WO2005105761A1 - Morpholinylanilinoquinazo- line derivatives for use as antiviral agents - Google Patents

Morpholinylanilinoquinazo- line derivatives for use as antiviral agents Download PDF

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WO2005105761A1
WO2005105761A1 PCT/GB2005/001598 GB2005001598W WO2005105761A1 WO 2005105761 A1 WO2005105761 A1 WO 2005105761A1 GB 2005001598 W GB2005001598 W GB 2005001598W WO 2005105761 A1 WO2005105761 A1 WO 2005105761A1
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alkyl
group
halogen
haloalkyl
hydrogen
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PCT/GB2005/001598
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French (fr)
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Keith Spencer
Helena Dennison
Neil Mathews
Michael Barnes
Surinder Chana
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Arrow Therapeutics Limited
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Priority claimed from GB0409494A external-priority patent/GB0409494D0/en
Priority claimed from GB0425268A external-priority patent/GB0425268D0/en
Application filed by Arrow Therapeutics Limited filed Critical Arrow Therapeutics Limited
Priority to JP2007510104A priority Critical patent/JP2007534735A/en
Priority to AU2005238270A priority patent/AU2005238270A1/en
Priority to EP05738732A priority patent/EP1748991A1/en
Priority to US11/587,687 priority patent/US20080311076A1/en
Priority to CA002564175A priority patent/CA2564175A1/en
Publication of WO2005105761A1 publication Critical patent/WO2005105761A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a series of quinazoline derivatives which are useful in treating or preventing a flaviviridae infection.
  • Viruses of the family flaviviridae are small, icosahedral, enveloped viruses that contain a positive-sense RNA genome.
  • the family consists of three genera, flavivirus, pestivirus and hepacivirus.
  • Many of the flaviviridae viruses are important human pathogens. Indeed, the hepacivirus genus includes the hepatitis C virus.
  • WO 98/02434 discloses quinazolines as protein tyrosine kinase inhibitors.
  • Ri represents hydrogen, halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C 1 -C 4 haloalkoxy, -COaR.', -CONR , -A, -A-L-A', -Z-L-A or -A-L-Z-L-A, wherein R and R ; are the same or different and each represent hydrogen or C ⁇ -C 4 alkyl; R 2 represents hydrogen, halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C alkoxy or C ⁇ -C 4 haloalkoxy; R 3 represents hydrogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, -C 4 alkoxy or C ⁇ -C 4 haloalkoxy; and represents hydrogen, Ci-C ⁇ alkyl or C ⁇ -C 6 haloalkyl, wherein: - A represents a
  • X is -S-, -O- or -NR / - wherein R 7 is as defined above, L ; is a direct bond or a C ⁇ -C 4 alkylene group and Y is hydrogen, -COR / , -CO 2 R / , -S(O) 2 R/ or -S(O)R/, wherein R/ is hydrogen or C,-C 4 alkyl.
  • orientation of the Z moiety is such that the left hand side of the depicted groups is attached to the quinazoline group or to the -A-L- moiety.
  • the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I),
  • R] represents hydrogen, halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy, -A or -A-L-A 7 and R 2 represents hydrogen, halogen, C ⁇ -C 4 alkyl, Cp C 4 haloalkyl, C ⁇ -C 4 alkoxy or C ⁇ -C 4 haloalkoxy, wherein: A represents a C 6 to Cio aryl, 5- to 10- membered heteroaryl or 5- to 10- membered heterocyclyl group; L is a direct bond or a C ⁇ -C alkylene group; and A ; is a 5- to 10- membered heteroaryl or heterocyclyl group, the aryl, heteroaryl and heterocyclyl moieties in Ri being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C C 4 alkyl, C ⁇ -C 4 haloalkyl
  • the aryl, heteroaryl and heterocyclyl moieties in Ri in the formula (I) are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C ⁇ -C 4 alkyl, -C 4 haloalkyl, C ⁇ -C 4 haloalkoxy, hydroxy, thiol, -NH 2 , -C hydroxyalkyl, C C 4 thioalkyl, C r C 4 aminoalkyl, cyano, nitro, -COR 7 , -CO 2 R ; , -CONR'R 7 and -L'-X-l/'- Y substituents, wherein each R' and R ; is the same or different and is selected from hydrogen and C ⁇ -C 4 alkyl, l!
  • a C ⁇ -C 6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms.
  • a C ⁇ -C 6 alkyl group or moiety is a C ⁇ -C alkyl group or moiety.
  • a C ⁇ -C 4 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 4 carbon atoms.
  • Examples of Ci- C 6 alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and 3 -methyl-butyl.
  • C ⁇ -C 4 alkyl groups and moieties examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
  • the alkyl moieties may be the same or different.
  • a Cj-C 4 alkylene group or moiety is a linear or branched alkylene group or moiety. Examples include methylene, ethylene and n-propylene groups and moieties.
  • a C ⁇ -Cio aryl group or moiety is phenyl or naphthyl.
  • a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine.
  • a C ⁇ -C 4 alkoxy group is typically a said C ⁇ -C 4 alkyl group attached to an oxygen atom.
  • a haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX 3 and -OCX 3 wherein X is a said halogen atom, for example chlorine and fluorine.
  • Particularly preferred haloalkyl groups are -CF 3 and -CC1 3 .
  • Particularly preferred haloalkoxy groups are -OCF 3 and
  • a Cj-C 4 hydroxyalkyl group is a C]-C alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group.
  • a preferred hydroxyalkyl group is -CH 2 -OH.
  • a C ⁇ -C 4 thioalkyl group is a -C 4 alkyl group substituted by one or more thio groups (-SH). Typically, it is substituted by one, two or three thio groups. Preferably, it is substituted by a single thio group.
  • C ⁇ -C 4 aminoalkyl group is a C]-C 4 alkyl group substituted by one or more -NH 2 groups. Typically, it is substituted by one, two or three -NH 2 groups. Preferably, it is substituted by a single -NH 2 group.
  • a 5- to 10- membered heteroaryl group or moiety is a monocyclic 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N.
  • Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridazolyl and pyrazolyl groups.
  • Preferred examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl and pyrazolyl groups.
  • Furanyl, thienyl, pyridazolyl, pyrazolyl, pyrimidinyl and thiazolyl groups are preferred.
  • Furanyl, thienyl, pyrimidinyl and thiazolyl groups are further preferred.
  • a 5- to 10- membered heterocyclyl group or moiety is a monocyclic non-aromatic, saturated or unsaturated C5-C 1 0 carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O) 2 . Typically, it is a 5- to 6- membered ring.
  • Suitable heterocyclyl groups and moieties include pyrazolidinyl, piperidyl, piperazinyl, thiomo ⁇ holinyl, S-oxo-thiomo ⁇ holinyl, S,S-dioxo-thiomo ⁇ holinyl, mo ⁇ holinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, 1,3-dioxolanyl, 1,4- dioxolyl and pyrazolinyl groups and moieties.
  • Piperazinyl, thiomo ⁇ holinyl, S,S- dioxothiomorpholinyl, mo ⁇ holinyl and 1,3-dioxolanyl groups and moieties are preferred.
  • the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C ⁇ -C 4 alkyl, C 1 -C haloalkyl, Cj-C haloalkoxy, C ⁇ -C 4 hydroxyalkyl, cyano, -COR ; , -CO 2 R / , -S(O)R 7 , -S(O) 2 R ; and -iZ-X-l/'-Y substituents, wherein R.', L ; , X, l," and Y are as defined above.
  • L is a direct bond or a Cj-C 2 alkylene group
  • L / is a direct bond or a C ⁇ -C 2 alkylene group, preferably a C]-C 2 alkylene group.
  • Y is hydrogen, -COR / , -CO 2 R / , -S(O) 2 R / or -S(O)R / , wherein R / is a C ⁇ -C 4 alkyl group.
  • Y is hydrogen, -COR /, -S(O) 2 R / or -S(O)R / , wherein R, is a C]-C alkyl group.
  • the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted with 1 or 2 substituents selected from halogen, C ⁇ -C 2 alkyl, C r C 2 haloalkyl, C,-C 2 hydroxyalkyl, cyano, -COR, -CO ⁇ , -S(O)R 7 , -S(O) 2 R / , - (C,-C 2 alky -NR ⁇ , C C 2 alkoxy, -NR'-COR / , NR'-CO ⁇ R/, -(C ⁇ -C 2 alky -NR'-CO ⁇ / , -NR / -S(O) 2 -R / and -(C r C 2 alkyl)-NR-(C C 2 alkyl)-S(O) 2 -R ;/ substituents, wherein each R', R ;/ and R / are the same or different
  • the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I) and, typically, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C ⁇ -C 4 alkyl, C]-C 4 haloalkyl, C ⁇ -C 4 haloalkoxy, C ⁇ -C 4 hydroxyalkyl, -COR'', - CO 2 R ; , -S ⁇ R, -SO-W and -L y -X-L ;/ -Y substituents, wherein R, L 7 , X, " and Y are as defined above.
  • the aryl, heteroaryl and heterocyclyl moieties in the Rj substituent are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 haloalkoxy, C ⁇ -C 4 hydroxyalkyl, -COR and -L'-X-L ⁇ -Y substituents, wherein R', L 1 , X, L 7/ and Y are as defined above.
  • the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cj-C 2 alkyl, C ⁇ -C 2 alkoxy, C C 2 haloalkyl, C C 2 hydroxyalkyl, -COR, -CO 2 R ; , -S(O)R ; , -S(O) 2 R / , - (C,-C 2 alky -NRV and -(C,-C 2 alky -NR ⁇ Q-Cz alkyl)-S(O) 2 -R ;/ substituents, wherein each R and R ; are the same or different and represent hydrogen or C ⁇ -C 2 alkyl.
  • the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted with 1 or 2 substituents selected from halogen, C ⁇ -C 2 alkyl, C C 2 haloalkyl, d-C 2 hydroxyalkyl, -COR', -(C,-C 2 alky ⁇ -NR ⁇ and -(C C 2 alkyl)-NR-(C ) -C 2 alkyl)-S(O) 2 -R ;/ substituents, wherein each R 1 and R ; are the same or different and represent hydrogen or C ⁇ -C 2 alkyl.
  • A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
  • A is a phenyl or 5- to 6- membered heteroaryl group.
  • A is a phenyl, furanyl, thienyl, pyrimidinyl, thiazolyl or pyridazolyl group.
  • A is a phenyl, furanyl, thienyl, pyrimidinyl or thiazolyl group.
  • A is a phenyl, furanyl, thienyl or thiazolyl group.
  • L is a direct bond or a C ⁇ -C 2 alkylene group.
  • A is a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
  • ! is a 5- to 6- membered heteroaryl group it is a pyrazolyl group.
  • a ; is a 5- to 6- membered heterocyclyl or heteroaryl group, which group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl and C ⁇ -C 4 haloalkoxy substituents.
  • A is a mo ⁇ holinyl, thiomorpholinyl, piperazinyl, 1,3-dioxolanyl, S,S- dioxothiomo ⁇ holino or pyrazolyl group which is unsubstituted or substituted by one or two substituents selected from C]-C 2 alkyl, halogen and Cj-C 2 haloalkyl groups.
  • the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I) and, preferably A is a 5- to 6- membered heterocyclyl group.
  • A' is a 5- to 6- membered heterocyclyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, C]-C 4 alkyl, C ⁇ -C 4 haloalkyl and -C 4 haloalkoxy substituents.
  • A is a morpholinyl, thiomo ⁇ holinyl, piperazinyl, 1,3-dioxoanyl or S,S-dioxothiomo ⁇ holino group which is unsubstituted or substituted by one or two substituents selected from C ⁇ -C 2 alkyl, halogen and C ⁇ -C 2 haloalkyl groups.
  • Z is -O-, -CONR -, -NR / C(O)- or -NRCO 2 -, wherein R'is as defined above.
  • Z is -O-, -CONH-, -CON(d-C 2 alkyl)-, -NHC(O)- or -NHCO 2 -.
  • Ri is halogen, C ⁇ -C 4 alkyl, C ⁇ -C haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy, -CO 2 R 7 , -CONR'R , -A, -A-L-A , -Z-L-A, or -A-L-Z-L-A wherein R ; , R y , A, L, A ; and Z are as defined above.
  • Ri is halogen, C ⁇ -C 2 alkoxy, C ⁇ -C 2 haloalkoxy, -CONR , -A, -Ar-L-A', -Z-L-A or -Ar-Z-L-Ar, wherein R ; and R 7/ are the same or different and each represent hydrogen or a C ⁇ -C 2 alkyl group, A and A are as defined above, Ar is an unsubstituted furanyl or unsubstituted phenyl group, L is a direct bond or a methylene group and Z is -O-, -C ⁇ NR -, -NR ; C(O)- or -NR ; CO 2 -, wherein R ; is as defined above.
  • the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I) and, typically, Ri is halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, Ci- C 4 alkoxy, d-C 4 haloalkoxy, -A or -A-L-A ; , wherein A, L and A f are as defined above.
  • Ri is halogen, C ⁇ -C 2 alkoxy, C ⁇ -C 2 haloalkoxy, -A or -Ar-L- A! wherein A and A 1 are as defined above, Ar is an unsubstituted furanyl group and L is a direct bond or a methylene group.
  • R 2 is hydrogen, C ⁇ -C 4 alkyl or C ⁇ -C 4 alkoxy.
  • R 2 is hydrogen or C ⁇ -C 2 alkoxy.
  • R 3 is hydrogen, Q-C 2 alkyl, C]-C 2 haloalkyl or C]-C 2 alkoxy.
  • R 3 is hydrogen, methyl, trifluoromethyl or methoxy.
  • 1 ⁇ is hydrogen or Ci-C ⁇ alkyl.
  • Preferred compounds of the invention are those in which: Ri is halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkyl, C ⁇ -C 4 alkoxy, Q-C 4 haloalkoxy, -COsR', -CONR R , -A, -A-L-A', -Z-L-A, or -A-L-Z-L-A;
  • R 2 is hydrogen, C ⁇ -C 4 alkyl or C ⁇ -C 4 alkoxy;
  • R 3 is hydrogen, C ⁇ -C 2 alkyl, C ⁇ -C 2 haloalkyl or CpC 2 alkoxy;
  • R- is hydrogen or C ⁇ -C 6 alkyl;
  • A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group;
  • quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, C C 4 alkyl, C ⁇ -C 4 haloalkyl, C]-C alkoxy, C ⁇ -C 4 haloalkoxy, -A or -A-L-A'; R 2 is hydrogen, C ⁇ -C 4 alkyl or d-C 4 alkoxy; - A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group; L is a direct bond or a C ⁇ -C 4 alkylene group; and A 1 is a 5- to 6- membered heteroaryl or heterocyclyl group, the aryl, heteroaryl and heterocyclyl moieties in the ⁇ substituent being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C ⁇ -C 4 alkyl, C,-C 4 halo
  • quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, C ⁇ -C 4 alkyl, C]-C 4 haloalkyl, C ⁇ -C 4 alkoxy, C ⁇ -C 4 haloalkoxy, -A or -A-L-A 7 ; R 2 is hydrogen, C ⁇ -C 4 alkyl or C)-C 4 alkoxy; - A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group; L is a direct bond or a C ⁇ -C 4 alkylene group; and A is a 5- to 6- membered heteroaryl or heterocyclyl group, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C ⁇ -C 4 alkyl, C ⁇ -C 4 haloalkoxy, -A or
  • Ri is halogen, d-C 2 alkoxy, d-C 2 haloalkoxy, -CONRR 77 , -A, -Ar-L-A 7 , -Z-L- A, or -Ar-Z-L-Ar, wherein R 7 and R 7 are the same or different and each represent hydrogen or a Cj-C 2 alkyl group; R 2 is hydrogen or C]-C 2 alkoxy; A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl, pyrimidinyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, C ⁇ -C 2 alkyl, C ⁇ -C 2 haloalkyl, C C 2 hydroxyalkyl, cyano, -COR 7 , -CO 2 R 7 , -S(O)R 7 ,
  • quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, C ⁇ -C 2 alkoxy, C ⁇ -C 2 haloalkoxy, -A or -Ar-L-A ; - R 2 is hydrogen or Cj-C 2 alkoxy; A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl, pyrimidinyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, C ⁇ -C 2 alkyl, C ⁇ -C 2 alkoxy, C ⁇ -C 2 haloalkyl, C C 2 hydroxyalkyl, -COR 7 , -CO R 7 , -S(O)R 7 , -S(O) 2 R 7 , -(C r C 2 alkyl)-NRR 77
  • quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, C ⁇ -C 2 alkoxy, C C 2 haloalkoxy, -A or -Ar-L-A 7 ; R 2 is hydrogen or C ⁇ -C 2 alkoxy; A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, C ⁇ -C 2 alkyl, C ⁇ -C 2 haloalkyl, C ⁇ -C 2 hydroxyalkyl, -COR 7 , -(C]-C 2 alkyl)-NRR 77 and -(C ⁇ -C 2 alkyl)-NR 7 -(C,-C 2 alkyl)-S(O) 2 -R 77 substituents, wherein: Ri is halogen, C ⁇ -
  • Particularly preferred compounds of formula (la) include: (6-bromo-quinazolin-4-yl)-(4-mo ⁇ holin-4-yl-phenyl)-amine; (6-iodo-quinazolin-4-yl)-(4-mo ⁇ holin-4-yl-phenyl)-amine; (6,7-dimethoxy-quinazolin-4-yl)-(4-mo ⁇ holin-4-yl-phenyl)-amine;
  • Compounds of formula (la) 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 (la) can, if desired, be used in the form of solvates.
  • 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.
  • Scheme l is represented by Scheme 1.
  • the reaction is performed under palladium catalysis (eg 20mol% tris (dibenzylideneacetone)dipalladium (II) or 20mol% dichlorobis (triphenylphosphine)palladium (0)) in the presence of an organic base (eg triethylamine) or an inorganic base (eg sodium carbonate or potassium phosphate).
  • an organic base eg triethylamine
  • an inorganic base eg sodium carbonate or potassium phosphate.
  • additional additives may be beneficial eg lithium chloride, silver oxide and conveniently the reaction is performed in toluene and at reflux temperature.
  • reagent (V) is a boronic acid derivative
  • reagent (V) is a boronic acid derivative
  • one skilled in the art will recognise the reaction as an example of a Suzuki-Miyaura coupling which may be conveniently performed at 60°C in tetrahydrofuran.
  • the conversion of compounds of formula (III) to compounds of formula (Ila) and (II), respectively is accomplished by converting the 4- hydroxy group of compounds of formula (III) to a suitable leaving group eg chloro using a reagent such as thionyl chloride as solvent with the addition of a catalytic activator eg dimethylformamide, and subsequent reaction with 4-morpholinoaniline in a suitable solvent eg acetonitrile.
  • a suitable leaving group eg chloro
  • a catalytic activator eg dimethylformamide
  • the compounds of the present invention are therapeutically useful.
  • the present invention therefore provides a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof, for use in treating the human or animal body.
  • a pharmaceutical composition comprising a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • 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 provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
  • the compounds of the invention are active against a flaviviridae infection.
  • the present invention therefore provides the use of a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing a flaviviridae infection.
  • a method for treating a patient suffering from or susceptible to a flaviviridae infection which method comprises administering to said patient an effective amount of a quinazoline derivative of formula (la) or a pharmaceutically acceptable salt thereof.
  • the flaviviridae family contains three genera. These are hepacivirus, flavivirus and pesti virus.
  • the compounds of the invention are active in treating or preventing a hepacivirus infection, a flavivirus infection or a pestivirus infection.
  • Typical pestivirus infections which can be treated with the compounds of the invention include bovine viral diarrhea virus, classical swine fever virus and border disease virus.
  • Typical flavivirus infections which can be treated with the compounds of the invention include yellow fever virus, dengue fever virus, Japanese encephalitis virus and tick borne encephalitis virus.
  • Typical hepacivirus infections that can be treated with the compounds of the invention include hepatitis C virus.
  • Compounds of the present invention are especially active against hepatitis C. Typically, said flavivirus is therefore hepatitis C virus.
  • 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.
  • 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.
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone
  • disaggregating agents e.g. starch, alginic acid, alginates or sodium starch glycolate
  • dyestuffs effervescing mixtures
  • sweeteners effervesc
  • 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, and derivatives thereof, which are known for the treatment of hepatitis C (Clinical Microbiology Reviews, Jan. 2000, 67-82).
  • the said medicament therefore typically further comprises interferon or a derivative thereof and/or ribavirin or a derivative thereof.
  • the present invention provides a pharmaceutical composition comprising:
  • interferon or a derivative thereof and/or ribavirin or a derivative thereof for separate, simultaneous or sequential use in the treatment of the human or animal body.
  • a preferred interferon derivative is PEG-interferon.
  • a preferred ribavirin derivative is viramidine.
  • 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, The following Examples illustrate the invention.
  • Example 1 (6-Bromo-quinazolin-4-yI)-(4-morpholin-4-yl-phenyI)-amine 5-Bromo-2-aminobenzoic acid (5g, 23.1mmol) was suspended in formamide (5eq) and heated to 155°C under N 2 for 16h. The mixture was allowed to cool and added to water. The resulting precipitate was isolated by filtration and dried to give an intermediate 6-bromoquinazolin-4-ol. A portion of this material (lg) was dissolved in thionyl chloride (10ml) and DMF (0.3ml) added before being refluxed for 5h.
  • Example 5 (6-Furan-2-yl-quinazolin-4-yI)-(4-morpholin-4-yl-phenyl)-amine (6-Iodo-quinazoline-4-yl)-(4-mo ⁇ holin-4-yl-phenyl)-amine (Example 2,
  • Example 9 (6- ⁇ 5-[(2-MethanesuIfonyl-ethylamino)-methyI]-furan-2-yl ⁇ - quinazolin-4-yI)-(4-morphoIin-4-yl-phenyI)-amine
  • Example 7 The carboxaldehyde of Example 7 (150mg) was treated with 2- methanesulfonylethylamine (46mg, prepared by the route in Bioorganic & Medicinal Chemistry Letters 14, 1, , pi 11-114 Yue-Mei Zhang et al) and 5A molecular sieves (300mg) at 40° in CH 2 C1 2 (15ml) for 5hr. Acetic acid (2ml) and sodium triacetoxyborohydride (139mg, 2eq) added and stirred overnight at room temperature. The mixture was concentrated to dryness and purified by suction chromatography to give the title compound (70mg)
  • Example 11 ⁇ 6-[5-(4-Methyl-piperazin-l-ylmethyI)-furan-2-yl]-quinazolin-4-yl ⁇ - (4-morpholin-4-yl-phenyI)-amine
  • the title compound was obtained as a yellow solid
  • Example 23 (4-Morpholin-4-yI ⁇ phenyI)-[6-(3-pyrazol-l-yl-phenyl)-quinazoIin-4- yl]-amine
  • Example 24 4-[4-(4-Morpholin-4-yl-phenylamino)-quinazoIin-6-yI]-benzonitrile
  • Example 25 Furan-2-carboxylic acid [4-(4-morpholin-4-yI-phenyIamino)- quinazolin-6-yl]-amide
  • Step 1 (4-Morpholin-4-yl-phenyl)-(6-nitro-quinazolin-4-yl)-amine (prepared by the method of Example 1, 3.60 LC-MS ES+ 352 ES- 350, 0.5g) was added to a stirred solution of THF:MeOH (1:1, 25ml) followed by Raney nickel (2 spatula, excess). The mixture was heated to 50°C at which stage hydrazine (1ml) was added and left to stir for 5 hr at this temperature. The mixture was allowed to cool and filtered through celite.
  • Step 2 To a portion of the amine (50mg) in pyridine (4ml) was added 2-furoyl chloride ( 0.033g, 1.2eq) and stirred for 4h. The pyridine was removed in vacuo and the residue purified by chromatography to give the title compound ⁇ (DMSO) 8.77 (IH, s); 8.43 (IH, s); 8.01 (IH, d, J8.5Hz); 7.97 (IH, s); 7.72 (IH, d, J8.85Hz); 7.64 (2H, d, J8.85Hz); 7.42 (IH, d, J3.16Hz); 6.96 (2H, d, J8.85Hz); 6.73 (IH, m); 3.75 (4H, m); 3.08 (4H, m), LC-MS m/z 416 rt 2.22
  • Example 26 4-(4-Morpholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid 4- methoxy-benzylamide
  • Step 1 Preparation of 4-(4 ⁇ mo ⁇ holin-4-yl-phenylamino)-quinazoline-6- carboxylic acid A solution of Example 2 (2.0g, 4.6mMol), potassium carbonate (1.4g,
  • Example 27 3- ⁇ [4-(4-Morpholin-4-yl-phenylamino)-quinazoline-6-carbonyI]- amino ⁇ -benzoic acid ethyl ester ⁇ (DMSO) 10.68 (IH, s); 10.00 (IH, s); 9.13 (IH, s); 8.57 (IH, s); 8.47 (IH, s); 8.30 (IH, dd, J 8.8Hz, 1.3Hz); 8.13 (IH, d, J 8.2Hz); 7.84 (IH, d, J 8.8Hz); 7.72 (IH, d, J 8.2Hz); 7.67 (2H, d, J 8.8Hz); 7.50-7.59 (IH, m); 6.99 (2H, d, J 8.8Hz); 4.33 (2H, q, J 7.2Hz); 3.75 (4H, t, J 4.4Hz); 3.10 (4H, t, J 4.4Hz), 1.33 (3H, t, J 6.9Hz),
  • Example 28 4-(4-Morpholin-4-yI-phenyIamino)-quinazoline-6-carboxylic acid 3- methoxy-benzylamide ⁇ (DMSO) 9.75 (lH,s); 8.93 (IH, t, J 5.7Hz); 8.85 (IH, s); 8.35 (IH, s); 8.05 (IH, d, J 8.2Hz); 7.76 (IH, s); 7.60 (IH, d, J 8.2Hz); 7.46 (2H, d, J 8.2Hz); 7.07 (IH, t, J 7.6Hz); 6.72-6.82 (3H, m); 6.63 (IH, d, J 8.8Hz); 4.34 (2H, d, J 5.1Hz); 3.11-3.17 (7H, m); 2.87-2.94 (3H, m), LC-MS m/z 470 rt 2.48
  • Example 29 4-(4-Morpholin-4-yl-phenyIamino)-quinazoline-6-carboxylic acid 4- methyl-benzylamide ⁇ (DMSO) 10.14 (IH, s); 9.30 (IH, t, J 6.1Hz); 9.24 (IH, s); 8.76 (IH, s); 8.44 (IH, dd,
  • Example 31 4-(4-Morpholin-4-yl-phenyIammo)-quinazoIine-6-carboxyIic acid dimethylamide ⁇ (DMSO) 9.60 (IH, s); 8.43 (IH, s); 8.35 (IH, s); 7.63 (IH, dd, J 8.2Hz, 1.3Hz); 7.57 (2H, d, J 8.8Hz); 6.79 (2H, d, J 8.8Hz); 3.53-3.59 (4H, m); 2.89-2.94 (4H, m); 2.86 (3H, s); 2.79 (3H, s), LC-MS rt 2.09, m/z 378
  • Example 32 4-(4-Morpholin-4-yl-phenylamino)-quinazolme-6-carboxyIic acid ethylamide ⁇ (DMSO) 9.96 (IH, s); 9.01 (IH, s); 8.63 (IH, t, J 5.4Hz); 8.57 (IH, s); 8.21
  • Example 34 ⁇ 4-[4-(4-Morpholin-4-yI-phenylamino)-quinazolin-6-yl]-phenyI ⁇ - carbamic acid benzyl ester
  • ⁇ (DMSO) 3.10-3.14 (t,2H), 3.75-3.93 (t, 2H)
  • Example 36 ⁇ 4-[4-(4-Morpholin-4-yI-phenyIamino)-quinazolin-6-yI]-phenyI ⁇ - carbamic acid tert-butyl ester
  • Example 37 ⁇ 3-[4-(4-Morpholin-4-yl-phenyIamino)-quinazoIin-6-yl]-benzyI ⁇ - carbamic acid tert-butyl ester
  • Example 38 N- ⁇ 3-[4-(4-Morpholin-4-yl-phenyIamino)-quinazolin-6-yI]-phenyl ⁇ - methanesulfonamide
  • Example 39 (6-Iodo-quinazolin-4-yl)-(4-morphoIin-4-yl-2-trifluoromethyl-phenyI)- amine
  • Step 1 A solution of 5-fluoro-2-nitrobenzotrifluoride (2.1g, lOmM) and triethylamine (2.50ml, 24mMol) in acetonitrile (35ml) was treated with mo ⁇ holine (1.74ml, 20mMol). The resulting solution was heated at reflux overnight. On cooling, the reaction solvent was removed under vacuum and the crude residue partitioned between dichloromethane and 10% (w/v) citric acid solution.
  • Step 3 Treatment of the product from step 2 ( 280mg) with 4-chloro-6-iodo- quinazoline (300mg, l.lmMol) in acetonitrile (4ml) at reflux overnight, gave a precipitate.
  • Example 40 (4-Morpholin-4-yl-2-trifluoromethyl-phenyI)-(6-thiophen-2-yI- quinazolin-4-yI)-amme
  • a solution of Example 39 (170mg, 0.4mMol), 2-thiopheneboronic acid (50mg, 0.4mMol), triethylamine (120 ⁇ l, l.OmMol) and tris(dibenzylideneacetone)- dipalladium(O) (50mg, 15Mol%) in anhydrous tetrahydrofuran (3ml) was heated at reflux overnight.
  • Step 2 Hydrogenation of the nitro group using palladium on carbon as catalyst at rt in ethanol gave 3-methoxy-4-mo ⁇ holin-4-yl-phenylamine as a brown solid (76%,
  • Step 3 Heating of 3-methoxy-4-mo ⁇ holin-4-yl-phenylamine (136mg ) and 4- chloro-6-iodoquinazoline (186mg) in acetonitrile (10ml) at reflux overnight gave, on cooling, a precipitate that was isolated by filtration, washed with water then slurried with IN NaOH and washed with further water and dried. This gave the title compound
  • Example 42 (3-Methoxy-4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl-quinazolin-4- yl)-amine
  • a similar method to Example 15, using Example 41 as starting material gave the title compound ( 14mg, 11%) ⁇ (DMSO) 9.96 (IH, s); 8.86 (IH, s); 8.61 (IH, s); 8.22 (IH, d, J8.85Hz); 7.87 (IH, d, J8.85Hz); 7.83 (IH, d, J3.79Hz); 7.76 (IH, d, J5.06Hz); 7.48 (2H, m); 7.33 (IH, t J5.05,3.79Hz); 7.03 (IH, d, J8.85Hz); 3.92 (3H, s); 3.84 (4H, m); 3.07 (4H, m), LC- MS rt 3.63, m/z E+419
  • Example 43 (2-Methyl-4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl-quinazolin-4- yl)-amine Step 1: A solution of 5-fluoro-2-nitrotoluene (1.22ml, lOmM) and triethylamine
  • Step2 A suspension of 4-(3-methyl-4-nitrophenyl)-mo ⁇ holine 1.96g, (8.9mMol) and 10% palladium on carbon (lOOmg) in toluene (30ml) was placed under an atmosphere of hydrogen, using standard procedures, until reaction was complete. The reaction mixture was filtered through celite and the liquors reduced under vacuum to give 2-methyl-4-mo ⁇ holin-4-yl-phenylamine as a dark brown solid.
  • reaction solvent was reduced under vacuum and the residue taken into morpholine. This solution was heated at 100°C until the reaction was complete by TLC.
  • the reaction mixture was diluted with dichloromethane and washed with IM citric acid solution. The organics were dried over magnesium sulphate and reduced under vacuum to give an oil. This was further purified by flash chromatography (eluting with a petrol - 9:1 petrol : ethyl acetate gradient) to give 4-(2- methyl-4-nitro-phenyl)-mo ⁇ holine as an orange solid.
  • Step 2 A suspension of 4-(2-methyl-4-nitro-phenyl)-morpholine (0.53g, 2.4mMol) and 10% palladium on carbon (55mg) in 1:1 toluene : ethanol (25ml) was placed under an atmosphere of hydrogen, using standard procedures, until reaction was complete.
  • Step 3 A suspension of 4-chloro-6-iodo-quinazoline (300mg) and 3-methyl-4- mo ⁇ holin-4-yl-phenylamine (240mg) in acetonitrile (4ml) was heated at reflux overnight, during which a precipitate developed. The reaction was cooled and the precipitate filtered off. This was washed with IM sodium hydroxide solution and water before being air dried to give (6-iodo-quinazolin-4-yl)-(3-methyl-4-mo ⁇ holin-4-yl- phenyl)-amine.
  • Example 45 Ethyl-(4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl-quinazolin-4-yI)- amine
  • Step 1 To a stirred solution of dry DMF (10ml) was added N-(4- aminophenyl)morpholine (0.5g, 2.80mmol) followed by Et 3 N (0.70g, 7.0mmol) . Acetyl chloride (0.24g, 3.10mmol) was added slowly and the mixture stirred at room temperature overnight. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2 x 20 ml).
  • Example 46 (6-Iodo-quinazolin-4-yI)-methyl-(4-morpholin-4-yl-phenyl)-amine Step 1 : Formic acid ( 0.41g) was added to acetic anhydride (0.75g) with stirring at 0° then heated to 50° for 2h. The cooled mixture was diluted with dry THF ( 5ml) and 4-mo ⁇ holinoaniline (0.5g) added and the mixture returned to for 3h.
  • Step 3 Heating of methyl-(4-mo ⁇ holin-4-yl-phenyl)-amine (37mg ) and 4- chloro-6-iodoquinazoline (52mg) in acetonitrile (6ml) at reflux overnight gave, on cooling, a precipitate that was isolated by filtration, washed with water then slurried with IN NaOH and washed with further water and dried. This gave the title compound
  • Example 47 (6-Iodo-quinazolin-4-yl)-(3-methyl-butyl)-(4-morpholin-4-yl-phenyl)- amine
  • Step 1 To a carousel tube was added N-(4-aminophenyl)mo ⁇ holine (0.25g, 1.40mmol).
  • DCM DCM (DRY 15ml), molecular sieve 3A ( excess 0.2g) and 3-methyl- butylaldehyde (0.14g, 1.4mmol). The mixture was stirred for 1 hr at room temperature and then at 45°C for 2 hr.
  • Example 48 Isopropyl-(4-morpholin-4-yI-phenyl)-(6-thiophen-2-yl-quinazolin-4- yl)-amine
  • step 4 the title compound (4.5mg) ⁇ (DMSO) 8.61 (IH, s); 7.90 (IH, d, J7.58Hz); 7.67 (IH, d, J8.85Hz); 7.51 (IH, d, J4.42Hz); 7.09 (7H, m); 5.51 (IH, m); 3.77 (4H, m); 3.23 (4H, m); 1.18 (6H, d, J6.32Hz) , LC-MS rt 2.74, m/z E+431
  • Example 49 (3-Methyl-butyl)-(4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl- quinazolin-4-yl)-amine
  • a similar method to Example 44 step 4 was obtained the title compound (12.5mg) ⁇ (DMSO) 8.63 (IH, ); 8.21 (IH, s); 7.94 (IH d, J8.85Hz); 7.72 (2H, m); 7.52 (IH, d, J5.06Hz); 7.12 (5H, m); 4.13 (2H, m); 3.78 (4H, m); 3.20 (4H, m); 3.0 (3H, m); 1.15 (6H, t, J7.58Hz) , LC- MS rt 2.98, m/z E+459
  • Example 50 [6-(2-Benzyloxy-phenyl)-quinazolin-4-yI]-(4-morpholin-4-yl-phenyI)- amine
  • Example 50 [6-(2-Benzyloxy-phenyl)-quinazolin-4-yI]-(4-morpholin-4-yl-phenyI)- amine
  • Example 51 [6-(4-Benzyloxy-phenyI)-quinazoIin-4-yI]-(4-morpholin-4-yl-phenyl)- amine
  • 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.
  • Cell culture conditions Cells were cultured at 37°C in a 5% CO 2 environment and split twice a week on seeding at 2 x 10E6 cells/flask on day 1 and 1 x 10E6 3 days later. Some 0.25mg/ml G418 was added to the culture medium (125ul per 25ml) but not the assay medium.
  • the culture medium consisted of DMEM with 4500g/l glucose and glutamax
  • Assay procedure A flask of cells was trypsinised and a cell count carried out. Cells were diluted to 100,000 cells/ml and 100 ⁇ l of this used to seed one opaque white 96-well plate (for the replicon assay) and one flat-bottomed clear plate (for the tox assay) for every seven compounds to be tested for IC50. Wells G12 and H12 were left empty in the clear plate as the blank. Plates were then incubated at 37°C in a 5% CO 2 environment for 24 h.
  • the M injector of the microplate luminometer (Lmax, Molecular Devices) was primed with 4 x 300 1 injections. Plate were 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 IC50 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 RT for lh, followed by solvation of the absorbed methylene blue in 100 ⁇ 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 620nm vs drug concentration.

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Abstract

Compounds of formula (Ia) are found to be active in inhibiting replication of flaviviridae viruses, wherein R1, R2, R3 and R4 are as defined in the claims.

Description

ILIN UINAZ LINE DERIVATIVE F R U E AS ANTIVIRAL AGENTS
The present invention relates to a series of quinazoline derivatives which are useful in treating or preventing a flaviviridae infection. Viruses of the family flaviviridae are small, icosahedral, enveloped viruses that contain a positive-sense RNA genome. The family consists of three genera, flavivirus, pestivirus and hepacivirus. Many of the flaviviridae viruses are important human pathogens. Indeed, the hepacivirus genus includes the hepatitis C virus. However, there exists, as yet, no effective and safe treatment for flaviviridae infections. WO 98/02434 discloses quinazolines as protein tyrosine kinase inhibitors. None of the compounds specifically disclosed in that document carry a morpholino-aniline- group at the 6- position. It has now surprisingly been found that the quinazoline derivatives of the formula (la) are active in inhibiting replication of flaviviridae viruses and are therefore effective in treating or preventing a flaviviridae infection. The present invention therefore provides a quinazoline derivative of formula (la), or a pharmaceutically acceptable salt thereof,
Figure imgf000002_0001
wherein Ri represents hydrogen, halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C4 alkoxy, C1-C4 haloalkoxy, -COaR.', -CONR , -A, -A-L-A', -Z-L-A or -A-L-Z-L-A, wherein R and R; are the same or different and each represent hydrogen or Cι-C4 alkyl; R2 represents hydrogen, halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C alkoxy or Cι-C4 haloalkoxy; R3 represents hydrogen, Cι-C4 alkyl, Cι-C4 haloalkyl, -C4 alkoxy or Cι-C4 haloalkoxy; and represents hydrogen, Ci-Cβ alkyl or Cι-C6 haloalkyl, wherein: - A represents a C6 to Cι0 aryl, 5- to 10- membered heteroaryl or 5- to 10 membered heterocyclyl group; each L is the same or different and is a direct bond or a Cι-C4 alkylene group; A; is a 5- to 10- membered heteroaryl or 5- to 10- membered heterocyclyl group; and - Z is -S-, -O-, -NR'-, -CO2-, -C(O)NR;-, -OO )-, -NR;C(O)-, -OCO2-, -NR;CO2-, -OC(O)NR-J or -NR/C(O)NR//-, wherein R'and R; are the same or different and represent hydrogen or -C4 alkyl, the aryl, heteroaryl and heterocyclyl moieties in R\ being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C4 haloalkoxy, hydroxy, thiol, -NH2, -C hydroxyalkyl, Cι-C4 thioalkyl, Cι-C4 aminoalkyl, cyano, nitro, -COR7, -CO^, -S(O)R;, -S^^-CONR^7 and -L'-X-l/'-Y substituents, wherein each R and R7 is the same or different and is selected from hydrogen and Cι-C4 alkyl, l! is a direct bond or a Cι-C4 alkylene group, X is -S-, -O- or -NR/- wherein R7 is as defined above, L; is a direct bond or a Cι-C4 alkylene group and Y is hydrogen, -COR/, -CO2R/, -S(O)2R/ or -S(O)R/, wherein R/ is hydrogen or C,-C4 alkyl. For the avoidance of doubt, the orientation of the Z moiety is such that the left hand side of the depicted groups is attached to the quinazoline group or to the -A-L- moiety. Thus, for example, when Z is -C(O)NR/- and R1 is -Z-L-A, R1 is - OjNR'-L- A. In one embodiment, the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I),
Figure imgf000004_0001
wherein R] represents hydrogen, halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C4 alkoxy, Cι-C4 haloalkoxy, -A or -A-L-A7 and R2 represents hydrogen, halogen, Cι-C4 alkyl, Cp C4 haloalkyl, Cι-C4 alkoxy or Cι-C4 haloalkoxy, wherein: A represents a C6 to Cio aryl, 5- to 10- membered heteroaryl or 5- to 10- membered heterocyclyl group; L is a direct bond or a Cι-C alkylene group; and A; is a 5- to 10- membered heteroaryl or heterocyclyl group, the aryl, heteroaryl and heterocyclyl moieties in Ri being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C C4 alkyl, Cι-C4 haloalkyl, Cι-C4 haloalkoxy, hydroxy, thiol, -NH2, Cι-C4 hydroxyalkyl, Cι-C4 thioalkyl, CpC4 aminoalkyl, cyano, nitro, -COR, -CO2R;, -CONR'R , -SOR7, -S(O)2R7 and -L'-X-l/'-Y substituents, wherein each R; and R; is the same or different and is selected from hydrogen and Cι-C4 alkyl, li is a direct bond or a Cι-C4 alkylene group, X is -S-, -O- or -NR/- wherein R7 is as defined above, L; is a Cι-C4 alkylene group and Y is hydrogen, -COR/, -CO2R/, -S(O)2-R/ or -S(O)R/, wherein R/ is hydrogen or d-C alkyl. Typically, the aryl, heteroaryl and heterocyclyl moieties in Ri in the formula (I) are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, -C4 haloalkyl, Cι-C4 haloalkoxy, hydroxy, thiol, -NH2, -C hydroxyalkyl, C C4 thioalkyl, CrC4 aminoalkyl, cyano, nitro, -COR7, -CO2R;, -CONR'R7 and -L'-X-l/'- Y substituents, wherein each R' and R; is the same or different and is selected from hydrogen and Cι-C4 alkyl, l! is a direct bond or a Cι-C4 alkylene group, X is -S-, -O- or -NR;- wherein R; is as defined above, !' is a Cι-C4 alkylene group and Y is hydrogen, - COR/, -CO2R/, -S(O)2R/ or -S(O)R/, wherein R/ is hydrogen or C C alkyl. As used herein, a Cι-C6 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 6 carbon atoms. Typically a Cι-C6 alkyl group or moiety is a Cι-C alkyl group or moiety. A Cι-C4 alkyl group or moiety is a linear or branched alkyl group or moiety containing from 1 to 4 carbon atoms. Examples of Ci- C6 alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and 3 -methyl-butyl. Examples of Cι-C4 alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. For the avoidance of doubt, where two alkyl moieties are present in a group, the alkyl moieties may be the same or different. As used herein, a Cj-C4 alkylene group or moiety is a linear or branched alkylene group or moiety. Examples include methylene, ethylene and n-propylene groups and moieties. Typically, as used herein, a Cδ-Cio aryl group or moiety is phenyl or naphthyl. Phenyl is preferred. As used herein, a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine. As used herein, a Cι-C4 alkoxy group is typically a said Cι-C4 alkyl group attached to an oxygen atom. A haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX3 and -OCX3 wherein X is a said halogen atom, for example chlorine and fluorine. Particularly preferred haloalkyl groups are -CF3 and -CC13. Particularly preferred haloalkoxy groups are -OCF3 and
-OCCl3. As used herein a Cj-C4 hydroxyalkyl group is a C]-C alkyl group substituted by one or more hydroxy groups. Typically, it is substituted by one, two or three hydroxy groups. Preferably, it is substituted by a single hydroxy group. A preferred hydroxyalkyl group is -CH2-OH. As used herein, a Cι-C4 thioalkyl group is a -C4 alkyl group substituted by one or more thio groups (-SH). Typically, it is substituted by one, two or three thio groups. Preferably, it is substituted by a single thio group. As used herein, Cι-C4 aminoalkyl group is a C]-C4 alkyl group substituted by one or more -NH2 groups. Typically, it is substituted by one, two or three -NH2 groups. Preferably, it is substituted by a single -NH2 group. As used herein, a 5- to 10- membered heteroaryl group or moiety is a monocyclic 5- to 10- membered aromatic ring, such as a 5- or 6- membered ring, containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from O, S and N. Examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridazolyl and pyrazolyl groups. Preferred examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, imidazolyl and pyrazolyl groups. Furanyl, thienyl, pyridazolyl, pyrazolyl, pyrimidinyl and thiazolyl groups are preferred. Furanyl, thienyl, pyrimidinyl and thiazolyl groups are further preferred. Furanyl, thienyl and thiazolyl groups are still further preferred. As used herein, a 5- to 10- membered heterocyclyl group or moiety is a monocyclic non-aromatic, saturated or unsaturated C5-C10 carbocyclic ring in which one or more, for example 1, 2 or 3, of the carbon atoms are replaced with a moiety selected from N, O, S, S(O) and S(O)2. Typically, it is a 5- to 6- membered ring. Suitable heterocyclyl groups and moieties include pyrazolidinyl, piperidyl, piperazinyl, thiomoφholinyl, S-oxo-thiomoφholinyl, S,S-dioxo-thiomoφholinyl, moφholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, 1,3-dioxolanyl, 1,4- dioxolyl and pyrazolinyl groups and moieties. Piperazinyl, thiomoφholinyl, S,S- dioxothiomorpholinyl, moφholinyl and 1,3-dioxolanyl groups and moieties are preferred. Typically, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, C1-C haloalkyl, Cj-C haloalkoxy, Cι-C4 hydroxyalkyl, cyano, -COR;, -CO2R/, -S(O)R7, -S(O)2R;and -iZ-X-l/'-Y substituents, wherein R.', L;, X, l," and Y are as defined above. Typically, L; is a direct bond or a Cj-C2 alkylene group. Typically, X is -O- or
-NR7- wherein R is as defined above. Typically, L/; is a direct bond or a Cι-C2 alkylene group, preferably a C]-C2 alkylene group. Typically, Y is hydrogen, -COR/, -CO2R/, -S(O)2R/or -S(O)R/, wherein R/ is a Cι-C4 alkyl group. Preferably, Y is hydrogen, -COR/, -S(O)2R/or -S(O)R/, wherein R, is a C]-C alkyl group. Preferably, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cι-C2 alkyl, CrC2 haloalkyl, C,-C2 hydroxyalkyl, cyano, -COR, -CO^, -S(O)R7, -S(O)2R/, - (C,-C2 alky -NR^, C C2 alkoxy, -NR'-COR/, NR'-CO^R/, -(Cι-C2 alky -NR'-CO^/, -NR/-S(O)2-R/ and -(CrC2 alkyl)-NR-(C C2 alkyl)-S(O)2-R;/ substituents, wherein each R', R;/ and R/ are the same or different and represent hydrogen or Cι-C2 alkyl. In one embodiment the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I) and, typically, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, C]-C4 haloalkyl, Cι-C4 haloalkoxy, Cι-C4 hydroxyalkyl, -COR'', - CO2R;, -S^R, -SO-W and -Ly-X-L;/-Y substituents, wherein R, L7, X, " and Y are as defined above. Preferably, the aryl, heteroaryl and heterocyclyl moieties in the Rj substituent are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C C4 alkyl, Cι-C4 haloalkyl, Cι-C4 haloalkoxy, Cι-C4 hydroxyalkyl, -COR and -L'-X-L^-Y substituents, wherein R', L1, X, L7/ and Y are as defined above. More preferably, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cj-C2 alkyl, Cι-C2 alkoxy, C C2 haloalkyl, C C2 hydroxyalkyl, -COR, -CO2R;, -S(O)R;, -S(O)2R/, - (C,-C2 alky -NRV and -(C,-C2 alky -NR^Q-Cz alkyl)-S(O)2-R;/ substituents, wherein each R and R; are the same or different and represent hydrogen or Cι-C2 alkyl. Yet more preferably, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cι-C2 alkyl, C C2 haloalkyl, d-C2 hydroxyalkyl, -COR', -(C,-C2 alky^-NR^ and -(C C2 alkyl)-NR-(C)-C2 alkyl)-S(O)2-R;/ substituents, wherein each R1 and R; are the same or different and represent hydrogen or Cι-C2 alkyl. Typically, A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. Preferably, A is a phenyl or 5- to 6- membered heteroaryl group. More preferably, A is a phenyl, furanyl, thienyl, pyrimidinyl, thiazolyl or pyridazolyl group. Yet more preferably, A is a phenyl, furanyl, thienyl, pyrimidinyl or thiazolyl group. Most preferably, A is a phenyl, furanyl, thienyl or thiazolyl group. Typically, L is a direct bond or a Cι-C2 alkylene group. Typically, A; is a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. Preferably, when ! is a 5- to 6- membered heteroaryl group it is a pyrazolyl group. More preferably, A; is a 5- to 6- membered heterocyclyl or heteroaryl group, which group is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, Cι-C4 haloalkyl and Cι-C4 haloalkoxy substituents. Most preferably, A; is a moφholinyl, thiomorpholinyl, piperazinyl, 1,3-dioxolanyl, S,S- dioxothiomoφholino or pyrazolyl group which is unsubstituted or substituted by one or two substituents selected from C]-C2 alkyl, halogen and Cj-C2 haloalkyl groups. In one embodiment the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I) and, preferably A is a 5- to 6- membered heterocyclyl group. More preferably, A' is a 5- to 6- membered heterocyclyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, C]-C4 alkyl, Cι-C4 haloalkyl and -C4 haloalkoxy substituents. Most preferably, A is a morpholinyl, thiomoφholinyl, piperazinyl, 1,3-dioxoanyl or S,S-dioxothiomoφholino group which is unsubstituted or substituted by one or two substituents selected from Cι-C2 alkyl, halogen and Cι-C2 haloalkyl groups. Typically, Z is -O-, -CONR -, -NR/C(O)- or -NRCO2-, wherein R'is as defined above. Preferably Z is -O-, -CONH-, -CON(d-C2 alkyl)-, -NHC(O)- or -NHCO2-. Typically Ri is halogen, Cι-C4 alkyl, Cι-C haloalkyl, Cι-C4 alkoxy, Cι-C4 haloalkoxy, -CO2R7, -CONR'R , -A, -A-L-A , -Z-L-A, or -A-L-Z-L-A wherein R;, Ry, A, L, A; and Z are as defined above. Preferably, Ri is halogen, Cι-C2 alkoxy, Cι-C2 haloalkoxy, -CONR , -A, -Ar-L-A', -Z-L-A or -Ar-Z-L-Ar, wherein R; and R7/ are the same or different and each represent hydrogen or a Cι-C2 alkyl group, A and A are as defined above, Ar is an unsubstituted furanyl or unsubstituted phenyl group, L is a direct bond or a methylene group and Z is -O-, -C^NR -, -NR;C(O)- or -NR;CO2-, wherein R;is as defined above. In one embodiment the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I) and, typically, Ri is halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Ci- C4 alkoxy, d-C4 haloalkoxy, -A or -A-L-A;, wherein A, L and Af are as defined above. Preferably, Ri is halogen, Cι-C2 alkoxy, Cι-C2 haloalkoxy, -A or -Ar-L- A! wherein A and A1 are as defined above, Ar is an unsubstituted furanyl group and L is a direct bond or a methylene group. Typically, R2 is hydrogen, Cι-C4 alkyl or Cι-C4 alkoxy. Preferably, R2 is hydrogen or Cι-C2 alkoxy. Typically, R3 is hydrogen, Q-C2 alkyl, C]-C2 haloalkyl or C]-C2 alkoxy.
Preferably, R3 is hydrogen, methyl, trifluoromethyl or methoxy. Typically, 1^ is hydrogen or Ci-Cβ alkyl. Preferred compounds of the invention are those in which: Ri is halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C4 alkoxy, Q-C4 haloalkoxy, -COsR', -CONR R , -A, -A-L-A', -Z-L-A, or -A-L-Z-L-A; R2 is hydrogen, Cι-C4 alkyl or Cι-C4 alkoxy; R3 is hydrogen, Cι-C2 alkyl, Cι-C2 haloalkyl or CpC2 alkoxy; R- is hydrogen or Cι-C6 alkyl; A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group; L is a direct bond or a C]-C2 alkylene group; A; is a 5- to 6- membered heteroaryl or heterocyclyl group; and Z is -O-, -CONR'-, -NR;C(O)- or -NRCO2-, wherein R; is hydrogen or d-C4 alkyl, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C haloalkoxy, Cι-C4 hydroxyalkyl, cyano, -COR, -CO2R/, -S(O)Ry, -S(O)2R;and -L'-X-I Y substituents, wherein R;, \J, X, l!' and Y are as defined above. Further preferred compounds of the invention are those in which the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, C C4 alkyl, Cι-C4 haloalkyl, C]-C alkoxy, Cι-C4 haloalkoxy, -A or -A-L-A'; R2 is hydrogen, Cι-C4 alkyl or d-C4 alkoxy; - A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group; L is a direct bond or a Cι-C4 alkylene group; and A1 is a 5- to 6- membered heteroaryl or heterocyclyl group, the aryl, heteroaryl and heterocyclyl moieties in the ^ substituent being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, C,-C4 haloalkyl, CrC4 haloalkoxy, CrC4 hydroxyalkyl, -COR7, -CO2R7, -S(O)R7, -S(O)2R7 and -L -X-L -Y substituents, wherein R7, L7, X, L77 and Y are as defined above. Further preferred compounds of the invention are those in which the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, Cι-C4 alkyl, C]-C4 haloalkyl, Cι-C4 alkoxy, Cι-C4 haloalkoxy, -A or -A-L-A7; R2 is hydrogen, Cι-C4 alkyl or C)-C4 alkoxy; - A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group; L is a direct bond or a Cι-C4 alkylene group; and A is a 5- to 6- membered heteroaryl or heterocyclyl group, the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, d-C4 haloalkoxy, d-C4 hydroxyalkyl, -COR and -L7-X-L7-Y substituents, wherein R7, L7, X, L77 and Y are as defined above. Further preferred compounds of the invention are those wherein: Ri is halogen, d-C2 alkoxy, d-C2 haloalkoxy, -CONRR77, -A, -Ar-L-A7, -Z-L- A, or -Ar-Z-L-Ar, wherein R7 and R7 are the same or different and each represent hydrogen or a Cj-C2 alkyl group; R2 is hydrogen or C]-C2 alkoxy; A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl, pyrimidinyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cι-C2 alkyl, Cι-C2 haloalkyl, C C2 hydroxyalkyl, cyano, -COR7, -CO2R7, -S(O)R7, -S(O)2R7, -(C,-C2 alkyl)- NR7R77, Cι-C2 alkoxy, -NR7-COR/, NR7-CO2R/, -(Cι-C2 alkyl)-NR-CO2R/, -NR7- S(O)2-R7and -(d-C2 alkyl)-NR-(Cι-C2 alkyl)-S(O)2-R77 substituents, wherein each R7 and R77 are the same or different and represent hydrogen or C]-C2 alkyl; - Ar is an unsubstituted furanyl or unsubstituted phenyl group; L is a direct bond or a methylene group; A7 is a 5- to 6- membered heterocyclyl or heteroaryl group, for example moφholinyl, thiomoφholinyl, piperazinyl, 1,3-dioxolanyl, S,S- dioxothiomoφholinyl and pyrazolyl, which is unsubstituted or substituted by one or two substituents selected from Cι-C2 alkyl, halogen and Cj-C2 haloalkyl groups; and Z is -O-, -CONH-, -CON(C] -C2 alkyl)- or -NHC(O)-. Further preferred compounds of the invention are those in which the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, Cι-C2 alkoxy, Cι-C2 haloalkoxy, -A or -Ar-L-A ; - R2 is hydrogen or Cj-C2 alkoxy; A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl, pyrimidinyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cι-C2 alkyl, Cι-C2 alkoxy, Cι-C2 haloalkyl, C C2 hydroxyalkyl, -COR7, -CO R7, -S(O)R7, -S(O)2R7, -(CrC2 alkyl)-NRR77 and -(d-C2 alkyl)-NR7-(Cι-C2 alkyl)-S(O)2-R77 substituents, wherein each R7 and R77 are the same or different and represent hydrogen or d- C2 alkyl; Ar is an unsubstituted furanyl group; L is a direct bond or a methylene group; and - A7 is a 5- to 6- membered heterocyclyl group, for example moφholinyl, thiomorpholinyl, piperazinyl, 1,3-dioxoanyl and S,S-dioxothiomorpholinyl, which is unsubstituted or substituted by one or two substituents selected from C]-C2 alkyl, halogen and Cι-C2 haloalkyl groups. Further preferred compounds of the invention are those in which the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I), wherein: Ri is halogen, Cι-C2 alkoxy, C C2 haloalkoxy, -A or -Ar-L-A7; R2 is hydrogen or Cι-C2 alkoxy; A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cι-C2 alkyl, Cι-C2 haloalkyl, Cι-C2 hydroxyalkyl, -COR7, -(C]-C2 alkyl)-NRR77 and -(Cι-C2 alkyl)-NR7-(C,-C2 alkyl)-S(O)2-R77 substituents, wherein each R7 and R77 are the same or different and represent hydrogen or d-C2 alkyl; Ar is an unsubstituted furanyl group; L is a direct bond or a methylene group; and A7 is a 5- to 6- membered heterocyclyl group, for example morpholinyl, thiomoφholinyl, piperazinyl, 1,3-dioxoanyl and S,S-dioxothiomorpholinyl, which is unsubstituted or substituted by one or two substituents selected from Cj-C2 alkyl, halogen and C C2 haloalkyl groups. Particularly preferred compounds of formula (la) include: (6-bromo-quinazolin-4-yl)-(4-moφholin-4-yl-phenyl)-amine; (6-iodo-quinazolin-4-yl)-(4-moφholin-4-yl-phenyl)-amine; (6,7-dimethoxy-quinazolin-4-yl)-(4-moφholin-4-yl-phenyl)-amine;
(6-trifluoromethoxy-quinazolin-4-yl)-(4-moφholin-4-yl-phenyl)-amine; (6-fiιran-2-yl-quinazolin-4-yl)-(4-morpholin-4-yl-phenyl)-amine; [6-(5-[l,3]dioxolan-2-yl-furan-2-yl)-quinazolin-4-yl]-(4-morpholin-4-yl-phenyl)-amine; 5-[4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl]-furan-2-carbaldehyde; {5-[4-(4-moφhoIin-4-yl-phenylamino)-quinazolin-6-yl]-furan-2-yl}-methanol; (6- { 5-[(2-methanesulfonyl-ethylamino)-methyl]-furan-2-yl } -quinazolin-4-yI)-(4- moφholin-4-yl-phenyl)-amine;
{6-[5-(l,l-dioxo-l-λ-6-thiomoφholin-4-ylmethyl)-furan-2-yl]-quinazolin-4-yl}-(4- moφholin-4-yl-phenyl)-amine; { 6-[5-(4-methyl-piperazin- 1 -ylmethyl)-furan-2-yl]-quinazolin-4-yl} -(4-moφholin-4-yl- phenyl)-amine;
[6-(5-morpholin-4-ylmethyl-furan-2-yl)-quinazolin-4-yl]-(4-moφholin-4-yl-phenyl)- amine;
[6-(5-dimethylaminomethyl-furan-2-yl)-quinazolin-4-yl]-(4-moφholin-4-yl-phenyl)- amine;
[6-(5-methylaminomethyl-furan-2-yl)-quinazolin-4-yl]-(4-moφholin-4-yl-phenyl)- amine;
(4-moφholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine; (6-chloro-quinazolin-4-yl)-(4-moφholin-4-yl-phenyl)-amine; (4-moφholin-4-yl-phenyl)-(6-o-tolyl-quinazolin-4-yl)-amine;
(4-moφholin-4-yl-phenyl)-(6-thiazol-2-yl-quinazolin-4-yl)-amine;
(4-moφholin-4-yl-phenyl)-[6-(3-pyrazol-l-yl-phenyl)-quinazolin-4-yl]-amine;
4-[4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl]-benzonitrile; [6-(2-methoxy-pyrimidin-5-yl)-quinazolin-4-yl]-(4-morpholin-4-yl-phenyl)-amine;
[6-(4-methyl-thiophen-2-yl)quinazolin-4-yl]-(4-morpholin-4-yl-phenyl)-amine;
5-[4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl]-thiophene-2-carboxylic acid;
[6-(4-methanesulfonyl-phenyl)-quinazolin-4-yl]-(4-moφholin-4-yl-phenyl)-amine; furan-2-carboxylic acid [4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl]-amide;
4-(4-morpholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid 4-methoxy- benzylamide;
3-{[4-(4-morpholin-4-yl-phenylamino)-quinazoline-6-carbonyl]amino}-benzoic acid ethyl ester; 4-(4-morpholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid 3-methoxy- benzylamide;
4-(4-morpholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid 4-methyl- benzylamide;
4-(4-moφholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid methylamide ; 4-(4-moφholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid dimethylamide;
4-(4-moφholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid ethylamide;
N- { 3 -[4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl] -phenyl } -acetamide;
{4-[4-(4-morpholin-4-yl-phenylamino)-quinazolin-6-yl]-phenyl}-carbamic acid benzyl ester; N- {4-[4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl]-phenyl } acetamide;
{4-[4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl]-phenyl} -carbamic acid tert- butyl ester;
{3-[4-(4-moφholin-4-yl-phenylamino)-quinazolin-6-yl]benzyl} -carbamic acid tert- butyl ester; N- {3-[4-(4-moφholin-4-yl-phenylamino-quinazolin-6-yl]-phenyl} - methanesulfonamide;
(6-iodo-quinazolin-4-yl)-(4-moφholin-4-yl-2-trifluoromethyl-phenyl)-amine;
(4-moφholin-4-yl-2-trifluoromethyl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine;
(6-iodo-quinazolin-4-yl)-(3-methoxy-4-moφholin-4-yl-phenyl)-amine; (3-methoxy-4-moφholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine;
(2-methyl-4-moφholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine;
(3-methyl-4-moφholin-4-yl-phenyl-(6-thiophen-2-yl-quinazolin-4-yl)-amine; ethyl-(4-moφholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine; (6-iodo-quinazolin-4-yl)-methyl-(4-moφholin-4-yl-phenyl)-amine;
(6-iodo-quinazolin-4-yl)-(3-methyl-butyl)-(4-morpholin-4-yl-phenyl)-amine; isopropyl-(4-morpholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine;
(3-methyl-butyl-(4-moφholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine; [6-(2-benzyloxy-phenyl)-quinazolin-4-yl]-(4-morpholin-4-yl-phenyl)-amine;
[6-(4-benzyloxy-phenyl)-quinazolin-4-yl]-(4-morpholin-4-yl-phenyl)-amine; and pharmaceutically acceptable salts thereof. Compounds of formula (la) containing one or more chiral centre may be used in enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers. For the avoidance of doubt, the compounds of formula (la) 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. As used herein, 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 -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. The compounds of the invention in which R\ is other than hydrogen or halogen, can, for example, be prepared according to the following reaction schemes.
Scheme la
Figure imgf000015_0001
In one embodiment, Scheme l is represented by Scheme 1.
Scheme 1
Figure imgf000015_0002
an appropriate leaving group, for example halogen. Referring to Schemes la and 1, the treatment of compounds of formula (Ila) and (II), respectively, with an organometaUic reagent (V) is conveniently carried out in a suitable solvent (such as tetrahydrofiiran, dimethylformamide or toluene) and at elevated temperature (eg from 50°C to reflux). Conveniently, the reaction is performed under palladium catalysis (eg 20mol% tris (dibenzylideneacetone)dipalladium (II) or 20mol% dichlorobis (triphenylphosphine)palladium (0)) in the presence of an organic base (eg triethylamine) or an inorganic base (eg sodium carbonate or potassium phosphate). Where reagent (V) is an organostannane (eg M = SnBu3), one skilled in the art will recognise the reaction as an example of a Stille coupling where additional additives may be beneficial eg lithium chloride, silver oxide and conveniently the reaction is performed in toluene and at reflux temperature. Where reagent (V) is a boronic acid derivative, one skilled in the art will recognise the reaction as an example of a Suzuki-Miyaura coupling which may be conveniently performed at 60°C in tetrahydrofuran. Referring to Schemes la and 1, the conversion of compounds of formula (III) to compounds of formula (Ila) and (II), respectively, is accomplished by converting the 4- hydroxy group of compounds of formula (III) to a suitable leaving group eg chloro using a reagent such as thionyl chloride as solvent with the addition of a catalytic activator eg dimethylformamide, and subsequent reaction with 4-morpholinoaniline in a suitable solvent eg acetonitrile. Referring to Schemes la and I, the conversion of compounds of formula (IV) to compounds of formula (III) will be well known to one skilled in the art, being conveniently performed with formamide as solvent and at elevated temperature eg reflux. Compounds of formula (la) or (I) in which Ri is hydrogen or halogen can, of course, be prepared using compounds of formula (IV) in which X is hydrogen or halogen, converting the compounds of formula (IV) to corresponding compounds of formula (III) as described above and reacting with a compound of formula (Via) or
(VI), respectively, as described above. Compounds of formula (la) or (I) in which Ri is alkyl, haloalkyl, alkoxy and haloalkoxy can, of course, also be prepared in an analogous manner. The starting materials in the above reaction scheme are known compounds, or can be prepared by analogy with known methods. In particular, compounds of formula (Via) may be prepared by known methods such as those outlined in scheme 2. Scheme 2 reductfon
Figure imgf000017_0001
Figure imgf000017_0002
The compounds of the present invention are therapeutically useful. The present invention therefore provides a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof, for use in treating the human or animal body. Also provided is a pharmaceutical composition comprising a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 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. Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer. As explained above, the compounds of the invention are active against a flaviviridae infection. The present invention therefore provides the use of a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing a flaviviridae infection. Also provided is a method for treating a patient suffering from or susceptible to a flaviviridae infection, which method comprises administering to said patient an effective amount of a quinazoline derivative of formula (la) or a pharmaceutically acceptable salt thereof. The flaviviridae family contains three genera. These are hepacivirus, flavivirus and pesti virus. The compounds of the invention are active in treating or preventing a hepacivirus infection, a flavivirus infection or a pestivirus infection. Typical pestivirus infections which can be treated with the compounds of the invention include bovine viral diarrhea virus, classical swine fever virus and border disease virus. Typical flavivirus infections which can be treated with the compounds of the invention include yellow fever virus, dengue fever virus, Japanese encephalitis virus and tick borne encephalitis virus. Typical hepacivirus infections that can be treated with the compounds of the invention include hepatitis C virus. Compounds of the present invention are especially active against hepatitis C. Typically, said flavivirus is therefore hepatitis C virus. 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. For example, 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. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. 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, and derivatives thereof, which are known for the treatment of hepatitis C (Clinical Microbiology Reviews, Jan. 2000, 67-82). The said medicament therefore typically further comprises interferon or a derivative thereof and/or ribavirin or a derivative thereof. Further, the present invention provides a pharmaceutical composition comprising:
(a) a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof;
(b) interferon or a derivative thereof and/or ribavirin or a derivative thereof; and
(c) a pharmaceutically acceptable carrier or diluent. Also provided is a product comprising:
(a) a quinazoline derivative of the formula (la), as defined above, or a pharmaceutically acceptable salt thereof; and
(b) interferon or a derivative thereof and/or ribavirin or a derivative thereof, for separate, simultaneous or sequential use in the treatment of the human or animal body. A preferred interferon derivative is PEG-interferon. A preferred ribavirin derivative is viramidine. 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. Preferably, 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, The following Examples illustrate the invention. They do not however, limit the invention in any way. In this regard, it is important to understand that the particular assay used in the Examples section is designed only to provide an indication of antiviral activity. There are many assays available to determine such activity, and a negative result in any one particular assay is therefore not determinative.
EXAMPLES
All temperatures are in °C. Thin layer chromatography (TLC) was carried out on Si 60G coated plastic plates with uv254 indicator (Polygram). All NMR spectra were obtained at 250MHz in d6-DMSO unless stated otherwise.
LC-MS CONDITIONS Samples were run on a MicroMass ZMD, using electrospray with simultaneous positive - negative ion detection. Column : Synergi Hydro-RP, 30 x 4.6mm I.D, 4μm.
Gradient : 95:5 to 5:95 v/v H2O/CH3CN + 0.05% Formic. Acid over 4.0 min, hold 3 min, return to 95:5 v/v H2O/CH3CN + 0.05% Formic Acid over 0.2 min and hold at
95:5 v/v H2O/CH3CN + 0.05% Formic Acid over 3 min.
Detection : PDA 250 - 340 nm. Flow rate : 1.5 ml/min
Example 1 : (6-Bromo-quinazolin-4-yI)-(4-morpholin-4-yl-phenyI)-amine 5-Bromo-2-aminobenzoic acid (5g, 23.1mmol) was suspended in formamide (5eq) and heated to 155°C under N2 for 16h. The mixture was allowed to cool and added to water. The resulting precipitate was isolated by filtration and dried to give an intermediate 6-bromoquinazolin-4-ol. A portion of this material (lg) was dissolved in thionyl chloride (10ml) and DMF (0.3ml) added before being refluxed for 5h. The solvents were removed and the residue azeotroped with toluene (3x10ml) to remove traces of thionyl chloride. The resulting material was dissolved in MeCN (10ml), 4- moφholinoaniline (l.leq, Lancaster) added and the reaction mixture heated to reflux for 24hr. On cooling the precipitate was isolated by filtration to give the title compound as a beige solid (867mg).
δ(DMSO) 11.5 (IH, br s); 9.17 (IH, d, J2.5Hz); 8.9 (IH, s); 8.22 (IH, dd, J 8.8, 1.9Hz); 7.88 (IH, d, J 8.8Hz); 7.61 (2H, d, J 8.8Hz); 7.06 (2H, d, J 8.8Hz); 3.78 (4H, m); 3.18 (4H, m) LC-MS ES+ =385, rt 3.89 Example 2: (6-Iodo-quinazolin-4-yl)-(4-morpholin-4-yI-phenyI)-amine
By a similar procedure to Example 1, using 5-iodo-2-aminobenzoic acid as starting material gave the title compound as an orange solid (568mg)
δ (DMSO)11.5 (IH, br s); 9.17 (IH, d, J2.5Hz); 8.89 (IH, s); 8.22 (IH, dd, J 8.8, 1.9Hz); 7.88 (IH, d, J 8.8Hz); 7.62 (2H, d, J 8.8Hz); 7.07 (2H, d, J 8.8Hz); 3.78 (4H, m); 3.18 4H, m) LC-MS ES+ = 433, rt 3.97
Example 3: (6,7-Dimethoxy-quinazoIin-4-yI)-(4-morpholin-4-yl-phenyl)-amine
By a similar procedure to Example 1, using 4, 5-dimethoxy-2-aminobenzoic acid as starting material gave the title compound.
LC-MS ES+ =367 rt 3.76
Example 4: (6-trifluoromethoxy-quinazolm-4-yl)-(4-morphoIin-4-yI-phenyI)-amine
By a similar procedure to Example 1, using 5-trifluoromethoxy-2-amino benzoic acid as starting material, the title compound was obtained (1 lOmg)
δ (DMSO) 10.0 (IH, s); 8.66 (IH, s); 8.62 (IH, s); 7.91(2H, s); 7.68 (2H, d, J 8.85Hz); 7.0 (2H, d, J 8.85Hz); 3.80 (2H, m); 3.10 (2H, m) LC-MS 391 rt. 4.89
Example 5: (6-Furan-2-yl-quinazolin-4-yI)-(4-morpholin-4-yl-phenyl)-amine (6-Iodo-quinazoline-4-yl)-(4-moφholin-4-yl-phenyl)-amine (Example 2,
0.23mmol) was dissolved in toluene (5ml) and treated with tributylstannylfuran (Aldrich, 1.1 eq) , lithium chloride (5eq) and bis(triphenylphosphine) palladium dichloride (5mol%) and heated to reflux under nitrogen for 24h. Aqueous workup followed by column chromatography gave the title compound (22mg)
δ (DMSO) 9.92 (IH, s); 8.89 (IH, s); 8.55 (IH, s); 8.23 (IH, dd, J 8.85, 1.89Hz); 7.95 (IH, d, 1.26Hz); 7.84 (IH, d, 8.85Hz); 7.72 (2H, d, J 8.85Hz); 7.19 (IH, d, J 1.89Hz); 7.07 (2H, d, 9.48Hz); 6.77 (lh, dd, J 3.16Hz, 1.89Hz); 3.83 (4H, m); 3.18 (4H, m) LC-MS ES+ = 373 rt 4.31
Example 6: [6-(5-[l,3]DioxoIan-2-yl-furan-2-yl)-quinazoIin-4-yI]-(4-morphoIin-4- yl-phenyl)-amine
The method of Example 5, using 5-[l,3]dioxolan-2-yl-2-tributylstannylfuran gave the title compound (30mg)
δ (DMSO) 8.56 (IH, s); 8.24 (IH, s); 7.96 (IH, dd, J 8.85, 1.89Hz); 7.86 (IH, d , J
8.85Hz); 7.75 (2H, d, 8.85Hz); 6.88 (2H, d, J 8.85Hz); 6.83 (IH, d, J 3.16Hz); 6.5 (IH, d, J 3.8Hz); 5.95 (IH, s); 4.11 (2H, m); 4.01 (2H, m); 3.81 (4H, m); 3.11 (4H, m)LC- MS ES+ = 445 rt 4.21
Example 7: 5-[4-(4-Morpholin-4-yI-phenylamino)-quinazoIm-6-yI]-furan-2- carbaldehyde
[6-(5-[l,3]Dioxolan-2-yl-furan-2-yl)-quinazolin-4-yl]-(4-moφholin-4-yl- phenyl)-amine (lOOmg) was dissolved in THF (10ml) with heating, 2MHC1 (2ml) added followed by water (10ml) and heated at 75° until TLC (SiO2, CH2C12/ iPrOH 20%) showed deprotection was complete. The cooled reaction mixture was basified to pH 8 with 2M NaOH and the title compound isolated as a yellow solid by filtration (45 mg)
δ (DMSO) 10.07 (IH, br s); 9.72 (IH, s); 9.04 (IH, s); 8.56 (IH, s), 8.32 (IH, d, J 8.21Hz); 7.87 (IH, d, J 8.84Hz); 7.79 (IH, d, J 3.79Hz); 7.67 (2H, d 8.84Hz), 7.46 (IH, d J 3.16Hz); 7.05 (2H, d J 8.84Hz); 3.81 (4H, m); 3.17 (4H, m) LC-MS ES+ = 401 rt 4.16 Example 8: {5-[4-(4-morphoIin-4-yl-phenylamino)-quinazolm-6-yl]-furan-2-yI}- methanol
Reduction of 5-[4-(4-Morpholin-4-yl-phenylamino)-quinazolin-6-yl]-furan-2- carbaldehyde (450mg) in CH2C12 (15ml) and acetic acid (1ml) with sodium triacetoxyborohydride (0.477g, 2eq) for 2h followed by aqueous workup gave the title compound.
δ (DMSO) 9.86 (IH, br); 8.77 (IH, d, J 1.26Hz); 8.47 (IH, s); 8.13 (IH, dd J 8.85, 1.89Hz); 7.76 (IH, d, 8.85Hz); 7.65 (2H, d, J 8.85Hz); 7.05 (IH, d J 3.16Hz); 7.0 (2H, d J 8.85Hz); 6.50 (IH, d, 3.16Hz), 5.76 (IH, s); 5.34 (IH, br); 4.53 (2H, s); 3.70 (4H, m); 3.10 (4H, m) LC-MS ES+ = 403 rt 4.66
Example 9 : (6-{5-[(2-MethanesuIfonyl-ethylamino)-methyI]-furan-2-yl}- quinazolin-4-yI)-(4-morphoIin-4-yl-phenyI)-amine
The carboxaldehyde of Example 7 (150mg) was treated with 2- methanesulfonylethylamine (46mg, prepared by the route in Bioorganic & Medicinal Chemistry Letters 14, 1, , pi 11-114 Yue-Mei Zhang et al) and 5A molecular sieves (300mg) at 40° in CH2C12 (15ml) for 5hr. Acetic acid (2ml) and sodium triacetoxyborohydride (139mg, 2eq) added and stirred overnight at room temperature. The mixture was concentrated to dryness and purified by suction chromatography to give the title compound (70mg)
δ (CDC13) 8.60 (IH, br); 8.29 (IH, d, 1.42Hz); 7.88 91H, dd, J 8.68, 1.74Hz); 7.78 (IH, d, 8.86 Hz); 7.60 (2H, d, 9.0Hz); 6.91 (2H, d, 9.10Hz); 6.62 (IH, d, 3.32Hz); 6.25 (IH, d, 3.30Hz); 3.86 (2H, s); 3.81 (4H, m); 3.22 (4H, s), 3.10 (4H, m); 2.83 (3H, s) LC-MS ES+ = 508 rt 4.95 Example 10: {6-[5-(l,l-Dioxo-l-λ-6-thiomorpholin-4-yImethyl)-furan-2-yl]- quinazolin-4-yl}-(4-morpholin-4-yl-phenyl)-amine
By the method of Example 9, the title compound was obtained as a yellow solid (25mg)
δ (DMSO) 9.82 (IH, s); 8.76 (IH, s); 8.48 (IH, s); 8.14 (IH, dd, J 8.85, 1.89Hz); 7.79 (IH, d, J 8.85Hz); 7.64 (2H, d, J 8.85Hz); 7.08 (IH, d, J 3.16Hz); 7.01 (2H, d, J 8.85Hz); 6.59 (IH, d, J 3.16Hz); 3.85 (2H, s); 3.8 (4H, m); 3.15 (8H, m); 3.0 (4H, m) LC-MS ES+ = 520 rt 4.85
Example 11: {6-[5-(4-Methyl-piperazin-l-ylmethyI)-furan-2-yl]-quinazolin-4-yl}- (4-morpholin-4-yl-phenyI)-amine By the method of Example 9, the title compound was obtained as a yellow solid
(30mg)
δ (DMS) 9.75 (IH, s); 8.64 (IH, d, J 1.26Hz); 8.37 (IH, s); 8.03 (IH, dd, J 8.85, 1.26Hz); 7.86 (IH, s); 7.67 (IH, d, J 8.21 Hz); 7.54 (2H, d, 8.85Hz); 6.96 (IH, d, J 3.16Hz); 6.91 (2H, d, J 9.48Hz); 6.40 (IH, d, J 3.16Hz); 3.67 (4H, m); 3.50 (2H, s); 3.27 (8H, b); 3.02 (4H, m); 2.03 (3H, s) LC-MS m/z 485 rt 4.48
Example 12: [6-(5-Morpholin-4-yImethyl-furan-2-yl)-quinazolin-4-yl]-(4- morpholin-4-yl-phenyl)-amine
By the method of Example 9, the title compound was obtained as a pale yellow solid (20mg)
δ (DMSO) 9.92 (IH, s); 8.80 (IH, s); 8.49 (IH, s); 8.15 (IH, d, J 8.21Hz); 7.79 (IH, d, J 8.85Hz); 7.65 (2H, d, J 8.85Hz); 7.09 (IH, d, J 3.16Hz); 7.01 (2H, d, J 8.85Hz); 6.57 (IH, d, J 3.16Hz); 6.53 (IH, s); 3.80 (10H, m); ;3.33(4H, m); 3.20 (4H, m) LC-MS m/z 472 rt 4.12 Example 13: [6-(5-DimethylammomethyI-furan-2-yl)-quinazolin-4-yl]-(4- morphoIin-4-yl-phenyl)-amine By the method of Example 9, the title compound was obtained as a pale yellow solid (20mg)
δ (DMSO) 9.93 (IH, s); 8.85 (IH, s); 8.56 (IH, s); 8.22 (IH, dd, J 8.85, 1.26Hz); 7.86 (IH, d, J 8.85Hz); 7.73 (2H, d, J 9.48Hz); 7.16 (IH, d, J 3.16Hz); 7.09 (2H, d, J 8.85Hz); 6.63 (IH, d, J 3.16Hz); 3.86 (4H, m); 3.73 (2H, s); 3.21 (4H, m); 2.37 (6H, s) LC-MS 430 rt 4.51
Example 14: [6-(5-MethyIaminomethyl-furan-2-yI)-quinazoIin-4-yl]-(4-morpholm 4-yl-phenyl)-amine
By the method of Example 9, the title compound was obtained as a pale yellow solid (8mg)
δ (DMSO) 9.69 (IH, s); 8.63 (IH, s); 8.35 (IH, s); 8.02 (IH, d, J 8.85Hz); 7.64 (IH, d, J 8.85Hz); 7.53 (2H, d, J 8.21Hz); 6.90 (3H, m); 6.35 (IH, m); 3.65 (6H, m); 3.10 (4H, m); 2.23 (3H, s) LC-MS m/z 4.16
Example 15 : (4-Morpholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yI)-amine
A suspension of (6-Iodo-quinazoline-4-yl)-(4-morpholin-4-yl-phenyl)-amine (Example 2, 2.66g) and thiophene-2-boronic acid (Lancaster, 1.18g, 1.5eq) in THF (26ml) was treated with triethylamine (2.6ml, 3eq.) and warmed to 60° before tris(dibenzylideneacetone)dipalladium(0) (282mg) added and heating continued for 18h. The resulting precipitate was isolated from the cooled reaction mixture by filtration and washed with THF (10ml). The solid was dissolved in DMSO (40ml) and passed through a pad of Celite before being diluted with water and the precipitate isolated by filtration and dried in vacuo to give the title compound as a yellow solid (1.2g, 50%) δ (DMSO)10.75 (IH, br s); 8.9 (IH, s); 8.61 (IH, s); 8.20 (IH, dd, J 8.85, 1.89Hz); 7.8 (2H, d, 8.85Hz); 7.76 (IH, s); 7.66 (IH, d, J 4.42Hz); 7.58 (2H, d, J 8.85Hz), 7.21(1H, t, 3.79Hz); 7.0 (2H, d, J 8.85Hz); 3.70 (4H, m); 3.10 (4H, m) LC-MS ES+ = 389 rt 4.32
Example 16: (6-ChIoro-quinazolin-4-yI)-(4-morpholin-4-yl-phenyl)-amine
By a similar method to example 15 was obtained the title compound (42mg)
δ (DMSO) 11.86 (IH, s); 9.26 (IH, s); 8.97 (IH, s); 8.5 (IH, dd, J 8.85, 1.9Hz); 8.06
(2H, d 8.85Hz); 7.73 (2H, d, J 8.85Hz); 7.67 (2H, d, J 8.85Hz); 7.28 (IH, d, J 8.85Hz);
7.16 (IH, d, J 9.48Hz); 7.11 (IH, d, J 9.48Hz); 3.81 (4H,m); 3.2 (4H, m)
LC-MS ES+ = 417.5 rt 4.4
Example 17: (4-Morpholin-4-yl-phenyl)-(6-o-toIyI-quinazolin-4-yI)-amine
By a similar method to example 15 was obtained the title compound (25mg)
δ (MeOD) 8.58 (IH, s); 8.44 (IH, d, J 1.26Hz); 7.93 (IH, d, J 1.89Hz); 7.91 (IH, s);
7.65 (2H, d, J 8.85Hz); 7.39 (4H, m); 7.10 (2H, d, J 8.85Hz); 6.96 (2H, s); 3.92 (2H, m); 3.24 (4H, m); 2.39 (3H, s) LC-MS ES+ = 397 rt 4.26
Example 18: (4-MorphoUn-4-yl-phenyl)-(6-thiazol-2-yl-qu azolin-4-yl)-amine
A similar method to example 5 gave the title compound (5.3mg)
δ (DMSO) 10.16 (IH, s), 9.17 (IH, s), 8.61 (IH, s), 8.5 (IH, d), 8.48 (IH, d, J 8.8Hz), 8.10 (IH, d, J 3Hz), 7.98 (IH, d, J 3Hz), 7.91 (IH, d, 8.8Hz), 7.72 (2H, d, J 8.8Hz), 7.09 (2H, d, J8.8Hz), 3.85 (4H, m), 3.2 (4H, m) LC-MS m/z 390 rt 3.31 Example 19: [6-(2-Methoxy-pyrimidin-5-yI)-quinazolin-4-yI]-(4-morpholin-4-yI- phenyl)-amine
By a similar method to Example 15, the title compound was obtained as a yellow solid (120mg) δ (DMSO) 9.75 (IH, s), 9.15 (2H, s), 8.86 (IH, s), 8.53 (IH, s), 8.23 (IH, d, J 8.85Hz), 7.83 (IH, d, J 8.85Hz), 7.64 (2H, d, J 8.85 Hz), 6.996 (2H, d, J 8.85Hz), 4.0 (3H, s), 3.76 (4H, m), 3.11 (4H, m) LC-MS m/z 415
Example 20 : [6-(4-Methyl-thiophen-2-yl)-quinazolin-4-yl]-(4-morpholin-4-yl- phenyl)-amine
By a similar method to Example 15, the title compound was obtained as a red solid. δ (DMSO) 11.8 (IH, br s), 9.18 (IH, s), 8.83 (IH, s), 8.31 (IH, d, J 8.85Hz), 7.97 (IH, d, J 8.2Hz), 7.77 (IH, s), 7.61 ( 2H, d, J 8.85Hz), 7.32 ( IH, s), 7.08 (IH, s), 3.78 (4H, m), 3.19 ( 4H, m), 2.3 ( 3H, s)
LC-MS m/z 403
Example 21: 5-[4-(4-MorphoIin-4-yl-phenylamino)-quinazolin-6-yI]-thiophene-2- carboxylic acid
By a similar method to Example 15, the title compound was obtained as a red- brown solid. δ (DMSO) 11.97 ( IH, br s), 9.36 (IH, s), 8.86 (IH, s), 8.43 (IH, d, J 8.2Hz), 7.99 (2H, m), 7.82 (IH, d, J 3.8Hz), 7.61(2H, d, J 8.85Hz), 7.08 (2H, d, J 9.5Hz), 3.77 (4H, m),
3.18 (4H, m)
LC-MS m/z 433 Example 22: [6-(4-MethanesuIfonyl-phenyI)-quinazolin-4-yI]-(4-morpholin-4-yI- phenyl)-amine
By a similar method to Example 15, the title compound was obtained as a yellow solid δ (DMSO) 9.91 (IH, br s), 8.91 (IH, s), 8.53 (IH, s), 8.15 (4H, m), 7.86 (IH, d, J
8.85Hz), 7.64 (2H, d, J 8.85Hz), 6.99 (2H, d, J 8.85Hz), 3.76 ( 4H, m), 3.29 (3H, s),
3.11 (4H, m)
LC-MS M/z 461
Example 23 : (4-Morpholin-4-yI~phenyI)-[6-(3-pyrazol-l-yl-phenyl)-quinazoIin-4- yl]-amine By a similar method to Example 15, the title compound was isolated as a brown solid by preparative LC-MS (5mg), δ (DMSO) 3.12 (s, 4H) 3.75 (s, 4H) 6.25 (s, IH) 7.01 (d, 2H) 7.54 (m, 4H) 7.65 (d, 2H) 7.89 (d, IH) 8.11 (m, 2H) 8.55 (s, IH) 8.72 (s, IH) 9.99 (s, IH), LC/MS RT= 3.62 min Found ES+ = 449.4
Example 24: 4-[4-(4-Morpholin-4-yl-phenylamino)-quinazoIin-6-yI]-benzonitrile By a similar method to Example 15, the title compound was isolated as a brown solid by preparative LC-MS (5mg).δ (DMSO) 3.12 (s, 4H) 3.77 (s, 4H) 7.01 (d, 2H) 7.62 (d, 2H) 7.82 (d, 2H) 8.03-8.24 (m, 5H) 8.50 (s, IH) 8.90 (s, IH) 9.91 (bs, IH) , LC/MS RT= 2.50 min Found ES+ = 408.5
Example 25: Furan-2-carboxylic acid [4-(4-morpholin-4-yI-phenyIamino)- quinazolin-6-yl]-amide Step 1: (4-Morpholin-4-yl-phenyl)-(6-nitro-quinazolin-4-yl)-amine (prepared by the method of Example 1, 3.60 LC-MS ES+ 352 ES- 350, 0.5g) was added to a stirred solution of THF:MeOH (1:1, 25ml) followed by Raney nickel (2 spatula, excess). The mixture was heated to 50°C at which stage hydrazine (1ml) was added and left to stir for 5 hr at this temperature. The mixture was allowed to cool and filtered through celite. The solvent was removed under vacuum to afford a solid which was purified by column chromatography on silica using 2.5-5% MeOH:DCM. Yield 0.16g (35%). LCMS: RT 2.01, ES+322, ES_320 δ (DMSO) 9.28 (IH, s); 8.25 (IH, s); 7.67 (2H, d, J8.85Hz); 7.50 (IH, d, J8.85Hz); 7.34 (IH, d, 1.90Hz), 7.22 (IH, dd, J8.85Hz, 1.90Hz); 6.96 (2H, d, J8.85Hz); 5.53 (2H, s); 3.77 (4H, m), 3.09 (4H, m). Step 2: To a portion of the amine (50mg) in pyridine (4ml) was added 2-furoyl chloride ( 0.033g, 1.2eq) and stirred for 4h. The pyridine was removed in vacuo and the residue purified by chromatography to give the title compound δ (DMSO) 8.77 (IH, s); 8.43 (IH, s); 8.01 (IH, d, J8.5Hz); 7.97 (IH, s); 7.72 (IH, d, J8.85Hz); 7.64 (2H, d, J8.85Hz); 7.42 (IH, d, J3.16Hz); 6.96 (2H, d, J8.85Hz); 6.73 (IH, m); 3.75 (4H, m); 3.08 (4H, m), LC-MS m/z 416 rt 2.22
Example 26: 4-(4-Morpholin-4-yl-phenylamino)-quinazoline-6-carboxylic acid 4- methoxy-benzylamide Step 1 : Preparation of 4-(4~moφholin-4-yl-phenylamino)-quinazoline-6- carboxylic acid A solution of Example 2 (2.0g, 4.6mMol), potassium carbonate (1.4g,
11.6mMol), tetrakis(triphenylphosphine)-palladium(0) (0.27g, 0.23mMol) and dichlorobis-(triphenylphosphine)palladium(II) (0.16g, 0.23mMol) in 4:1 dimethylformamide: water (75ml) was placed under an atmosphere of carbon monoxide and heated to 100°C for 6 hours. On cooling, the reaction solvent was removed under vacuum and the residue taken into water. On acidification to pH2, with IM hydrochloric acid, an orange precipitate formed. This was filtered off and slurried in methanol. The resulting suspension was filtered and air-dried to give 4-(4-morpholin-4-yl- phenylamino)-quinazoline-6-carboxylic acid as a yellow solid. Yield = 0.56g (1.6mMol, 35%) LC/MS: RT - 2.05, MH" @ 351, δ (DMSO) 10.37 (IH, s); 9.46(1H, s); 8.79 (IH, s); 8.49 (IH, dd, J 8.4Hz, 1.2Hz); 8.01 (IH, d, J 8.2Hz); 7.87 (2H, d, J 8.8Hz); 7.21 (2H, d, J 8.8Hz); 3.98 (4H, t, J 4.4Hz); 3.33 (4H, t, J 4.4Hz) Step 2: A solution of 4-(4-moφholin-4-yl-phenylamino)-quinazoline-6- carboxylic acid (50mg, 0.14mMol), O-(7-azabenzotriazol-l-yl)-N-N-N'-N'- tetramethyluronium hexaflurophosphate (55mg, 0.14mMol) and triethylamine (45μl, 0.32mMol) in dimethylformamide (2ml) was treated with 4-methoxybenzylamine and stirred overnight. On addition of water to the reaction mixture, a precipitate developed. This was collected by filtration and air-dried to give the title compound δ (DMSO) 10.06 (IH, s); 9.20 (IH, s); 9.16 (IH, s); 8.36 (IH, d, J 8.2Hz); 7.92 (IH, d, J 8.8Hz); 7.78 (2H, d, J 8.8Hz); 7.45 (2H, d, J 8.8Hz); 7.12 (2H, d, J 8.8Hz); 7.05 (2H, d, J 8.2Hz); 4.62 (2H, d, J 5.1Hz); 3.85-3.94 (7H, m); 3.24 (4H, t, J 3.6Hz), LC-MS m/z 470 rt 2.46
Prepared in a similar fashion to Example 26 , using the appropriate amine (1.2eq) either pure or as a solution in tetrahydrofiiran, (where available) in Step 2 were:
Example 27: 3-{[4-(4-Morpholin-4-yl-phenylamino)-quinazoline-6-carbonyI]- amino}-benzoic acid ethyl ester δ (DMSO) 10.68 (IH, s); 10.00 (IH, s); 9.13 (IH, s); 8.57 (IH, s); 8.47 (IH, s); 8.30 (IH, dd, J 8.8Hz, 1.3Hz); 8.13 (IH, d, J 8.2Hz); 7.84 (IH, d, J 8.8Hz); 7.72 (IH, d, J 8.2Hz); 7.67 (2H, d, J 8.8Hz); 7.50-7.59 (IH, m); 6.99 (2H, d, J 8.8Hz); 4.33 (2H, q, J 7.2Hz); 3.75 (4H, t, J 4.4Hz); 3.10 (4H, t, J 4.4Hz), 1.33 (3H, t, J 6.9Hz), LC-MS m/z 498 112.70
Example 28: 4-(4-Morpholin-4-yI-phenyIamino)-quinazoline-6-carboxylic acid 3- methoxy-benzylamide δ (DMSO) 9.75 (lH,s); 8.93 (IH, t, J 5.7Hz); 8.85 (IH, s); 8.35 (IH, s); 8.05 (IH, d, J 8.2Hz); 7.76 (IH, s); 7.60 (IH, d, J 8.2Hz); 7.46 (2H, d, J 8.2Hz); 7.07 (IH, t, J 7.6Hz); 6.72-6.82 (3H, m); 6.63 (IH, d, J 8.8Hz); 4.34 (2H, d, J 5.1Hz); 3.11-3.17 (7H, m); 2.87-2.94 (3H, m), LC-MS m/z 470 rt 2.48
Example 29: 4-(4-Morpholin-4-yl-phenyIamino)-quinazoline-6-carboxylic acid 4- methyl-benzylamide δ (DMSO) 10.14 (IH, s); 9.30 (IH, t, J 6.1Hz); 9.24 (IH, s); 8.76 (IH, s); 8.44 (IH, dd,
J 8.8Hz, 1.3Hz); 8.00 (IH, d, J 8.8Hz); 7.87 (2H, d, J 8.8Hz); 7.47 (2H, d, J 8.2Hz);
7.36 (2H, d, J 7.6Hz); 7.20 (2H, d, 8.8Hz); 4.73 (2H, d, J 5.7Hz); 3.94-4.00 (4H, m);
3.29-3.35 (4H, m); 2.49 (3H, s) LC-MS m/z 454 rt 2.58 Example 30: 4-(4-Morpholin-4-yI-phenylamino)-quinazoline-6-carboxylic acid methylamide δ (DMSO) 9.81 (IH, s); 8.86 (IH, s); 8.39-8.45 (2H, m); 8.04 (IH, dd, J 8.8Hz, 1.9Hz); 7.65 (IH, d, J 8.2Hz); 7.53 (2H, d, J 8.8Hz); 6.86 (2H, d, J 8.8Hz); 3.59-3.67 (4H, m); 2.95-3.01 (4H, m); 2.73 (3H, d, J 4.4Hz), LC-MS rt 2.08, m/z 364
Example 31: 4-(4-Morpholin-4-yl-phenyIammo)-quinazoIine-6-carboxyIic acid dimethylamide δ (DMSO) 9.60 (IH, s); 8.43 (IH, s); 8.35 (IH, s); 7.63 (IH, dd, J 8.2Hz, 1.3Hz); 7.57 (2H, d, J 8.8Hz); 6.79 (2H, d, J 8.8Hz); 3.53-3.59 (4H, m); 2.89-2.94 (4H, m); 2.86 (3H, s); 2.79 (3H, s), LC-MS rt 2.09, m/z 378
Example 32: 4-(4-Morpholin-4-yl-phenylamino)-quinazolme-6-carboxyIic acid ethylamide δ (DMSO) 9.96 (IH, s); 9.01 (IH, s); 8.63 (IH, t, J 5.4Hz); 8.57 (IH, s); 8.21
(IH, dd, J 8.8Hz, 1.9Hz); 7.80 (IH, d, J 8.8Hz); 7.69 (2H, d, J 9.5Hz); 7.02 (2H, d, J 8.8Hz); 3.75-3.82 (4H, m); 3.38 (2H, q, J 6.9Hz); 3.11-3.17 (4H, m); 1.21 (3H, t, J 6.9Hz), LC-MS rt 2.15, m/z 378
Example 33: N-{3-[4-(4-Morpholin-4-yl-phenylamino)-quinazolin-6-yl]-phenyl}- acetamide
By a similar method to Example 15, the title compound was isolated as a brown solid by preparative LC-MS (5mg). δ (DMSO) 2.10 (s, 3H) 3.13 (s, 4H) 3.77 (s, 4H) 7.01 (d, 2H) 7.54 (m, 2H) 7.67 (d, 2H) 7.85 (d, IH) 8.03 (m, 2H) 8.53 (s, IH) 8.79 (s, IH) 9.89 (s, IH) 10.15 (s, IH) LC/MS RT= 3.62 min Found ES+ =449.4
Example 34: {4-[4-(4-Morpholin-4-yI-phenylamino)-quinazolin-6-yl]-phenyI}- carbamic acid benzyl ester By the method of Example 15, δ (DMSO) 3.10-3.14 (t,2H), 3.75-3.93 (t, 2H),
5.19 (s, 2H), 6.99-7.03 (d, 2H, J=9Hz), 7.36-7.48 (m,5H), 7.64-7.68 (t, 3H), 7.78-7.87 (m, 3H), 8.13-8.16 (dd, IH), 8.33-8.35 (d, IH), 8.50 (s, IH), 8.77 (s, IH), 9.82 (s, IH), 9.97 (s, IH); LC-MS m/z 533, rt 2.81 Example 35: N-{4-[4-(4-Morpholin-4-yl-phenylamino)-quinazoIin-6-yI]-phenyl}- acetamide By the method of Example 15, δ (DMSO) 2.17-2.19 (s, 3H), 3.21-3.24 (t, 4H), 3.85-3.89 (t, 4H), 7.10-7.13 (d, 2H), 7.75-7.79 (d, 2H), 7.84-7.98 (m, SH), 8.24-8.27 (d, IH), 8.60 (s, IH), 8.88 (s, IH), 9.92 (s, IH), 10.23 (s, IH), LC-MS m/z 440, rt 2.44
Example 36: {4-[4-(4-Morpholin-4-yI-phenyIamino)-quinazolin-6-yI]-phenyI}- carbamic acid tert-butyl ester By the method of Example 15, δ 1.47 (s, 9H), 3.06-3.10 (t, 4H), 3.71-3.74 (t,
4H), 6.95-6.99 (d, 2H), 7.57-7.64 (m, 4H), 7.76-7.79 (t, 3H), 8.10-8.12 (d, IH), 8.45 (s, IH), 8.75 (s, IH), 9.50 (s, IH), 9.75 (s, IH); LC-MS m/z 498, rt 2.86
Example 37: {3-[4-(4-Morpholin-4-yl-phenyIamino)-quinazoIin-6-yl]-benzyI}- carbamic acid tert-butyl ester By the method of Example 15, δ 1.17 (s, 3H), 2.87-2.90 (t, 4H), 3.51-3.55 (t, 4H), 4.01-4.03 (d, 2H), 6.75-6.79 (d, 2H), 7.27-7.31 (d, 2H), 7.41-7.44 (t, 2H), 7.49- 7.51 (d, IH), 7.58-7.62 (d, IH), 7.87 (d, IH), 7.9 (d, IH), 8.2 (s, IH), 8.28 (s, IH), 8.56 (s, IH), 9.65 (s, IH), LC-MS m/z 514, rt 2.18
Example 38: N-{3-[4-(4-Morpholin-4-yl-phenyIamino)-quinazolin-6-yI]-phenyl}- methanesulfonamide By the method of Example 15 δ (DMSO,) 2.86-2.89 (s, 3H), 2.95-2.98 (t, 4H , 3.53-3.57 (t, 4H), 6.86-6.89 (d, 2H), 7.07-7.10 (d, IH), 7.31-7.45 (m, 5H), 7.88 (d, IH), 8.07-8.10 (d, IH), 8.65 (s, IH), 9.05 (s, IH), 9.35 (s(broad), IH), 9.78 (s, IH), 11.79 (s, IH), LC-MS m/z 476 rt 2.54
Example 39: (6-Iodo-quinazolin-4-yl)-(4-morphoIin-4-yl-2-trifluoromethyl-phenyI)- amine Step 1: A solution of 5-fluoro-2-nitrobenzotrifluoride (2.1g, lOmM) and triethylamine (2.50ml, 24mMol) in acetonitrile (35ml) was treated with moφholine (1.74ml, 20mMol). The resulting solution was heated at reflux overnight. On cooling, the reaction solvent was removed under vacuum and the crude residue partitioned between dichloromethane and 10% (w/v) citric acid solution. The organics were separated, dried over magnesium sulphate and reduced under vacuum to give 4-(4-nitro- 3-trifluoromethyl-phenyl)-moφholine (2.63g, 95%), LC/MS: RT- 3.69, no ionization δ (CDC13) 8.04 (IH, d, J 8.8Hz); 7.17 (IH, d, J 3.2Hz); 6.96 (IH, dd, J 8.8Hz, 2.5Hz); 3.89 (4H, t, J 4.5Hz); 3.40 (4H, t, J 4.5Hz) Step 2: A suspension of 4-(4-nitro-3-trifluoromethyl-phenyl)-moφholine (2.63g, 0.95mMol) and 10% palladium on carbon (263mg) in 2:1 toluene : ethanol (75ml) was placed under an atmosphere of hydrogen, using standard procedures, until reaction was complete. The reaction mixture was filtered through a pad of celite, which was then washed with ethanol. The filtrates were reduced under vacuum to give 4-morpholin-4- yl-2-trifluoromethyl-phenylamine as a beige solid.(1.25g , 53%), LC/MS: RT - 2.40, no ionization, δ (CDC13) 7.05-7.12 (2H, m); 6.83 (IH, d, J 8.8Hz); 3.96 (4H, t, J 4.4Hz); 3.14 (4H, t, 4.4Hz) Step 3 : Treatment of the product from step 2 ( 280mg) with 4-chloro-6-iodo- quinazoline (300mg, l.lmMol) in acetonitrile (4ml) at reflux overnight, gave a precipitate. The reaction was cooled and the precipitate filtered off. This was washed with IM sodium hydroxide solution and water before being air dried to the title compound δ (DMSO) 9.79 (IH, s); 8.85 (IH, s); 8.27 (IH, d, J 12.0Hz); 8.03 (IH, d, J 7.0Hz); 7.17-7.43 (4H, m); 3.72-3.78 (4H, m); 3.16-3.23 (4H, m), LC/MS: RT-2.80, MH+ @ 501,
Example 40 : (4-Morpholin-4-yl-2-trifluoromethyl-phenyI)-(6-thiophen-2-yI- quinazolin-4-yI)-amme A solution of Example 39 (170mg, 0.4mMol), 2-thiopheneboronic acid (50mg, 0.4mMol), triethylamine (120μl, l.OmMol) and tris(dibenzylideneacetone)- dipalladium(O) (50mg, 15Mol%) in anhydrous tetrahydrofuran (3ml) was heated at reflux overnight. On cooling, the reaction mixture was reduced onto silica and flash chromatography (eluting with a dichloromethane - 2.5% methanol in dichloromethane gradient) gave the title compound as a yellow solid. δ (DMSO) 9.84 (IH, s); 8.71 (IH, s); 8.31 (IH, s); 8.09 (IH, d, J 8.2Hz); 7.73 (IH, d, J 8.8Hz); 7.65 (IH, d, J 3.2Hz); 7.60 (IH, d, J 5.1Hz); 7.14-7.36 (4H, m); 3.67-3.77 (4H, m); 3.13-3.19 (4H, m). LC/MS: RT- 2.80, MH" @457 Example 41 : (6-Iodo-quinazoIin-4-yI)-(3-methoxy-4-morpholin-4-yl-phenyI)-amine Step 1: 2-bromo-5-nitro-anisole ( 0.5g) and moφholine ( 1.92g) were heated together at 130° overnight. The cooled reaction mixture was added to ice and the resulting precipitate washed with water and dried to give the desired 4-(2-methoxy-4- nitro-phenyl)-moφholine (91%, m/z 239) Step 2: Hydrogenation of the nitro group using palladium on carbon as catalyst at rt in ethanol gave 3-methoxy-4-moφholin-4-yl-phenylamine as a brown solid (76%,
0.159g) which was used without further purification. Step 3: Heating of 3-methoxy-4-moφholin-4-yl-phenylamine (136mg ) and 4- chloro-6-iodoquinazoline (186mg) in acetonitrile (10ml) at reflux overnight gave, on cooling, a precipitate that was isolated by filtration, washed with water then slurried with IN NaOH and washed with further water and dried. This gave the title compound
(263mg, 88%) δ (DMSO) 11.01 (IH, br s); 9.20 (IH, s); 8.83 (IH, s); 8.29 (IH, d, J8.85Hz);
7.67 (IH, d, J8.85Hz); 7.40 (2H, m); 6.98 (IH, d, J8.85Hz); 8.83 (3H, s); 3.76 (4H, m);
3.01 (4H, m)., LC-MS rt 2.74, m/z E+463
Example 42 : (3-Methoxy-4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl-quinazolin-4- yl)-amine A similar method to Example 15, using Example 41 as starting material gave the title compound ( 14mg, 11%) δ (DMSO) 9.96 (IH, s); 8.86 (IH, s); 8.61 (IH, s); 8.22 (IH, d, J8.85Hz); 7.87 (IH, d, J8.85Hz); 7.83 (IH, d, J3.79Hz); 7.76 (IH, d, J5.06Hz); 7.48 (2H, m); 7.33 (IH, t J5.05,3.79Hz); 7.03 (IH, d, J8.85Hz); 3.92 (3H, s); 3.84 (4H, m); 3.07 (4H, m), LC- MS rt 3.63, m/z E+419
Example 43: (2-Methyl-4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl-quinazolin-4- yl)-amine Step 1: A solution of 5-fluoro-2-nitrotoluene (1.22ml, lOmM) and triethylamine
(2.10ml, 20mMol) in acetonitrile (30ml) was treated with moφholine (1.74ml, 20mMol). The resulting solution was heated at reflux overnight. On cooling, the reaction solvent was removed under vacuum and the crude residue partitioned between dichloromethane and 10% (w/v) citric acid solution. The organics were separated, dried over magnesium sulphate and reduced under vacuum to give 4-(3-methyl-4- nitroρhenyl)-moφholine. ( 1.96g , 88%) LC/MS: RT - 2.76, no ionization • Step2: A suspension of 4-(3-methyl-4-nitrophenyl)-moφholine 1.96g, (8.9mMol) and 10% palladium on carbon (lOOmg) in toluene (30ml) was placed under an atmosphere of hydrogen, using standard procedures, until reaction was complete. The reaction mixture was filtered through celite and the liquors reduced under vacuum to give 2-methyl-4-moφholin-4-yl-phenylamine as a dark brown solid. (1.07g, 63%), LC/MS: RT- 0.71, Mrf" @ 193; δ (CDC13) 6.74 (IH, s); 6.64-6.70 (2H, m); 3.88 (4H, t, J 4.5Hz); 3.06 (4H, t, J 4.5Hz); 1.99 (3H, s) Step3: A suspension of 4-chloro-6-iodo-quinazoline (5.00mg, l.SmMol) and 2- methyl-4-moφholin-4-yl-phenylamine (360mg, 1.9mMol) in acetonitrile (3 ml) was heated at reflux overnight, during which a precipitate developed. The reaction was cooled and the precipitate filtered off. This was washed with IM sodium hydroxide solution and water before being air dried to give (6-iodo-quinazolin-4-yl)-(2-methyl-4- moφholin-4-yl-phenyl)-amine(738mg , 95%). LC/MS: RT- 3.55, MH1" @ 447 δ (DMSO) 10.35 (IH, br s); 9.04 (IH, d, 1.3Hz); 8.55 (IH, s); 8.20 (IH, dd, J 8.8Hz, 1.3Hz); 7.60 (IH, d, J 8.8Hz); 7.14 (IH, d, J 8.8Hz); 6.92 (IH, d, J 2.5); 6.87 (IH, dd, J 8.2Hz, 1.9Hz); 3.77 (4H, t, 4.4Hz); 3.15 (4H, t, 4.4Hz); 2.15 (3H, s) Step 4: A solution of (6-iodo-quinazolin-4-yl)-(2-methyl-4-moφholin-4-yl- phenyl)-amine (250mg, 0.6mMol), 2-thiopheneboronic acid (75mg, 0.6mMol), triethylamine (150μl, 1.2mMol) and tris(dibenzylideneacetone)dipalladium(0) (50mg, 10Mol%) in anhydrous tetrahydrofiiran (10ml) was heated at reflux overnight. On cooling, the reaction mixture was reduced onto silica and flash chromatography (eluting with a 200:8:1 dichloromethane:ethanol:aqueous ammonia mixture) gave (2-methyl-4- moφholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine as a yellow solid. LC/MS: RT- 3.54, MH" @ 403; δ (DMSO) 9.89 (IH, s); 8.89 (IH, d, J 1.9Hz); 8.46 (IH, s); 8.25 (IH, dd, J 8.8Hz, 1.9Hz); 7.89 (IH, d, J 8.8Hz); 7.84 (IH, 3.8Hz), 7.78 (IH, d, J 5.0Hz); 7.36 (IH, dd, J 5.0Hz, 3.8Hz); 7.30 (IH, d, 8.2Hz); 7.05 (IH, d, 1.9Hz); 6.98 (IH, dd, J 8.8Hz, 3.2Hz); 3.90 (4H, t, J 4.4Hz); 3.28 (4H, t, J 4.4Hz); 2.29 (3H, s) Example 44: (3-Methyl-4-morpholin-4-yI-phenyl)-(6-thiophen-2-yl-quinazolin-4- yl)-amine Step 1: A solution of 2-fluoro-5-nitrotoluene (1.65g, 10.6mMol), triethylamine (2.96ml, 21.2mMol) and morpholine (1.86ml, 21.2mMol) in acetonitrile (30ml) was heated at reflux overnight. On cooling, the reaction solvent was reduced under vacuum and the residue taken into morpholine. This solution was heated at 100°C until the reaction was complete by TLC. The reaction mixture was diluted with dichloromethane and washed with IM citric acid solution. The organics were dried over magnesium sulphate and reduced under vacuum to give an oil. This was further purified by flash chromatography (eluting with a petrol - 9:1 petrol : ethyl acetate gradient) to give 4-(2- methyl-4-nitro-phenyl)-moφholine as an orange solid. (0.53g, 22%), LC/MS: RT- 3.76, no ionization; δ (CDCh) 7.99-8.02 (2H, m); 6.94 (IH, d, J 9.5Hz); 3.81 (4H, t, J 4.5Hz); 2.95 (4H, t, J 4.5Hz); 2.31 (3H, s) Step 2: A suspension of 4-(2-methyl-4-nitro-phenyl)-morpholine (0.53g, 2.4mMol) and 10% palladium on carbon (55mg) in 1:1 toluene : ethanol (25ml) was placed under an atmosphere of hydrogen, using standard procedures, until reaction was complete. The reaction mixture was filtered through a pad of celite, which was then washed with ethanol. The filtrates were reduced under vacuum to give 3-methyl-4- moφholin-4-yl-phenylamine as a tan solid.( 0.47g , 100%), LC/MS: RT - 2.66, MH* @ 193; δ (CDCI3) 6.82 (IH, d, J 8.2Hz); 6.48-6.54 (2H, m); 3.76 (4H, t, J 4.4Hz); 2.76 (4H. 4.4Hz); 2.18 (3H, s) Step 3: A suspension of 4-chloro-6-iodo-quinazoline (300mg) and 3-methyl-4- moφholin-4-yl-phenylamine (240mg) in acetonitrile (4ml) was heated at reflux overnight, during which a precipitate developed. The reaction was cooled and the precipitate filtered off. This was washed with IM sodium hydroxide solution and water before being air dried to give (6-iodo-quinazolin-4-yl)-(3-methyl-4-moφholin-4-yl- phenyl)-amine. LC/MS: RT - 2.81, M-H @ 447; δ (DMSO) 9.82 (IH, s); 9.03 (IH, d, J 1.9Hz); 8.59 (IH, s); 8.12 (IH, dd, J 8.8Hz, 1.9Hz); 7.60-7.70 (2H, m); 7.58 (IH, d, J 8.8Hz); 7.09 (IH, d, J 8.8Hz); 3.78 (4H, t, J 4.1Hz); 2.87 (4H, t, J 4.1Hz); 2.32 (3H, s) Step 4: A solution of (6-iodo-quinazolin-4-yl)-(3-methyl-4-morpholin-4-yl- phenyl)-amine (170mg, 0.4mMol), 2-thiopheneboronic acid (50mg, 0.4mMol), triethylamine (120μl, l.OmMol) and tris(dibenzylideneacetone)dipalladium(0) (50mg, 15Mol%) in anhydrous tetrahydrofiiran (3ml) was heated at reflux overnight. On cooling, the reaction mixture was reduced onto silica and flash chromatography (eluting with a dichloromethane - 2.5% methanol in dichloromethane gradient) gave (3-methyl- 4-morpholin-4-yl-phenyl)-(6-thiophen-2-yl-quinazolin-4-yl)-amine as a yellow solid. LC/MS: RT-2.76, MH1" @ 403; δ (DMSO) 10.05 (IH, s); 8.97 (IH, d, J 1.9Hz); 8.71 (IH, s); 8.32 (IH, dd, J 8.8Hz, 1.9Hz); 7.99 (IH, d, J 8.8Hz); 7.93 (IH, dd, J 3.8Hz, 1.3Hz); 7.87 (IH, dd, J 5.1Hz, 1.3Hz); 7.75-7.85 (3H, m,); 7.44 (IH, dd, J 5.1Hz, 3.2Hz); 7.29 (IH, d, J 8.8Hz); 3.96 (4H, t, J 4.4Hz); 3.06 (4H, t, J 4.4Hz); 2.51 (3H, s)
Example 45: Ethyl-(4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl-quinazolin-4-yI)- amine Step 1 : To a stirred solution of dry DMF (10ml) was added N-(4- aminophenyl)morpholine (0.5g, 2.80mmol) followed by Et3N (0.70g, 7.0mmol) . Acetyl chloride (0.24g, 3.10mmol) was added slowly and the mixture stirred at room temperature overnight. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2 x 20 ml). The organic washings were combined and dried (Na2SO4) and the solvent was removed under vacuum to afford N-(4-morpholin-4-yl-phenyl)-4- acetamide as a solid. Yield 0.29g (47%). δ (DMSO) 9.71 (IH, bs); 7.42 (2H, d, J8.85HZ); 6.87 (2H, d, J9.48Hz); 3.72 (4H, m); 3.01 (4H, m); 1.98 (3H, s), LCMS : RT 1.97, ES+ 221 Step 2: Treatment of N-(4-moφholin-4-yl-phenyl)-4-acetamide (lg) in a similar manner to Example 46, Step 2, gave semi crude.ethyl-(4-morpholin-4-yl-phenyl)-amine (0.92g,) which was reacted with 4-chloro-6-iodoquinazoline as per Example 46, Step 3 and then reacted as per Example 44, Step 4 to give the title compound (104mg, 61%) δ(DMSO) 8.61 (IH, s); 8.18 (IH, s); 7.93 (IH, d, J8.85Hz); 7.70 (2H, d, J8.85Hz); 7.50 (IH, d, J4.42Hz); 7.14 (5H, m); 4.11 (2H, m); 3.76 (4H, m); 3.19 (4H, m); 1.22 (3H, t, J6.3 lHz), LC-MS rt 2.67, m/z E+417
Example 46 : (6-Iodo-quinazolin-4-yI)-methyl-(4-morpholin-4-yl-phenyl)-amine Step 1 : Formic acid ( 0.41g) was added to acetic anhydride (0.75g) with stirring at 0° then heated to 50° for 2h. The cooled mixture was diluted with dry THF ( 5ml) and 4-moφholinoaniline (0.5g) added and the mixture returned to for 3h. The solvent was removed in vacuo to give N-(4-moφholin-4-yl-phenyl)4-formamide as a yellow solid (450mg, 77%) , δ(DMSO) 8.72 (IH, s), 7.90 (1H, d, J8.85Hz); 7.51 (IH, d, J8.85Hz);
7.15 (5H, m); 3.81 (4H, m); 3.56 (3H, s); 3.21 (4H, m), LC-MS rt 2.62, m/z E+447. Step2: A solution of N-(4-morpholin-4-yl-phenyl)4-formamide (0.29g) in dry
THF (2ml) was treated with sodium borohydride (160mg) at 0° and stirred for 30minutes. A solution of BF3/Et2O (0.67ml) was added over a period of 10 min and stirred for a further 1 hr at 0°C. The mixture was then heated at reflux for 5 hr. The mixture was cooled and water (3ml) was added dropwise to hydrolyse excess sodium borohydride. The mixture was extracted with diethyl ether (2 x 10ml). The organic washings were combined dried (Na2SO4) and the solvent was removed under vacuum to afford methyl-(4-moφholin-4-yl-phenyl)-amine as a white solid. Yield 43mg (16%) δ
(DMSO) 6.76 (2H, d, J8.85Hz); 6.47 (2H, d, J8.85Hz); 5.17 (IH, bs); 3.69 (4H, m);
2.87 (4H, m); 2.60 (3H, s), LCMS : RT 2.35, ES+ 193 Step 3: Heating of methyl-(4-moφholin-4-yl-phenyl)-amine (37mg ) and 4- chloro-6-iodoquinazoline (52mg) in acetonitrile (6ml) at reflux overnight gave, on cooling, a precipitate that was isolated by filtration, washed with water then slurried with IN NaOH and washed with further water and dried. This gave the title compound
(22mg, 28%) δ(DMSO) 8.72 (IH, s), 7.90 (IH, d, J8.85Hz); 7.51 (IH, d, J8.85Hz);
7.15 (5H, m); 3.81 (4H, m); 3.56 (3H, s); 3.21 (4H, m), LC-MS rt 2.62, m/z E+447
Example 47: (6-Iodo-quinazolin-4-yl)-(3-methyl-butyl)-(4-morpholin-4-yl-phenyl)- amine Step 1: To a carousel tube was added N-(4-aminophenyl)moφholine (0.25g, 1.40mmol). DCM (DRY 15ml), molecular sieve 3A ( excess 0.2g) and 3-methyl- butylaldehyde (0.14g, 1.4mmol). The mixture was stirred for 1 hr at room temperature and then at 45°C for 2 hr. The mixture was cooled and acetic acid (1ml) was added followed by sodium triacetoxy borohydride (0.60g, 2.80mmol) and the mixture was left to stir overnight at room temperature. The solvent was removed under vacuum and the crude product was purified by column chromatography on silica using 2.5% MeOH : DCM, to give (3-methyl-butyl)-(4-moφholin-4-yl-phenyl)-amine Yield 0.20g (57%), δ (DMSO) 6.75 (2H, d, J8.85Hz); 6.50(2H, d, J8.85Hz); 3.71(4H, m); 3.17 (2H, m); 2.89 (4H, m); 1.66 (IH, m); 1.39 (2H, m); 0.91 (6H, d, J6.32Hz), LCMS : RT 2.22, ES+249 Step 2: Treatment of (3-methyl-butyl)-(4-morpholin-4-yl-phenyl)-amine (210mg) as per Example 47, step 3 gave the title compound (294mg, 71%), δ(DMSO) 8.69 (IH, s); 7.89 (IH, dd, J8.85Hz, 1.9Hz); 7.50 (IH, d, J8.85Hz); 7.16 (4H, AB, J8.85Hz); 7.06 (IH, d, J1.90Hz); 4.12 (2H, t, J7.58Hz); 3.80 (4H, m); 3.23 (4H, m); 1.62 (2H, m); 1.37 (IH, m); 0.94 (6H, d, 6.32Hz), LC-MS rt 3.11, m/z E+503
Example 48: Isopropyl-(4-morpholin-4-yI-phenyl)-(6-thiophen-2-yl-quinazolin-4- yl)-amine By a similar method to Example 47 followed by a similar method to Example 45 step 4 was obtained the title compound (4.5mg) δ(DMSO) 8.61 (IH, s); 7.90 (IH, d, J7.58Hz); 7.67 (IH, d, J8.85Hz); 7.51 (IH, d, J4.42Hz); 7.09 (7H, m); 5.51 (IH, m); 3.77 (4H, m); 3.23 (4H, m); 1.18 (6H, d, J6.32Hz) , LC-MS rt 2.74, m/z E+431
Example 49: (3-Methyl-butyl)-(4-morpholin-4-yl-phenyI)-(6-thiophen-2-yl- quinazolin-4-yl)-amine By a similar method to Example 44 step 4 was obtained the title compound (12.5mg) δ(DMSO) 8.63 (IH, ); 8.21 (IH, s); 7.94 (IH d, J8.85Hz); 7.72 (2H, m); 7.52 (IH, d, J5.06Hz); 7.12 (5H, m); 4.13 (2H, m); 3.78 (4H, m); 3.20 (4H, m); 3.0 (3H, m); 1.15 (6H, t, J7.58Hz) , LC- MS rt 2.98, m/z E+459
Example 50: [6-(2-Benzyloxy-phenyl)-quinazolin-4-yI]-(4-morpholin-4-yl-phenyI)- amine By a similar method to Example 15 was obtained the title compound LC-MS m/z 489.4 rt 2.82
Example 51 : [6-(4-Benzyloxy-phenyI)-quinazoIin-4-yI]-(4-morpholin-4-yl-phenyl)- amine By a similar method to Example 15 was obtained the title compound (DMSO, δ) 3.07-3.10 (t, 4H), 3.71-3.75 (t, 4H), 5.18 (s, 2H), 6.95-6.99 (d, 2H), 7.14-7.18 (d,
2H), 7.28-7.48 (m, 5H), 7.60-7.64 (d, 2H), 7.74-7.83 (m, 3H), 8.08-8.12 (d, IH), 8.45
(s, IH), 8.71 (s, IH), LC-MS m/z 490 rt 2.89
Activity Example
Cells used: 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.
Cell culture conditions: Cells were cultured at 37°C in a 5% CO2 environment and split twice a week on seeding at 2 x 10E6 cells/flask on day 1 and 1 x 10E6 3 days later. Some 0.25mg/ml G418 was added to the culture medium (125ul per 25ml) but not the assay medium. The culture medium consisted of DMEM with 4500g/l glucose and glutamax
(Gibco 61965-026) supplemented with 1 x non-essential amino acids, penicillin (100 IU/ml) / streptomycin (100 μg/ml), FCS (10%, 50ml) and 1 mg/ml G418 (Invitrogen cat no 10131-027) & 10 % foetal calf serum.
Assay procedure: A flask of cells was trypsinised and a cell count carried out. Cells were diluted to 100,000 cells/ml and 100 μl of this used to seed one opaque white 96-well plate (for the replicon assay) and one flat-bottomed clear plate (for the tox assay) for every seven compounds to be tested for IC50. Wells G12 and H12 were left empty in the clear plate as the blank. Plates were then incubated at 37°C in a 5% CO2 environment for 24 h.
On the following day compound dilutions are made up in medium at twice their desired final concentration in a clear round bottomed plate. All dilutions have a final DMSO concentration of 1%.
Once the dilution plate had been made up, controls and compounds were transferred to the assay plate (containing the cells) at lOOμl /well in duplicate plates.
Exception: in the white (replicon) plate, no compound was added to wells Al and A2 and 100 μl of 1% DMSO was added to these instead. In the clear (Tox) plate, wells El 2 & F12 only contained the DMSO control. Plates were then incubated at 37°C with 5% CO2 for 72h. At the end of the incubation time, the cells in the white plate were harvested by washing with 200 μl/ well of warm (37°C) PBS and lysed with 20 μl cell culture lysis buffer (Promega). After 5 min incubation @ RT, luciferin solution was added to the luciferase assay buffer (LARB at 200 μl per 10 ml LARB. The M injector of the microplate luminometer (Lmax, Molecular Devices) was primed with 4 x 300 1 injections. Plate were inserted into the luminometer and 100 μl 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 IC50, 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 μl 0.5% methylene blue in 50% ethanol at RT for lh, followed by solvation of the absorbed methylene blue in 100 μl 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 620nm vs drug concentration.
Table 1
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001

Claims

1. A compound which is a quinazoline derivative of formula (la), or a pharmaceutically acceptable salt thereof,
Figure imgf000045_0001
wherein Ri represents hydrogen, halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cj-C4 alkoxy, C C4 haloalkoxy, -COzR7, -CONR'R , -A, -A-L-A7, -Z-L-A or -A-L-Z-L-A, wherein R; and R; are the same or different and each represent hydrogen or Cι-C4 alkyl; R2 represents hydrogen, halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C4 alkoxy or Cι-C4 haloalkoxy; R3 represents hydrogen, Cι-C4 alkyl, Cι-C4 haloalkyl, Cι-C4 alkoxy or Cι-C4 haloalkoxy; and Ri represents hydrogen, Cι-C6 alkyl or -Ce haloalkyl, wherein: A represents a C6 to o aryl, 5- to 10- membered heteroaryl or 5- to 10 membered heterocyclyl group; each L is the same or different and is a direct bond or a Cι-C4 alkylene group; - A is a 5- to 10- membered heteroaryl or 5- to 10- membered heterocyclyl group; and Z is -S-, -O-, -NR7-, -CO2-, -C(O)NR7-, -OC(O)-, -NR'C(O)-, -OCO2-, -NR;CO2-, -OC(O)NR7-, or -NR'C^ R7'-, wherein R'and R/! are the same or different and represent hydrogen or -C4 alkyl, the aryl, heteroaryl and heterocyclyl moieties in Ri being unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, CpC4 alkyl, Cι-C4 haloalkyl, Cι-C4 haloalkoxy, hydroxy, thiol, -NH2, Cι-C4 hydroxyalkyl, Cι-C4 thioalkyl, Cι-C4 aminoalkyl, cyano, nitro, -COR7, -CO2R, -S(O)R7, -S(O)2R7, -CONR7R77 and -L-X-L -Y substituents, wherein each R7 and R7 is the same or different and is selected from hydrogen and Cι-C4 alkyl, L7 is a direct bond or a Cι-C4 alkylene group, X is -S-, -O- or -NR7- wherein R7 is as defined above, L is a direct bond or a Cι-C4 alkylene group and Y is hydrogen, -COR/, -CO2R/, -S(O)2R/ or -S(O)R/, wherein R/ is hydrogen or C C4 alkyl.
2. A compound according to claim 1, wherein L7 is a direct bond or a Cι-C2 alkylene group.
3. A compound according to claim 1 or 2, wherein X is -O- or -NR7- wherein R7 is as defined in claim 1.
4. A compound according to any one of the preceding claims, wherein L77 is a direct bond or a Cι-C2 alkylene group.
5. A compound according to any one of the preceding claims, wherein Y is hydrogen, -COR/, -CO2R/, -S(O)R or -S(O)2R/, wherein R/ is a d-C4 alkyl group.
6. A compound according to any one of the preceding claims, wherein the aryl, heteroaryl and heterocyclyl moieties in the Ri substituent are unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, Cι-C4 alkyl, Cι-C4 haloalkyl, C,-C4 haloalkoxy, C C4 hydroxyalkyl, cyano, -COR7 -CO2R, -S(O)R7, -S(O)2R, and -L7-X-L7/-Y substituents, wherein R7, L7, X, l!1 and Y are as defined in any one of the preceding claims.
7. A compound according to any one of the preceding claims, wherein the aryl, heteroaryl and heterocyclyl moieties in the R\ substituent are unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cj-C2 alkyl, Cι-C2 haloalkyl, Cι-C2 hydroxyalkyl, cyano, -COR7, -CO2R7, -S(O)R7, -S(O)2R7, -(C C2 alkyl)-NR7R77, CrC2 alkoxy, -NR7-COR/, NR-CO2R/, -(CrC2 alkyl)-NR-CO2R/, -NR-S(O)2-R/ and -(C1-C2 alkyl)-NR-(Cι-C2 alkyl)-S(O)2-R77 substituents, wherein each R7, R7 and R/ are the same or different and represent hydrogen or Cι-C2 alkyl.
8. A compound according to any one of the preceding claims, wherein A is a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group.
9. A compound according to any one of the preceding claims, wherein A is a phenyl, furanyl, thienyl, pyrimidinyl, thiazolyl or pyridazolyl group.
10. A compound according to any one of the preceding claims, wherein L is a direct bond or a CpC2 alkylene group.
11. A compound according to any one of the preceding claims, wherein A7 is a 5- to 6- membered heterocyclyl or heteroaryl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, CpC4 alkyl, Cι-C4 haloalkyl and Cι-C4 haloalkoxy substituents.
12. A compound according to any one of the preceding claims, wherein A7 is a moφholinyl, thiomoφholinyl, piperazinyl, 1,3-dioxolanyl, S,S-dioxothiomoφholinyl or pyrazolyl group which is unsubstituted or substituted by one or two substituents selected from Cj-C2 alkyl, halogen and Cι-C2 haloalkyl substituents.
13. A compound according to any one of the preceding claims, wherein Z is -O-, -CONR7-, -NR7C(O)- or -NR7CO2-, wherein R7 is as defined in any preceding claim.
14. A compound according to any one of the preceding claims, wherein Z is -O-, -CONH- or -CON(C C2 alkyl)- or -NHC(O)-, -NHCO2-.
15. A compound according to any one of the preceding claims, wherein Ri is halogen, Cι-C alkyl, Cι-C4 haloalkyl, d-C4 alkoxy, Cι-C4 haloalkoxy, -CO2R7,
-CONR7R7, -A, -A-L-A7, -Z-L-A, or -A-L-Z-L-A wherein R7, R77, A, L, A7 and Z are as defined in any one of the preceding claims.
16. A compound according to any one of the preceding claims, wherein Ri is halogen, Cι-C2 alkoxy, Cι-C2 haloalkoxy, -CONR7R77, -A, -Ar-L-A7, -Z-L-A or -Ar-Z-L- Ar, wherein R7 and R77 are the same or different and each represent hydrogen or a Cι-C2 alkyl group, A and A7 are as defined in any one of the preceding claims, Ar is an unsubstituted furanyl or unsubstituted phenyl group, L is a direct bond or a methylene group and Z is -O-, -C(O)NR7-, -NRC(O)- or -NR7CO2-, wherein R is hydrogen or a Cι-C4 alkyl group
17. A compound according to any one of the preceding claims, wherein R2 is hydrogen, Cι-C4 alkyl or Cι-C4 alkoxy.
18. A compound according to any one of the preceding claims, wherein R3 is hydrogen, Cι-C2 alkyl, Cι-C2 haloalkyl or Cι-C2 alkoxy.
19. A compound according to any one of the preceding claims, wherein IU is hydrogen or Cι-C6 alkyl.
20. A compound according to any one of the preceding claims, wherein the quinazoline derivative of formula (la) is a quinazoline derivative of formula (I),
wherein: Ri is halogen, Cι-C2 alkoxy, Cι-C2 haloalkoxy, -A or -Ar-L-A7; R2 is hydrogen or Cι-C2 alkoxy; A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl, pyrimidinyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cι-C2 alkyl, Cι-C2 alkoxy, Cι-C2 haloalkyl, d-C2 hydroxyalkyl, -COR7, -CO2R, -S(O)R7, -S(O)2R7, -(Cι-C2 alkyl)-NR7R77 and -(Cι-C2 alkyl)-NR-(Cι-C2 alkyl)-S(O)2-R77 substituents, wherein each R7 and R77 are the same or different and represent hydrogen or Ci- C2 alkyl; - Ar is an unsubstituted furanyl group; L is a direct bond or a methylene group; and A7 is a 5- to 6- membered heterocyclyl group, for example moφholinyl, thiomoφholinyl, piperazinyl, 1,3-dioxoanyl and S,S-dioxothiomorpholinyl, which is unsubstituted or substituted by one or two substituents selected from Cι-C2 alkyl, halogen and Cι-C2 haloalkyl groups.
21. A compound according to claim 20, wherein: Ri is halogen, Cι-C2 alkoxy, Cι-C2 haloalkoxy, -A or -Ar-L-A7; R2 is hydrogen or Cι-C2 alkoxy; - A is a phenyl or 5- to 6- membered heteroaryl group, for example furanyl, thienyl and thiazolyl, which group is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cι-C2 alkyl, Cι-C2 haloalkyl, Cι-C2 hydroxyalkyl, -COR7, -(C,-C2 alkyl)-NRR and -(Cι-C2 alkyl)-NR7-(d-C2 alkyl)-S(O)2-R77 substituents, wherein each R7 and R77 are the same or different and represent hydrogen or Cι-C2 alkyl; Ar is an unsubstituted furanyl group; L is a direct bond or a methylene group; and A7 is a 5- to 6- membered heterocyclyl group, for example moφholinyl, thiomoφholinyl, piperazinyl, 1,3-dioxoanyl and S,S-dioxothiomorpholinyl, which is unsubstituted or substituted by one or two substituents selected from Cι-C2 alkyl, halogen and Cι-C2 haloalkyl groups.
22. A quinazoline derivative of the formula (la), as defined in any one of the preceding claims, for use in treating the human or animal body.
23. A pharmaceutical composition which comprises a quinazoline derivative of the formula (la), as defined in any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
24. Use of a quinazoline derivative of the formula (la), as defined in any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing a flaviviridae infection.
25. Use according to claim 24, wherein the flaviviridae infection is a pestivirus infection.
26. Use according to claim 25, wherein the pestivirus infection is an infection by a bovine viral diarrhea virus, classical swine fever virus or border disease virus.
27. Use according to claim 24, wherein the flaviviridae infection is a flavivirus infection.
28. Use according to claim 27, wherein the flavivirus infection is an infection by a yellow fever virus, dengue fever virus, Japanese encephalitis virus or tick borne encephalitis virus.
29. Use according to claim 24,wherein the flaviviridae infection is a hepacivirus infection.
30. Use according to claim 29, wherein the hepacivirus infection is an infection by a hepatitis C virus.
31. Use according to claim 30, wherein the medicament further comprises (a) interferon or a derivative thereof and/or (b) ribavirin or a derivative thereof.
32. Use according to claim 31 wherein the interferon derivative is PEG-interferon and/or the ribavirin derivative is viramidine.
33. A product containing: (a) a quinazoline derivative of the formula (la), as defined in any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof; and (b) interferon, or an interferon derivative as defined in claim 31 or 32 and/or ribavirin or a ribavirin derivative as defined in claim 31 or 32; for simultaneous, separate or sequential use in the treatment of the human or animal body.
34. A method of treating a patient suffering from or susceptible to a flaviviridae infection, as defined in any one of claims 24 to 30, which method comprises administering to said patient an effective amount of a quinazoline derivative of the formula (I) as defined in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.
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Cited By (49)

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