0, 1 ou 2; R4 est un groupe alkyle en C1-C6 ou haloalkyle en C1-C6 ou un fragment -A4, -A4-A4', -L4-A4, -A4-L4-A4', -A4-Het4-L4-Het4'-L4' ou -L4-Het4-L4', - chaque A1, A4, A1', A1' et A4' sont identiques ou différents et représentent un phényle, un hétéroaryle ayant de 5 à 10 chaînons, un hétérocyclyle ayant de 5 à 10 chaînons ou un fragment carbocyclyle en C3-C6; chaque L1 et L4 est identique ou différent et représente un groupe alkylène en C1-C4 ou hydroxyalkylène en C1-C4; - Y1 représente -CO-NR'-, -CO-(alkylène en C1-C4)-, -CO-(alkylène en C1-C4)-NR'-, -NR'-CO-, -CO-, -O-CO- ou -CO-O-, où R' est un hydrogène ou un alkyle en C1-C4; L4' représente un hydrogène ou un groupe alkyle en C1-C4; Het4 et Het4' sont identiques ou différents et représentent -O-, -S- ou -NR'-, où R' est un hydrogène ou un groupe alkyle en C1-C4; les fragments phényle, hétéroaryle, hétérocyclyle et carbocyclyle dans R1 et R4 étant non substitués ou porteurs de substitutions avec (a) un seul substituant non substitué choisi parmi -CO2R', -SO2NR'R', -S(O)2-R', -CONR'R', -COR'', -CO-CO-OR''', -CO-(alkylène en C1-C4)-OR', -CO-(alkylène en C1-C4)-NR'R', -CO-(alkylène en C1-C4)-NR'-CO-R''', -CO-(alkylène en C1-C4)-CO-NR'R', -CO-(alkylène en C1-C4)-SO2-R'', -CO-(alkylène en C1-C4)-O-(alkylène en C1-C4)-OR', -CO-(alkylène en C1-C4)-O-(alkylène en C1-C4)-NR'R', -CO-(alkylène en C1-C4)-NR'-(alkylène en C1-C4)-OR', -CO-(alkylène en C1-C4)-NR'-(alkylène en C1-C4)- NR'R', -SO2-(alkylène en C1-C4)-OR', -NR'-SO2-R'', -(alkylène en C1-C4)-CO-(alkylène en C1-C4)-CO2-R'', -(alkylène en C1-C4)-CO-(alkylène en C1-C4)-CO-NR'R' et -SO2-(alkylène en C1-C4)-SO2-R' et/ou (b) 1, 2 ou 3 substituants non substitués choisi parmi un halogène, un alkyle en C1-C4, un alcoxy en C1-C4, un haloalkyle en C1-C4, un haloalcox
EP07712949A 2006-05-30 2007-03-21 Dérivés de biphényle et leur utilisation pour le traitement de l'hépatite c Withdrawn EP2038253A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0610664A GB0610664D0 (en) 2006-05-30 2006-05-30 Chemical compounds
GB0610663A GB0610663D0 (en) 2006-05-30 2006-05-30 Chemical compounds
PCT/GB2006/003469 WO2007031791A1 (fr) 2005-09-16 2006-09-18 Dérivés de biphényle et leur utilisation dans le traitement de l'hépatite c
PCT/GB2007/001024 WO2007138242A1 (fr) 2006-05-30 2007-03-21 Dérivés de biphényle et leur utilisation pour le traitement de l'hépatite c

Publications (1)

Publication Number Publication Date
EP2038253A1 true EP2038253A1 (fr) 2009-03-25

Family

ID=40134112

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07712949A Withdrawn EP2038253A1 (fr) 2006-05-30 2007-03-21 Dérivés de biphényle et leur utilisation pour le traitement de l'hépatite c

Country Status (10)

Country Link
EP (1) EP2038253A1 (fr)
JP (1) JP2009538890A (fr)
KR (1) KR20090012345A (fr)
AU (1) AU2007266915A1 (fr)
BR (1) BRPI0712806A2 (fr)
CA (1) CA2653924A1 (fr)
IL (1) IL195198A0 (fr)
MX (1) MX2008014990A (fr)
NO (1) NO20085034L (fr)
WO (1) WO2007138242A1 (fr)

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ566276A (en) 2005-09-16 2011-03-31 Arrow Therapeutics Ltd Biphenyl derivatives and their use in treating hepatitis C
US8303944B2 (en) 2006-08-11 2012-11-06 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7745636B2 (en) 2006-08-11 2010-06-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7759495B2 (en) 2006-08-11 2010-07-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7659270B2 (en) 2006-08-11 2010-02-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8329159B2 (en) 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7741347B2 (en) 2007-05-17 2010-06-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7728027B2 (en) 2007-08-08 2010-06-01 Bristol-Myers Squibb Company Process for synthesizing compounds useful for treating hepatitis C
US8629171B2 (en) 2007-08-08 2014-01-14 Bristol-Myers Squibb Company Crystalline form of methyl ((1S)-1-((25)-2-(5-(4'-(2-((25)-1((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt
BRPI0722228A2 (pt) * 2007-11-19 2014-06-03 Rx Networks Inc Métodos de gnss ou gps distribuído de propagação e modelagem de órbita
KR20100123717A (ko) 2008-02-12 2010-11-24 브리스톨-마이어스 스큅 컴퍼니 Ｃ형 간염 바이러스 억제제로서의 헤테로시클릭 유도체
US8147818B2 (en) 2008-02-13 2012-04-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7704992B2 (en) 2008-02-13 2010-04-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7906655B2 (en) 2008-08-07 2011-03-15 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8383094B2 (en) 2008-10-01 2013-02-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8394968B2 (en) 2009-02-17 2013-03-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
TWI438200B (zh) 2009-02-17 2014-05-21 必治妥美雅史谷比公司 Ｃ型肝炎病毒抑制劑
AU2010229975B2 (en) * 2009-03-24 2015-05-21 AbbVie Manufacturing Management Unlimited Company Process for preparing antiviral compound
US8796466B2 (en) 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
TW201038559A (en) 2009-04-09 2010-11-01 Bristol Myers Squibb Co Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8138215B2 (en) 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US20110274648A1 (en) 2009-11-11 2011-11-10 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110269956A1 (en) 2009-11-11 2011-11-03 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US20110281910A1 (en) 2009-11-12 2011-11-17 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9216952B2 (en) 2010-03-23 2015-12-22 Abbvie Inc. Process for preparing antiviral compound
CN103269586B (zh) 2010-10-26 2015-07-15 普雷西迪奥制药公司 丙型肝炎病毒抑制剂
US8552047B2 (en) 2011-02-07 2013-10-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9546160B2 (en) 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US20150023913A1 (en) 2013-07-02 2015-01-22 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
WO2017023631A1 (fr) 2015-08-06 2017-02-09 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002000606A1 (fr) * 2000-06-28 2002-01-03 Takeda Chemical Industries, Ltd. Compose biphenyle
GB0124941D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124928D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0308186D0 (en) * 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0308185D0 (en) * 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
MXPA06000915A (es) * 2003-07-25 2006-03-30 Novartis Ag Inhibidores de quinasa p-38.
TW200600492A (en) * 2004-05-18 2006-01-01 Achillion Pharmaceuticals Inc Substituted aryl acylthioureas and related compounds; inhibitors of viral replication
CA2598043A1 (fr) * 2005-02-25 2006-08-31 Rigel Pharmaceuticals, Inc. Benzisothiazoles utiles dans le traitement ou la prevention de l'infection a vhc

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007138242A1 *

Also Published As

Publication number Publication date
BRPI0712806A2 (pt) 2012-10-23
IL195198A0 (en) 2009-08-03
KR20090012345A (ko) 2009-02-03
NO20085034L (no) 2009-02-24
JP2009538890A (ja) 2009-11-12
AU2007266915A1 (en) 2007-12-06
MX2008014990A (es) 2008-12-09
CA2653924A1 (fr) 2007-12-06
WO2007138242A1 (fr) 2007-12-06

Similar Documents

Publication Publication Date Title
EP2038253A1 (fr) Dérivés de biphényle et leur utilisation pour le traitement de l'hépatite c
AU2006290442B2 (en) Biphenyl derivatives and their use in treating hepatitis C
DE69221290T2 (de) Auf aromatischen sulfonamiden basierende hydroxamsäurederivate
KR100733752B1 (ko) Ｎｐｙｙ５ 길항제
RU2198656C2 (ru) Сульфированные аминокислотные производные и содержащие их ингибиторы металлопротеиназ
DE69411176T2 (de) Amide und harnstoffderivate als 5ht1d rezeptor antagonisten
CA2436225C (fr) Derives de n-(arylsulfonyl)beta-aminoacides comportant un groupe aminomethyle substitue, leur procede de preparation et les compositions pharmaceutiques en contenant
US6683184B2 (en) Piperazine derivatives and process for the preparation thereof
CA2528093A1 (fr) Produits aryl-heteroaromatiques, compositions les contenant et utilisation
WO2007135106A1 (fr) Derives de piperidine comme inhibiteurs du virus du papillome humain
KR20040026626A (ko) 5-[비스(카르복시메틸)아미노]-3-카르복시메틸-4-시아노-2-티오펜카르복실산의 테트라에스테르의 산업적 합성 방법및 라넬산의 이가염 또는 그 수화물의 합성에의 적용
US20050014816A1 (en) Thiophene amino acid derivatives, process for preparing them and pharmaceutical compositions containing them
US2748125A (en) 1-substituted-4-sulfamylpiperazine and method of preparing the same
WO2006063294A2 (fr) Nouveaux inhibiteurs de l'histone deacetylase permettant de traiter une maladie
CA2722255A1 (fr) Inhibiteurs de serine-threonine proteine kinase ikk-.beta.
US6727266B2 (en) Substituted tryptophan derivatives
CA2441331C (fr) Derives bicycliques de guanidine et leurs utilisations therapeutiques
COSGROVE et al. Tetrazole derivatives I. Tetrazole alkamine ethers
RU2272807C2 (ru) Новые производные амидинов, их получение и их использование в качестве лекарственных средств
EP1773398A2 (fr) Nouveaux inhibiteurs sulfonamides de histone decacetylase pour le traitement de maladies
SK9842001A3 (en) ((aminoiminomethyl)amino) alkanecarboxamides and their applications in therapy
CN101506155A (zh) 联苯衍生物及其在治疗丙型肝炎中的用途
JPS61115074A (ja) ３，４‐ジアゾール誘導体、その製法、およびその化合物を含有する医薬品
BE898219A (fr) Nouveaux dérivés d'amine, leurs sels, procédé pour les préparer, et agent anti-ulcéreux les contenant.
FR2902427A1 (fr) Derives de phenylpentadienoyle

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20081230

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

17Q First examination report despatched

Effective date: 20090707

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1128689

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20100119

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1128689

Country of ref document: HK