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WO2007028789A1 - Quinazoline derivatives as antiviral agents - Google Patents

Quinazoline derivatives as antiviral agents Download PDF

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Publication number
WO2007028789A1
WO2007028789A1 PCT/EP2006/066002 EP2006066002W WO2007028789A1 WO 2007028789 A1 WO2007028789 A1 WO 2007028789A1 EP 2006066002 W EP2006066002 W EP 2006066002W WO 2007028789 A1 WO2007028789 A1 WO 2007028789A1
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Prior art keywords
chlorophenyl
amino
optionally substituted
hydroxy
hydrogen
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Inventor
Monica Donghi
Marco Ferrara
Uwe Koch
Frank Narjes
Jesus Maria Ontoria Ontoria
Vincenzo Summa
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
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Priority claimed from GB0518231A external-priority patent/GB0518231D0/en
Priority claimed from GB0601068A external-priority patent/GB0601068D0/en
Priority claimed from GB0604037A external-priority patent/GB0604037D0/en
Application filed by Istituto di Ricerche di Biologia Molecolare P Angeletti SpA filed Critical Istituto di Ricerche di Biologia Molecolare P Angeletti SpA
Publication of WO2007028789A1 publication Critical patent/WO2007028789A1/en
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    • 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
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C07D239/96—Two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • R 5 , R 6 and R 7 are independently selected from hydrogen, (CH 2 ) 0 _ 3 Het, (CH 2 ) 0 _ 3 aryl and (CH 2 )o_ 3 heteroaryl;
  • R 1 is (CH 2 ) 0 . 3 aryl, more preferably (CH 2 ) 0 . 3 phenyl, most preferably phenyl or benzyl, especially phenyl, optionally substituted by one or two groups independently selected from halo, hydroxy, Ci- ⁇ alkyl, CO 2 R 5 or CONR 5 R 6 where R 5 and R 6 are as hereinbefore defined, preferably halo, hydroxy, CO 2 H or CONHMe, more preferably, fluorine, chlorine, CO 2 H or CONHMe.
  • R 1 is substituted, it is preferably mono- or di-substituted.
  • Suitable NR c R d groups include:
  • R >4 substituent is attached to the 6- or 7- position of the bicyclic moiety:
  • R 4 substituent is attached to the 7-position of the bicyclic moiety.
  • R 4 is hydrogen, C ⁇ alkyl and Ci- ⁇ alkoxy groups are optionally substituted by hydroxy or 1 to 5 halogen atoms, and where R c and R d are as hereinbefore defined. More preferably, R 4 is hydroxy, halo or NR c R d where R c and R d are as hereinbefore defined. Most preferably, R 4 is chlorine, fluorine or NR c R d where R c and R d are as hereinbefore defined. Especially, R 4 is chlorine or NR c R d where R c and R d are as hereinbefore defined.
  • R c and R d are independently selected from hydrogen, methyl, ethyl, i-propyl, cyclohexyl, benzyl and piperidinyl, optionally substituted by hydroxy, methyl, CO 2 H, benzyl and (CH 2 )pyridyl.
  • Q 1 is hydrogen, hydroxy or halo. More preferably, Q 1 is hydroxy, fluorine or chlorine. Most preferably, Q 1 is chlorine.
  • Q 1 is at the 3 -position of the phenyl ring.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention includes within its scope prodrugs of the compounds of formula (I) above.
  • Step 2 7-chloro-3-(3-chlorophenyl)-l-methylquinazolme-2,4(lH.,3H)-dione
  • a solution (0.26 M) 7-chloro-3-(3-chlorophenyl)quinazoline-2,4(lH,3H)-dione (from Step 1) in DMF was treated with DBU (1.2 eq.) and MeI (1.2 eq.). The reaction mixture was stirred at RT for 1 h. After dilution with water, the resulting precipitate was filtered off affording the title compound (71%) as white solid.
  • Step 3 5-fluoro-l,2,3,4-tetrahvdroquinoline-8-carboxylic acid A solution (0.25 M) of 5-fluoroquinoline-8-carboxylic acid (from Step 2) in acetic acid was treated with PtO 2 (0.3 eq.) and stirred under hydrogen at atmospheric pressure for 3 h.
  • Step 1 methyl 3-chloro-5-nitrobenzoate A solution (0.96 M) OfNaNO 2 (7.0 eq.) in water was added to a solution (0.09 M) of 3-amino-5-nitrobenzoic acid in HCl (cone.) at 0 0 C. The reaction mixture was left to warm up to RT over a period of 30 min and then was added to a solution (1.37 M) of CuCl (10.0 eq.) in water. The reaction mixture was stirred at RT for 3 h and then heated to 70 0 C for 30 min. After addition Of Et 2 O and water, the organic phase was separated and the aqueous phase extracted with Et 2 O.
  • Step 5 l-benzyl-4- ⁇ r2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahvdro-lH5H-pyridor3,2,l-

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the use of quinazoline derivatives of formula (I) wherein A, B, R1, R2, R3 and R4 are defined herein, and pharmaceutically acceptable salts thereof, for the treatment or prevention of infection by hepatitis C virus.

Description

Quinazoline derivatives as antiviral agents
This invention relates to compounds which can act as inhibitors of viral polymerases, especially the hepatitis C virus (HCV) polymerase, to uses of such compounds in the treatment and prevention of infection by hepatitis C virus, and to their preparation.
The hepatitis C virus (HCV) is the major causative agent of parenterally-transmitted and sporadic non-A, non-B hepatitis (NANB-H). Some 1% of the human population of the planet is believed to be affected. Infection by the virus can result in chronic hepatitis and cirrhosis of the liver, and may lead to hepatocellular carcinoma. Currently no vaccine nor established therapy exists, although partial success has been achieved in a minority of cases by treatment with recombinant interferon-α, either alone or in combination with ribavirin. There is therefore a pressing need for new and broadly-effective therapeutics.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). Of these, the polymerase plays an essential role in replication of the virus and is therefore an important target in the fight against hepatitis C.
Certain quinazoline derivatives have been disclosed in the art but none are disclosed as being useful as inhibitors of hepatitis C virus (HCV) polymerase. For instance, quinazoline-2,4-diones are disclosed by Kakuta et al, Chem. Pharm. Bull. 51(11), 1273-1282 (2003), Horton et al, Chem. Rev. 2003, 103, 893-930 and Gouilleux et al, Tet. Lett. 1996, 7031-7034. However, none of these disclosures relate to the treatment of hepatitis C virus infections.
Published International application WO2006/027628 (Istituto Di Ricerche Di Biologia Molecolare P. Angeletti SpA) discloses certain naphthalimide derivatives useful for the treatment of prevention of infection by hepatitis C virus.
It has now surprisingly been found that certain quinazoline derivatives, including certain of the known compounds referred to above, act as inhibitors of the hepatitis C virus (HCV) polymerase enzyme. Thus, in one aspect, there is provided the use of a compound of formula (I):
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein A and B are each independently CH2, C=O or C=S, with the proviso that A and B are not both
CH2;
R1 is Ci-galkyl, C2.galkenyl, C2.galkynyl or (CH2)0_3Ra, optionally substituted by Q1 and Q2; Q1 and Q2 are independently selected from hydrogen, halo, hydroxy,
Figure imgf000003_0001
C2.6alkenyl, CN, S(O)0.2Rb, SO2NR5R6, NR7SO2NR5R6, CO2R5, CONR5R6, NR5COR6, NR5SO2R6, NR5CONR6, NR5CO2R6, OCONR5R6, CONR5SO2R6 or CONR7SO2NR5R6, optionally substituted by 1 to 8 halogen atoms; Ra is C3_7cycloalkyl, Het, aryl or heteroaryl;
Rb is Ci-βalkyl, heteroaryl or aryl;
R5, R6 and R7 are independently selected from hydrogen, d.6alkyl, (CH2) 1.3 OH, (CH2)0.3Het, (CH2)o_3aryl and (CH2)0.3heteroaryl;
R2 is hydrogen, Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl, (CH2)0_3Het, (CH2)0_3aryl, (CH2)o_3heteroaryl or (CH2)o.3θ(CH2)0.3aryl, optionally substituted by hydroxy, CN or 1 to 8 halogen atoms;
R3 is hydrogen, Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C3.gcycloalkyl, CO2R5, CONR5R6, NR5COR6, NR5SO2R6 or NR7CONR5R6, optionally substituted by hydroxy or 1 to 8 halogen atoms; or R2 and R3, together with the C=C-N group to which they are attached, form a 5-, 6- or 7- membered nitrogen-containing heterocyclic ring, which heterocyclic ring optionally contains 1 or 2 further heteroatoms selected from N and O, and which hetorcyclic ring is optionally substituted by Q3;
Q3 is hydrogen, halo, Ci_6alkyl, Ci_6alkoxy, (CH2)0_3aryl, (CH2)0_3Het, (CH2)0_3heteroaryl or (CH2)o.3C3.8cycloalkyl, which Ci.6alkyl, (CH2)0.3aryl, (CH2)0.3Het, (CH2)0.3heteroaryl and (CH2)o-3C3.8cycloalkyl groups are optionally substituted by hydroxy, CO2H or CO2Ci_6alkyl; R4 is hydrogen,
Figure imgf000003_0002
C2_6alkenyl, C2_6alkynyl, C3.gcycloalkyl, (CH2)0.3aryl, Het,
(CH2)o.3heteroaryl, hydroxy, d.6alkoxy, halo, d.6alkylene-SH, NRcRd, NRcC0Rd, NReC0NRcRd, NRcC02Rd, NRcS02Rd or NReS02NRcRd, where said Ci.6alkyl, C2.6alkenyl, C2-6alkynyl, C3.8cycloalkyl and Ci-βalkoxy groups are optionally substituted by hydroxy or 1 to 8 halogen atoms;
Rc, Rd and Re are independently selected from hydrogen,
Figure imgf000003_0003
C2.6alkenyl, C2.6alkynyl, C3_8cycloalkyl, (CH2)0.2aryl, (CH2)0_3Het and (CH2)0.3heteroaryl, optionally substituted by one to three substituents independently selected from halo, hydroxy,
Figure imgf000003_0004
C2.6alkenyl, C2.6alkynyl, CO2H, (CH2)o-_3aryl and (CH2)0.3heteroaryl; or B and R2 are joined to form a 5-, 6- or 7- membered nitrogen-containing heterocycle, which heterocycle optionally contains 1, 2 or 3 further heteroatoms selected from N, O and S, and which heterocycle is optionally substituted by Q4;
Q4 is hydrogen, halo, hydroxy,
Figure imgf000003_0005
(CH2)0_3aryl or (CH2)o_3C3_8cycloalkyl, optionally substituted by hydroxy, CO2H or CO2Ci_6alkyl.
In one embodiment of the present invention, there is provided the use of the compound of formula (Ii):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein
A, B and R3 are as defined in relation to formula (I); R1 is Ci-galkyl, C2_8alkenyl, C2_8alkynyl or (CH2)0-3Ra, optionally substituted by Q1 and Q2;
Q1 and Q2 are independently selected from hydrogen, halo, hydroxy,
Figure imgf000004_0002
C2.6alkenyl, CN, S(O)0.2Rb, SO2NR5R6, NR7SO2NR5R6, CO2R5, CONR5R6, NR5COR6, NR5SO2R6, NR5CONR6, NR5CO2R6, OCONR5R6, CONR5SO2R6 or CONR7SO2NR5R6, optionally substituted by 1 to 8 halogen atoms; Ra is Cs.γcycloalkyl, Het, aryl or heteroaryl;
Rb is Ci-βalkyl, heteroaryl or aryl;
R5, R6 and R7 are independently selected from hydrogen,
Figure imgf000004_0003
(CH2)0_3Het, (CH2)0_3aryl and (CH2)o_3heteroaryl;
R is hydrogen,
Figure imgf000004_0004
C2.6alkenyl, C2.6alkynyl, C3.gcycloalkyl, (CH2)0.3Het, (CH2)0.3aryl or (CH2)o-3θ(CH2)o_3aryl, optionally substituted by hydroxy or 1 to 8 halogen atoms;
R4 is hydrogen,
Figure imgf000004_0005
C2_6alkenyl, C2.6alkynyl, C3.gcycloalkyl, (CH2)0.3aryl, (CH2)o.3heteroaryl, hydroxy, d.6alkoxy, halo, d.6SH, NRcRd, NRcC0Rd, NReC0NRcRd, NRcCO2Rd, NRcS02Rd or NReS02NRcRd, where said Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl and d.6alkoxy groups are optionally substituted by hydroxy or 1 to 8 halogen atoms; Rc, Rd and Re are independently selected from hydrogen,
Figure imgf000004_0006
C2_6alkenyl, C2.6alkynyl,
C3.8cycloalkyl, (CH2)0.3aryl, (CH2)0.3Het and (CH2)0.3heteroaryl, optionally substituted by one to three substituents independently selected from halo, hydroxy,
Figure imgf000004_0007
C2_6alkenyl, C2_6alkynyl and (CH2)o.3aryl.
Preferably, one of A or B is C=O and the other is CH2 or C=O. More preferably, A is C=O and B is CH2 or C=O. Most preferably, A and B are C=O.
Preferably, R1 is (CH2)0.3aryl, more preferably (CH2)0.3phenyl, most preferably phenyl or benzyl, especially phenyl, optionally substituted by one or two groups independently selected from halo, hydroxy, Ci-βalkyl, CO2R5 or CONR5R6 where R5 and R6 are as hereinbefore defined, preferably halo, hydroxy, CO2H or CONHMe, more preferably, fluorine, chlorine, CO2H or CONHMe. When R1 is substituted, it is preferably mono- or di-substituted.
When R1 is phenyl and substituted, preferably it is substituted at the 3 -position of the phenyl group, especially when it is mono-substituted. When R1 is phenyl and disubstituted, preferably it is substituted at the 2- and 5- or the 3- and 5- positions. Preferably, R is hydrogen,
Figure imgf000005_0001
C2-6alkenyl, (CH2)o-3aryl or (CH2)o-3θ(CH2)o-3aryl, optionally substituted by hydroxy. More preferably, R2 is hydrogen,
Figure imgf000005_0002
C2-4alkenyl, (CH2)i-2aryl or (CH2)i.2θ(CH2)i.2aryl, optionally substituted by hydroxy. Examples of suitable R groups include hydrogen, methyl, ethyl, i-propyl, s-butenyl, benzyl, hydroxyethyl and benzyloxyethyl.
Preferably, R3 is hydrogen,
Figure imgf000005_0003
C2-6alkenyl or CONR5R6, optionally substituted by hydroxy or 1 to 5 halogen atoms. More preferably, R3 is hydrogen,
Figure imgf000005_0004
or CONHR5, optionally substituted by hydroxy or 1 to 3 halogen atoms. Most preferably, R3 is hydrogen, methyl or
Figure imgf000005_0005
Preferably, R4 is hydrogen,
Figure imgf000005_0006
C^alkyl and Ci-βalkoxy groups are optionally substituted by hydroxy or 1 to 5 halogen atoms, and where Rc and Rd are as hereinbefore defined. More preferably, R4 is hydroxy,
Figure imgf000005_0007
halo or NRcRd where Rcand Rd are as hereinbefore defined. Most preferably, R4 is chlorine, fluorine or NRcRd where Rcand Rdare as hereinbefore defined. Especially, R4 is chlorine or NRcRd where Rc and Rd are as hereinbefore defined.
When R4 is NRcRd, preferably Rc and Rd are independently selected from hydrogen,
Figure imgf000005_0008
C3.gcycloalkyl and Het, optionally substituted by hydroxy,
Figure imgf000005_0009
and (CH2)o-3aryl. More preferably, Rc and Rd are independently selected from hydrogen,
Figure imgf000005_0010
Czt-βcycloalkyl and piperidinyl, optionally substituted by hydroxy, methyl, ethyl and benzyl. Most preferably, Rc and Rd are independently selected from hydrogen, methyl, ethyl, i-propyl, cyclohexyl and piperidinyl, optionally substituted by hydroxy, methyl and benzyl.
Examples of suitable NRcRd groups include:
Figure imgf000005_0011
Preferably, the R >4 substituent is attached to the 6- or 7- position of the bicyclic moiety:
Figure imgf000005_0012
More preferably, the R4 substituent is attached to the 7-position of the bicyclic moiety.
In another embodiment of the present invention, there is provided the use of the compound of formula (Iia):
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
R2, R3 and R4 are as defined in relation to formula (Ii), and
Q1 and Q2 are independently selected from hydrogen, halo, hydroxy,
Figure imgf000006_0002
CN, CO2H, CO2(C i-6alkyl) and CONHR5 where R5 is as defined in relation to formula (Ii).
Preferably, R is hydrogen,
Figure imgf000006_0003
C2_6alkenyl, (CH2)0.3aryl or (CH2)o.3θ(CH2)0.3aryl, optionally substituted by hydroxy. More preferably, R2 is hydrogen,
Figure imgf000006_0004
C2_4alkenyl, (CH2)i_2aryl or (CH2)i_2O(CH2)i_2aryl, optionally substituted by hydroxy. Examples of suitable R2 groups include hydrogen, methyl, ethyl, i-propyl, s-butenyl, benzyl, hydroxyethyl and benzyloxyethyl.
Preferably, R3 is hydrogen, C^alkyl or CONHR5. More preferably, R3 is hydrogen, methyl or
Figure imgf000006_0005
Preferably, R4 is halo or NRcRd where Rc and Rd are as defined in relation to formula (Ii). More preferably, R4 is fluorine, chlorine or NRcRd where Rc and Rd are independently selected from hydrogen, Ci-βalkyl, C3.gcycloalkyl and Het, optionally substituted by hydroxy,
Figure imgf000006_0006
and (CH2)0.3aryl. Most preferably, R4 is chlorine or NRcRd where Rc and Rd are independently selected from hydrogen,
Figure imgf000006_0007
C4_6cycloalkyl and piperidinyl, optionally substituted by hydroxy, methyl and benzyl. Especially, R4 is chlorine, NH2,
Figure imgf000007_0001
In another embodiment of the invention, there is provided the use of the compound of formula (lib):
Figure imgf000007_0002
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
Q1 and Q2 are independently selected from hydrogen, CO2H, halo,
Figure imgf000007_0003
or
R is Ci-βalkyl, C2-6alkenyl, C2_6alkynyl or C3.gcycloalkyl, optionally substituted by hydroxy or OR8;
R3 is as defined in relation to formula (Ii);
R4 is halo or a group NRcRd, OR9 or Het, which Het group is optionally substituted by Rd;
Rc and Re are hydrogen or
Figure imgf000007_0004
optionally substituted by hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group; Rd is a Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3.8cycloalkyl or piperidinyl, optionally substituted by hydroxy, halo, d.4alkyl, benzyl, OR9, NReRf, S(O)i.2R8 or COR9;
Rf is hydrogen or an
Figure imgf000007_0005
group substituted by phenyl, hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group;
R8 is phenyl or
Figure imgf000007_0006
optionally substituted by phenyl; R9 is Ci_4alkyl group optionally substituted by hydroxy, halo or a group NReRf or a N-linked 5- or
6-membered heterocyclic ring optionally containing a further nitrogen atom and optionally substituted by R8.
Preferably, Q1 and Q2 are independently selected from hydrogen, halo and CO2H. More preferably, Q1 and Q2 are independently selected from hydrogen, fluoro, chloro and CO2H. Preferably, R2 is methyl, ethyl, i-propyl, CH2CH=C(CH3)2, CH2phenyl, CH2CH2OCH2phenyl or CH2CH2OH.
Preferably, R3 is hydrogen, methyl or
Figure imgf000008_0001
Preferably, R4 is chlorine,
Figure imgf000008_0002
In another embodiment of the present invention, there is provided the use of the compound of formula (Iii):
Figure imgf000008_0003
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein
A, B, R1 and R2 are as defined in relation to formula (I); or R2 and R3, together with the C=C-N group to which they are attached, form a 5-, 6- or 7- membered nitrogen-containing heterocyclic ring, which heterocyclic ring optionally contains 1 or 2 further heteroatoms selected from N and O, and which heterocyclic ring is optionally substituted by Q3;
Q3 is hydrogen, halo, Ci.6alkyl, Ci_6alkoxy, (CH2)0.3aryl, (CH2)0.3Het, (CH2)0.3heteroaryl or (CH2)o.3C3-8cycloalkyl, which Ci.ealkyl, (CH2)0.3aryl, (CH2)0.3Het, (CH2)0.3heteroaryl and (CH2)o.3C3.8cycloalkyl groups are optionally substituted by hydroxy, CO2H or CO2Ci_6alkyl;
R4 is hydrogen,
Figure imgf000008_0004
C2_6alkenyl, C2_6alkynyl, C3.gcycloalkyl, (CH2)0.3aryl, (CH2)o.3heteroaryl, hydroxy, d.6alkoxy, halo, d.6alkylene-SH, NRcRd, NRcCORd, NReC0NRcRd, NRcCO2Rd, NRcSO2Rd or NReSO2NRcRd, where said Ci.ealkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl and Ci-βalkoxy groups are optionally substituted by hydroxy or 1 to 8 halogen atoms; Rc, Rd and Re are independently selected from hydrogen,
Figure imgf000009_0001
C2-6alkenyl, C2-6alkynyl, C3_8cycloalkyL (CH2)o-3aryl, (CH2)o-3Het and (CH2)o-3heteroaryl, optionally substituted by one to three substituents independently selected from halo, hydroxy, Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, CO2H, (CH2)o-3aryl and(CH2)o-3heteroaryl. Preferably, one of A or B is C=O and the other is CH2 or C=O. More preferably, A is C=O and B is CH2 or C=O. Most preferably, A and B are C=O.
Preferably, R1 is (CH2)0.3aryl, more preferably (CH2)0.3phenyl, most preferably phenyl or benzyl, especially phenyl, optionally substituted by one or two groups independently selected from halo, hydroxy, Ci-βalkyl, CO2R5 or CONR5R6 where R5 and R6 are as hereinbefore defined, preferably halo, hydroxy, CO2H, CONHMe or CONH(CH2)L3OH, more preferably, fluorine, chlorine, CO2H, CONHMe or CONHCH2CH2OH.
When R1 is substituted, it is preferably mono- or di-substituted.
When R1 is phenyl and substituted, preferably it is substituted at the 3 -position of the phenyl group, especially when it is mono-substituted. When R1 is phenyl and disubstituted, preferably it is substituted at the 2- and 5- or the 3- and 5- positions.
Preferably, R is hydrogen,
Figure imgf000009_0002
C2_6alkenyl, (CH2)0_3aryl or (CH2)o.3θ(CH2)0.3aryl, optionally substituted by hydroxy. More preferably, R2 is hydrogen,
Figure imgf000009_0003
C2_4alkenyl, (CH2)i_2aryl or (CH2)i_2O(CH2)i_2aryl, optionally substituted by hydroxy. Examples of suitable R groups include hydrogen, methyl, ethyl, i-propyl, s-butenyl, benzyl, hydroxyethyl and benzyloxyethyl. Preferably, R3 is hydrogen,
Figure imgf000009_0004
C2_6alkenyl or CONR5R6, optionally substituted by hydroxy or 1 to 5 halogen atoms. More preferably, R3 is hydrogen,
Figure imgf000009_0005
or CONHR5, optionally substituted by hydroxy or 1 to 3 halogen atoms. Most preferably, R3 is hydrogen, methyl or
Figure imgf000009_0006
Preferably, R2 and R3, together with the C=C-N group to which they are attached, form a 6- membered nitrogen-containing heterocyclic ring, which heterocyclic ring optionally contains 1 or 2 further heteroatoms selected from N and O, and which heterocyclic ring is optionally substituted by Q3 as hereinbefore defined. More preferably, R2 and R3, together with the C=C-N group to which they are attached, form a 6-membered nitrogen-containing heterocyclic ring, which heterocyclic ring optionally contains one further N atom, and which heterocyclic ring is optionally substituted by Q3, where Q3 is Ci-βalkyl, (CH2)0.3phenyl or (CH2)0-3C3_6cycloalkyl, which Q3 group is optionally substituted by hydroxy, CO2H or CO2Ci_4alkyl. Most preferably, R2 and R3, together with the C=C-N group to which they are attached, form a piperidinyl or piperazinyl ring, which piperazinyl ring is optionally substituted by Q3, where Q3 is C2_3alkyl, CH2phenyl or CH2cyclopropyl, which Q3 group is optionally substituted by hydroxy, CO2H or CO2Ci_2alkyl. Examples of ring systems where R2 and R3, together with the C=C-N group to which they are attached, form a 6-membered nitrogen-containing heterocyclic ring include:
Figure imgf000010_0001
Preferably, R4 is hydrogen,
Figure imgf000010_0002
C^alkyl and Ci-βalkoxy groups are optionally substituted by hydroxy or 1 to 5 halogen atoms, and where Rc and Rd are as hereinbefore defined. More preferably, R4 is hydroxy,
Figure imgf000010_0003
halo or NRcRd where Rcand Rd are as hereinbefore defined. Most preferably, R4 is chlorine, fluorine or NRcRd where Rcand Rdare as hereinbefore defined. Especially, R4 is chlorine or NRcRd where Rc and Rd are as hereinbefore defined.
When R4 is NRcRd, preferably Rc and Rd are independently selected from hydrogen,
Figure imgf000010_0004
Cs.gcycloalkyl, (CH2)o-3aryl and Het, optionally substituted by hydroxy,
Figure imgf000010_0005
CO2H, (CH2)o-3aryl and (CH2)o-3heteroaryl. More preferably, Rcand Rd are independently selected from hydrogen,
Figure imgf000010_0006
C4.6cycloalkyl, (CH2)o-3phenyl and piperidinyl, optionally substituted by hydroxy, methyl, ethyl, CO2H, benzyl and (CH2)o_3pyridinyl. Most preferably, Rc and Rd are independently selected from hydrogen, methyl, ethyl, i-propyl, cyclohexyl, benzyl and piperidinyl, optionally substituted by hydroxy, methyl, CO2H, benzyl and (CH2)pyridyl.
Examples of suitable NRcRd groups include:
Figure imgf000010_0007
Preferably, the R4 substituent is attached to the 6- or 7- position of the bicyclic moiety:
Figure imgf000011_0001
More preferably, the R4 substituent is attached to the 7-position of the bicyclic moiety.
In another embodiment of the present invention, there is provided the use of the compound of formula (Iiia):
Figure imgf000011_0002
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
R2, R3 and R4 are as defined in relation to formula (Iii); and
Q1 and Q2 are independently selected from hydrogen, halo, hydroxy,
Figure imgf000011_0003
CN, CO2H, CO2(C i-6alkyl) and CONHR5 where R5 is as defined in relation to formula (I).
Preferably, R2 is hydrogen, Ci.6alkyl, C2.6alkenyl, (CH2)0.3aryl or (CH2)o.30(CH2)o.3aryl, optionally substituted by hydroxy. More preferably, R is hydrogen,
Figure imgf000011_0004
C2_4alkenyl, (CH2)i_2aryl or (CH2)i_2O(CH2)i_2aryl, optionally substituted by hydroxy. Examples of suitable R2 groups include hydrogen, methyl, ethyl, i-propyl, s-butenyl, benzyl, hydroxyethyl and benzyloxyethyl.
Preferably, R3 is hydrogen, C^alkyl or CONHR5. More preferably, R3 is hydrogen, methyl or
Figure imgf000011_0005
Preferably, R4 is halo or NRcRd where Rc and Rd are as defined in relation to formula (I). More preferably, R4 is fluorine, chlorine or NRcRd where Rc and Rd are independently selected from hydrogen, Ci-βalkyl, C3.gcycloalkyl and Het, optionally substituted by hydroxy,
Figure imgf000011_0006
and (CH2)0.3aryl. Most preferably, R4 is chlorine or NRcRd where Rc and Rd are independently selected from hydrogen,
Figure imgf000011_0007
Czt-βcycloalkyl and piperidinyl, optionally substituted by hydroxy, methyl and benzyl. Especially, R4 is chlorine, NH2,
Figure imgf000012_0001
In another embodiment of the invention, there is provided the use of the compound of formula (Iiib):
Figure imgf000012_0002
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein
Q1 and Q2 are independently selected from hydrogen, CO2H, halo, C
Figure imgf000012_0003
^haloalkyl, or S(O)L2R8;
R is Ci-βalkyl, C2-6alkenyl, C2-6alkynyl or C3.gcycloalkyl, optionally substituted by hydroxy or OR8;
R3 is as defined in relation to formula (Iii);
R4 is halo or a group NRcRd, OR9 or Het, which Het group is optionally substituted by Rd;
Rc and Re are hydrogen or
Figure imgf000012_0004
optionally substituted by hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group; Rd is a Ci-βalkyl, C2-6alkenyl, C2-6alkynyl, C3.gcycloalkyl or piperidinyl, optionally substituted by hydroxy, halo, CMalkyl, benzyl, OR9, NReRf, S(O)i.2R8 or COR9;
Rf is hydrogen or an
Figure imgf000012_0005
group substituted by phenyl, hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group;
R8 is phenyl or
Figure imgf000012_0006
optionally substituted by phenyl; R9 is Ci_4alkyl group optionally substituted by hydroxy, halo or a group NReRf or a N-linked 5- or
6-membered heterocyclic ring optionally containing a further nitrogen atom and optionally substituted by R8.
Preferably, Q1 and Q2 are independently selected from hydrogen, halo and CO2H. More preferably, Q1 and Q2 are independently selected from hydrogen, fluoro, chloro and CO2H. Preferably, R2 is methyl, ethyl, i-propyl, CH2CH=C(CH3)2, CH2phenyl, CH2CH2OCH2phenyl or CH2CH2OH.
Preferably, R3 is hydrogen, methyl or
Figure imgf000013_0001
Preferably, R4 is chlorine,
Figure imgf000013_0002
or
In another embodiment of the invention, there is provided the use of the compound of formula
(Iiic):
Figure imgf000013_0003
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein Q1, Q2, R4 and Q3 are as defined in relation to formula (Iii) and A is CH or N.
Preferably, Q1 and Q2 are independently selected from hydrogen, halo, CO2H and CONR5R6, where R5 and R6 are as defined in relation to formula (Iii). More preferably, Q1 and Q2 are independently selected from hydrogen, fluoro, chloro, CO2H and CONH(CH2)^3OH. Most preferably, Q1 and Q2 are independently selected from hydrogen, chloro, CO2H and CONH(CH2)2OH.
Preferably, R4 is hydrogen, hydroxy or NRcRd, where Rc and Rd are as defined in relation to formula (Iii). More preferably, R4 is hydrogen, hydroxy or NHRC, where Rc is as defined in relation to formula (I).
When R4 is NHRC, preferably Rc is d.6alkyl, C3.gcycloalkyl, (CH2)0.3aryl or (CH2)0.3Het, optionally substituted by hydroxy, CO2H, (CH2)0.3aryl and (CH2)0.3heteroaryl. More preferably, Rc is Ci_4alkyl, Cs-βcycloalkyl, (CH2)0.3phenyl or Het, optionally substituted by hydroxy, CO2H, CH2phenyl and CH2pyridinyl. Examples of suitable Rc groups include:
Figure imgf000014_0001
Preferably, Q3 is hydrogen,
Figure imgf000014_0002
(CH2)o-3phenyl or (CH2)o-3C3_6cycloalkyl, optionally substituted by hydroxy, CO2H or CO2Ci_4alkyl. More preferably, Q3 is hydrogen,
Figure imgf000014_0003
CH2phenyl or CH2cyclopropyl, optionally substituted by hydroxy, CO2H or CO2Ci_2alkyl. Examples of suitable groups include hydrogen, -(CH2)2OH, -(CH2)3OH,
Figure imgf000014_0004
When A is CH, preferably Q3 is hydrogen. When A is N, preferably Q3 is as hereinbefore defined.
In another embodiment of the present invention, there is provided the use of the compound of formula (Iiii):
Figure imgf000014_0005
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein
A, R1, R3 and R4 are defined in relation to formula (I); B and R are joined to form a 5-, 6- or 7-membered nitrogen- containing heterocycle, which heterocycle optionally contains 1, 2 or 3 further heteroatoms selected from N, O and S, and which heterocycle is optionally substituted by Q4;
Q4 is hydrogen, halo, hydroxy,
Figure imgf000015_0001
(CH2)o-3aryl or (CH2)o-3C3_8cycloalkyl, optionally substituted by hydroxy, CO2H or CO2Ci_6alkyl.
Preferably, A is C=O.
Preferably, R1 is (CH2)0.3aryl, more preferably (CH2)0.3phenyl, most preferably phenyl or benzyl, especially phenyl, optionally substituted by one or two halo or hydroxy groups, preferably halo, more preferably chlorine. When R1 is substituted, it is preferably mono-substituted.
When R1 is phenyl and substituted, preferably it is substituted at the 3 -position of the phenyl ring, especially when it is mono-substituted.
Preferably, R3 is hydrogen, C^alkyl or C2_6alkenyl, optionally substituted by hydroxy or 1 to 5 halogen atoms. More preferably, R3 is hydrogen or
Figure imgf000015_0002
optionally substituted by hydroxy or 1 to 3 halogen atoms. Most preferably, R3 is hydrogen or methyl.
Preferably, R4 is hydrogen,
Figure imgf000015_0003
C^alkyl and Ci-βalkoxy groups are optionally substituted by hydroxy or 1 to 5 halogen atoms, and where Rc and Rd are as hereinbefore defined. More preferably, R4 is hydroxy,
Figure imgf000015_0004
halo or NRcRd where Rcand Rd are as hereinbefore defined. Most preferably, R4 is chlorine, bromine or NRcRd where Rcand Rdare as hereinbefore defined. Especially, R4 is bromine or NRcRd where Rc and Rd are as hereinbefore defined.
When R4 is NRcRd, preferably Rc and Rd are independently selected from hydrogen,
Figure imgf000015_0005
C3_8cycloalkyl, (CH2)0_3aryl and Het, optionally substituted by hydroxy,
Figure imgf000015_0006
CO2H, (CH2)0_3aryl and (CH2)o_3heteroaryl. More preferably, Rcand Rd are independently selected from hydrogen,
Figure imgf000015_0007
Czt-βcycloalkyl, (CH2)0.3phenyl and piperidinyl, optionally substituted by hydroxy, methyl, ethyl, CO2H, benzyl and (CH2)o_3pyridinyl. Most preferably, Rc and Rd are independently selected from hydrogen, methyl, ethyl, cyclohexyl, benzyl and piperidinyl, optionally substituted by hydroxy, methyl, CO2H and benzyl. Examples of suitable NRcRd groups include:
Figure imgf000015_0008
Preferably, the R4 substituent is attached to the 6- or 7- position of the bicyclic moiety:
Figure imgf000015_0009
More preferably, the R4 substituent is attached to the 7-position of the bicyclic moiety.
Preferably, B and R2 are joined to form a 5- or 6-membered nitrogen- containing heterocycle, which heterocycle optionally contains 1 or 2 further heteroatoms selected from N and O, and which heterocycle is optionally substituted by Q4 as hereinbefore defined. More preferably, B and R2 are joined to form a 5-membered nitrogen-containing heterocycle, which heterocycle optionally contains 1 or 2 further N atoms, and which heterocycle is optionally substituted by Q4, where Q4 is
Figure imgf000016_0001
Most preferably, B and R2 are joined to form a 5-membered nitrogen-containing heterocycle, which heterocycle contains 1 or 2 further N atoms, and which heterocycle is optionally substituted by
Figure imgf000016_0002
E Exxaammppllees of ring systems where B and R2 are joined to form a suitable nitrogen-containing heterocycle include:
Figure imgf000016_0003
In another embodiment of the present invention, there is provided the use of the compound of formula (Iiiia):
(Iiiia)
Figure imgf000016_0004
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
Q1, Q4, R3 and R4 are as defined in relation to formula (Iiii); and D is N, CH or C(d.6alkyl).
Preferably, Q1 is hydrogen, hydroxy or halo. More preferably, Q1 is hydroxy, fluorine or chlorine. Most preferably, Q1 is chlorine.
Preferably, Q1 is at the 3 -position of the phenyl ring.
Preferably, Q4 is hydrogen or
Figure imgf000016_0005
More preferably, Q4 is hydrogen or
Figure imgf000016_0006
Most preferably, Q4 is hydrogen or methyl.
Preferably, R3 is hydrogen,
Figure imgf000016_0007
C2-6alkenyl, C2-βalkynyl or Cs.gcyclohexyl, optionally substituted by hydroxy or halo. More preferably, R3 is hydrogen or
Figure imgf000016_0008
optionally substituted by hydroxy, fluorine or chlorine. Most preferably, R3 is hydrogen or
Figure imgf000016_0009
Especially, R3 is hydrogen or methyl.
Preferably, R4 is hydrogen,
Figure imgf000016_0010
hydroxy, halo or NRcRd, where Rcand Rd are as defined in relation to formula (Iiii). More preferably, R4 is halo or NRcRd, where Rc and Rd are independently selected from hydrogen,
Figure imgf000017_0001
Cs.gcycloalkyl or (CH2)o-3Het, optionally substituted by halo, hydroxy, CO2H and (CH2)o-3aryl. Most preferably, R4 is chlorine, bromine or NRcRd, where Rc and Rd are independently selected from hydrogen,
Figure imgf000017_0002
C4.6cycloalkyl or piperidinyl, optionally substituted by hydroxy, CO2H and benzyl. Examples of suitable R4 groups include bromine,
Figure imgf000017_0003
Preferably, R4 is attached to the 7-position of the bicyclic moiety. Preferably, D is N, CH or C(d.4alkyl). Preferably, D is N or CH.
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
As used herein, the term "alkenyl" and "alkynyl" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. Suitable alkynyl groups are ethynyl and propargyl. When used herein, the term "halogen" or "halo" as a group or part of a group means fluorine, chlorine, bromine and iodine.
When used herein, the term "aryl" as a group or part of a group means a carbocyclic aromatic ring. Examples of suitable aryl groups include phenyl and naphthyl.
When used herein, the term "heteroaryl" as a group or part of a group means a 5- to 10-membered heteroaromatic ring system containing 1 to 4 heteroatoms selected from N, O and S. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, benzofuranyl, benzothiazolyl, benzoxazolyl and quinolinyl. When used herein, the term "Het" as a group or part of a group means a heteroaliphatic ring of 4 to 7 ring atoms, which ring may contain 1, 2 or 3 heteroatoms selected from N, O or S or a group S(O), S(O)2, NH or NCi.4alkyl.
Where a compound or group is described as "optionally substituted", one or more substituents may be present. Optional substituents may be attached to the compounds or groups which they substitute in a variety of ways, either directly or through a connecting group of which the following are examples: amine, amide, ester, ether, thioether, sulfonamide, sulfamide, sulfoxide, urea, thiourea, urethane, acylsulfonamide and acylsulfamide. As appropriate an optional substituent may itself be substituted by another substituent, the latter being connected directly to the former or through a connecting group such as those exemplified above.
Specific compounds within the scope of this invention include the compounds of Group (II) listed below:
Group (II) 3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione,
3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l-methylquinazoline-2,4(lH,3H)-dione, 7-chloro-3-(3-chlorophenyl)quinazoline-2,4(lH,3H)-dione, 7-chloro-3-(3-chlorophenyl)-l-methylquinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-7-(isobutylamino)-l-methylquinazoline-2,4(lH,3H)-dione, 1 -benzyl-3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione,
7-[(l -benzylpiperidin-4-yl)amino]-3-(3-chlorophenyl)- 1 -methylquinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l-(3-methylbut-2-en-l-yl)quinazoline-2,4(lH,3H)-dione, l-[2-(benzyloxy)ethyl]-3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-l-(2-hydroxyethyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-l-ethyl-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione,
3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l-isobutylquinazoline-2,4(lH,3H)-dione, 3-(5-chloro-2-fluorophenyl)-7-[(2-hydroxyethyl)amino]-l-methylquinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l,8-dimethylquinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-l-methyl-7-[(4-methylcyclohexyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(2-chlorophenyl)-l-methyl-7-(piperidin-4-ylamino)quinazoline-2,4(lH,3H)-dione, 6-amino-3-(3-chlorophenyl)-l-methylquinazoline-2,4(lH,3H)-dione,
2-[7-[(l-benzylpiperidin-4-yl)amino]-l-methyl-2,4-dioxo-l,4-dihydroquinazolin-3(2H)-yl]-4- chlorobenzoic acid, and N-(l-benzylpiperidin-4-yl)-3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-8-carboxamide,
and pharmaceutically acceptable salts thereof.
Further specific compounds within the scope of this invention include the compounds of Group (III) listed below:
Group (III) 2-(3-chlorophenyl)-8-fluoro-6,7-dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)-dione, 2-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino]-6,7-dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)- dione, l-benzyl-4-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}piperidinium trifluoroacetate, cώ-4-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid, frα«s-4-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid,
4-({[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}methyl)benzoic acid, l-benzyl-4-{[2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l- ij] quinazolin- 8 -yl] amino } piperidinium trifluoroacetate,
3-chloro-N-(2-hydroxyethyl)-5-[8-[(2-hydroxyethyl)amino]-l,3-dioxo-6,7-dihydro-lH,5H-pyrido[3,2,l- z/]quinazolin-2(3H)-yl]benzamide, 4-{[2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}piperidinium trifluoroacetate,
4-{[2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}-l-(pyridin-4-ylmethyl)piperidinium trifluoroacetate,
3-({[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}methyl)benzoic acid,
6-(3-chlorophenyl)-l-(2-hydroxyethyl)-2,3-dihydro-lH,5H-pyrazino[3,2,l-//]quinazoline-5,7(6H)-dione,
3-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl} benzoic acid, ethyl 2-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl} cyclopropanecarboxylate, methyl 3-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl}benzoate,
2-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl} cyclopropanecarboxylic acid, 6-(3-chlorophenyl)-l-(3-hydroxypropyl)-2,3-dihydro-lH,5H-pyrazino[3,2,l-//]quinazoline-5,7(6H)- dione,
4-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl} benzoic acid,
2-(3-chlorophenyl)-8-hydroxy-6,7-dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)-dione, 3-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid, cώ-3-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}cyclohexanecarboxylic acid, and cώ-3-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid,
and pharmaceutically acceptable salts thereof.
Yet further specific compounds within the scope of this invention include the compounds of
Group (IV) listed below:
Group (W)
4-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino]imidazo [l,2-α]quinazolin-5(4H)-one, l-benzyl-4-{[4-(3-chlorophenyl)-5-oxo-4,5-dihydroimidazo[l,2-α]quinazolin-8-yl]amino}piperidinium trifluoroacetate, 8-bromo-4-(3-chlorophenyl)-l-methyl[l,2,4]triazolo [4,3-α]quinazolin-5(4H)-one,
4-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino][l,2,4] triazolo[4,3-α]quinazolm-5(4H)-one,
4-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino]-9-methyl[l,2,4]triazolo[4,3-α]quinazolin-5(4H)-one, l-benzyl-4-{[4-(3-chlorophenyl)-9-methyl-5-oxo-4,5-dihydro[l,2,4]triazolo[4,3-α]quinazolin-8- yl]amino}piperidinium trifluoroacetate, cώ-4-{[4-(3-chlorophenyl)-9-methyl-5-oxo-4,5-dihydro[l,2,4]triazolo[4,3-α]quinazolin-8- yl]amino} cyclohexanecarboxylic acid,
and pharmaceutically acceptable salts thereof.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin. The present invention includes within its scope prodrugs of the compounds of formula (I) above.
In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the
"parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The present invention also includes within its scope any enantiomers, diastereomers, geometric isomers and tautomers of the compounds of formula (I). It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the invention.
In another aspect of the invention, there is provided a method of inhibiting hepatitis C virus polymerase and/or of treating or preventing an illness due to hepatitis C virus, the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition described below or of a compound of formula (I), (Ii), (Iia), (lib), (Iii), (liia), (Iiib), (liic), (Iiii) or (Iiiia) or a compound of Group (II), (III) or (IV) as defined above, or a pharmaceutically acceptable salt thereof. "Effective amount" means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
In a further embodiment of the present invention, there is provided the use of a compound of formula (I), (Ii), (Iia), (lib), (Iii), (liia), (Iiib), (liic), (Iiii) or (Iiiia) or a compound of Group (II), (III) or
(IV), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, in combination with one or more other agents for the treatment of viral infections such as an antiviral agent, and/or an immunomodulatory agent such as OC-, β- or γ-interferon, particularly α- interferon. Suitable antiviral agents include ribavirin and inhibitors of hepatitis C virus (HCV) polymerase, such as inhibitors of metalloprotease (NS2-3), serine protease (NS3), helicase (NS3) and RNA-dependent RNA polymerase (NS5B). A further aspect of the invention provides a pharmaceutical composition comprising a compound of formula (lib), (Iiib), (Iiic), (Iiii) or (Iiiia) or a compound of Group (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. The composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally. The composition may be prepared by admixing at least one active ingredient, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents. A further aspect of the invention provides a compound of formula (lib), (Iiib), (Iiic), (Iiii) or
(Iiiia) or a compound of Group (II), (III) or (IV) or a pharmaceutically acceptable salt thereof for use in therapy.
A further aspect of the invention provides a compound of formula (lib), (Iiib), (Iiic), (Iiii) or (Iiiia) or a compound of Group (II), (III) or (IV) or a pharmaceutically acceptable salt thereof. The dosage rate at which the compound is administered will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy. For the treatment or prevention of infection by hepatitis C virus, suitable dosage levels may be of the order of 0.02 to 5 or 10 g per day, with oral dosages two to five times higher. For instance, administration of from 10 to 50 mg of the compound per kg of body weight from one to three times per day may be in order. Appropriate values are selectable by routine testing. The compound may be administered alone or in combination with other treatments, either simultaneously or sequentially. For instance, it may be administered in combination with effective amounts of antiviral agents, immunomodulators, anti- infectives or vaccines known to those of ordinary skill in the art. It may be administered by any suitable route, including orally, intravenously, cutaneously and subcutaneously. It may be administered directly to a suitable site or in a manner in which it targets a particular site, such as a certain type of cell. Suitable targeting methods are already known.
Compounds of general formula (I) may be prepared by methods disclosed in the documents hereinbefore referred to and by methods known in the art of organic synthesis as set forth below.
General Synthetic Schemes
In general, for the compounds of formula (Ii), two synthetic schemes were used for the preparation of the compounds, particularly for compounds where A and B are both C=O. Method A
microwave
Figure imgf000023_0002
Figure imgf000023_0001
Figure imgf000023_0003
Secondary anilides with a carbamate group in the ortho position were synthesised by procedures reported in the literature (for example in Tetrahedron Lett. 1996, 37, 7031). Ring closure of these intermediates under microwave irradiation led to the 3,7-disubstituted quinazoline-2,4(lH,3H)-diones. The radical R was introduced by alkylation of the N atom in position 1 in the presence of a base (as described in Chem. Pharm. Bull. 1991, 39, 1753). Finally, introduction of the 7-amino substituent was performed by treatment with a primary or secondary amine under microwave irradiation or under standard cross- coupling conditions.
Method B
esterification <|ϊ °
Figure imgf000023_0005
(X = F, Cl, Br, I, NO2)
RcRαNH microwa
Figure imgf000023_0006
Figure imgf000023_0004
1,3,7,8-tetrasubstituted quinazoline-2,4(lH,3H)-diones were synthesised by reaction of o-aminobenzoic esters with isocyanates followed by treatment with sodium hydroxide (see J. Heterocyclic Chem. 1982, 19, 269). The introduction of the radicals in positions 1 and 7 were performed as described in Method A. Method C
Figure imgf000024_0001
Trisubstituted quinazoline-2,4(lH,3H)-diones were synthesised from o-aminobenzoic esters using the same ring closure and radical introduction procedures as described in Method B.
For the compounds of formula (Iii) where R2 and R3, together with the C=C-N group to which they are attached, form a 6-membered nitrogen-containing heterocyclic ring optionally containing one further nitrogen atom, in general, four synthetic schemes were used for the preparation of the compounds.
Method 5 ι) hydrogenation ιι) esterification
Figure imgf000024_0002
Figure imgf000024_0003
5,8-Disubstituted quinolines were prepared by reaction with glycerol following the procedure reported in Monatshefte fur Chemie 2002, 133, 1437. Then, oxidation of the methyl group followed by reduction in the presence of hydrogen led to the 1,2,3,4-tetrahydroquinoline as described in J. Med. Chem. 1989, 32, 396 and J. Org. Chem. 1990, 55, 738. Ring closure to obtain the 6,7-dihydro-lH,5H-pyrido[3,2,l- z/]quinazoline-l,3(2H)-diones was performed by reaction of o-aminobenzoic esters with isocyanates followed by treatment with sodium hydroxide as reported in J. Heterocyclic Chem. 1982, 19, 269. Finally, the introduction of the radicals in position 8 was performed by treatment with a primary or secondary amine under microwave irradiation. Method 6
oxidation
Figure imgf000025_0001
i) PhOCOCI RcRdNH ii) Et3N, MeOH cross coupling
Figure imgf000025_0003
Figure imgf000025_0002
5,8-Disubstituted quinolines were prepared by bromination of 5-methyl quinoline. Then, oxidation of the methyl group followed by amide formation and reduction in the presence of sodium cyanoborohydride and BF3. Et2O led to the 1, 2,3, 4-tetrahydroquino line as described in Tetrahedron 1996, 52, 1631. 6,7- Dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)-diones were synthesized by treatment with phenyl chloro formate and followed by ring closure of the derived carbamate intermediate under basic condition at high temperature. Finally, the introduction of the substituents in position 8 was performed by treatment with a primary or secondary amine under cross coupling conditions.
Method 7
Figure imgf000025_0004
Reduction of 5-bromoquinoline-8-carboxylic acid, prepared as described in Method 6, in the presence of hydrogen followed by treatment with phosgene afforded the 6,7-dihydro-lH,5H-[l,3]-oxazino[5,4,3- z/]quinoline-l,3-dione system as described in J. Heterocyclic Chem. 1978, 15, 645. Then treatment with the corresponding primary amines at high temperature followed by reaction with phenyl chloroformate led to 6,7-dihydro-lH,5H-pyrido[3,2,l-z/]quinazoline-l,3(2H)-diones. Finally, the introduction of the substituent in position 8 was performed as described in Method 6.
reductive animation _ i) PhOCOCI
R2CHO II) Et3N, MeOH
Figure imgf000025_0005
Figure imgf000025_0006
Figure imgf000025_0007
l,2,3,4-Tetrahydroquinoxaline-5-carboxyamides were prepared by amide formation followed by reduction in the presence of sodium borohydride as described in J. Org. Chem. 1979, 44, 1719. Then, reductive amination on the less hindered nitrogen followed by formation of the carbamate and later ring closure under basic conditions at high temperature led to 5,7-dioxo-2,3,6,7-tetrahydro-lH,5H- pyrazino[3,2,l-z/]quinazolmes.
For the compounds of formula (Iiii) where B and R are joined to form a 5-membered nitrogen- containing heterocycle containing 1 or 2 further N atoms, two synthetic schemes were used for the preparation of the compounds.
Method 9
Figure imgf000026_0001
R-3- Η, alkyl
RcRdNH microwave or
Figure imgf000026_0002
cross coupling
Figure imgf000026_0003
Substituted 2-amino-4-bromobenzamides were prepared by coupling reaction of 2-nitro-4-bromo benzoic acid with the corresponding amine followed by reduction of the nitro group following procedures described in the literature. Ring closure in the presence of carbon disulfide as reported in J. Heter. Chem. 1985, 22, 1535 led to 7-bromo-2-thioxo-2,3-dihydroquinazolin-4(lH)-ones. Treatment with SO2CI2, followed by reaction with dimethoxyethanamine and subsequent ring closure in the presence of HCl gave the imidazoquinazolin-one as described in J. Heterocyclic Chem. 1986, 23, 833. Finally, the introduction of the substituents in position 7 can be performed by treatment with a primary or secondary amine under microwave irradiation or via cross coupling reaction.
Method 10
I) NH2NH2 RcRdNH
II) HCO2H microwave or cross coupling
Figure imgf000026_0004
Figure imgf000026_0005
Figure imgf000026_0006
Reaction of 7-bromo-2-thioxo-2,3-dihydroquinazolin-4(lH)-ones, prepared as described in Method 9 with hydrazine followed by ring-closure with formic acid led to the 8,9-disubstituted triazoloquinazolinones as described in Bull. Chem. Soc. Jpn. 1983, 56 (4), 1227. Then, introduction of the radicals in position 7 can be performed by treatment with a primary or secondary amine under microwave irradiation or via cross coupling conditions. Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the invention.
The compounds of the invention were tested for inhibitory activity against the HCV RNA dependent RNA polymerase (NS5B) in an enzyme inhibition assay (example i)). The compounds in Table 1 are active against HCV polymerase with activities <50μM.
i) In-vitro HCV NS5B Enzyme Inhibition Assay
The HCV-BK cDNA sequence coding for the NS5B protein lacking of the 21 C-terminal residues (residues 1-570) was cloned in the pT7.7 vector downstream of the T7 promoter and in frame with the first ATG of the gene 10 protein of the T7 phage. A C-terminal HisTag was added to simplify purification procedure. Expression in E.coli BL21(DE3) was performed as described (Tomei et a\., JGV (2000), 81, 759). Bacteria were grown at 37°C in standard LB medium up to an absorbance of 0.8 at 600 nm. The temperature of the culture was then lowered to 18°C and expression induced with 0.4 mM IPTG for further 23 hrs. All the subsequent purification steps were performed at 4°C. Cells were harvested, washed with PBS (20 mM Na-phosphate [pH 7.5], 150 mM NaCl), resuspended in 100 ml of lysis buffer/liter of culture, and disrupted with a model 11 OS Microfluidizer. Lysis buffer contained 10 mM Tris [pH 8.0], 1 mM EDTA, 0.5 M NaCl, 50% glycerol, 10 mM β-mercaptoethanol, 0.1% n-octyl-β-D- glucopyranoside (Inalco; n-OG), Complete™ protease inhibitor cocktail (Roche). After addition of 10 mM MgCl2, the extract was incubated with 0.5 units/ml of DNaseI for 30 min. The insoluble material was pelletted by centrifugation for 60 min at 15,000 rpm in a Sorvall SS34 rotor. The clarified supernatant was incubated batchwise for 45 min with 50 ml/liter of culture of DEAE-Sepharose FF resin equilibrated in lysis buffer lacking glycerol. The flow-through from the DEAE-Sepharose was diluted to 0.3 M NaCl and loaded on a Ni-NTA Superflow column (Qiagen; 3 ml/liter of culture) equilibrated with A buffer + 10 mM Imidazole (A buffer: 10 mM Tris [pH 8.0], 20% glycerol, 0.3 M NaCl, 0.1% n-OG, 10 mM β-mercaptoethanol) and eluted with a 50 to 500 mM imidazole gradient in A buffer. Peak fraction were collected, dialysed vs D buffer (10 mM Hepes [pH 8.0], 20% glycerol, 0.2% n-OG, 1 mM EDTA, 5 mM DTT) containing 0.15 M NaCl and loaded on HiTrap Heparin column (Amersham) equilibrated with D buffer and eluted with a 0.15 to 0.8M NaCl gradient in D buffer. The protein was stored in aliquots in liquid nitrogen.
The purified enzyme was shown to possess in vitro RNA polymerase activity using RNA as template according to a description in Journal of General Virology 81:759-767 (2000). The reference describes a polymerisation assay using poly(A) and oligo(U) as a template/primer. Incorporation of tritiated UTP is quantified by measuring acid- insoluble radioactivity. The present inventors have employed this assay to screen the various compounds described above as inhibitors of HCV RdRp.
Incorporation of radioactive UMP was measured as follows. The standard reaction (50 μl) was carried out in a buffer containing 20 mM Tris/HCl pH 7.5, 5 mM MgCl2, 1 mM DTT, 10 mM NaCl, 0.01% Triton X-100, 1 μCi [3H]-UTP (40 Ci/mmol, NEN), 10 μM UTP and 10 μg/ml poly(A) /Oligo(U)i2 (1 μg/ml, Genset) as a template/primer. The final NS5B ΔC21 enzyme concentration was 5 nM. The order of assembly was: 1) compound, 2) enzyme, 3) template/primer, 4) NTP. After 1 h. incubation at 22°C the reaction was stopped by adding 50 μl of 20% TCA and applying samples to DE81 filters. The filters were washed thoroughly with 5% TCA containing IM Na2HPO4ZNaH2PO4, pH 7.0, rinsed with water and then ethanol, air dried, and the filter-bound radioactivity was measured in the scintillation counter. Carrying out this reaction in the presence of various concentrations of each compound set out above allowed determination of IC5O values by utilising the formula:
% Residual activity = 100/(l+[I]/IC50)s
where [I] is the inhibitor concentration and "s" is the slope of the inhibition curve.
ii) General Procedures
All solvents were obtained from commercial sources (Fluka, puriss.) and were used without further purification. With the exception of routine deprotection and coupling steps, reactions were carried out under an atmosphere of nitrogen in oven dried (110 0C) glassware. Organic extracts were dried over sodium sulfate, and were concentrated (after filtration of the drying agent) on rotary evaporators operating under reduced pressure. Flash chromatography was carried out on silica gel following published procedure (W.C. Still et al., J. Org. Chem. 1978, 43, 2923) or on semi-automated flash chromatography systems utilising pre-packed columns.
Reagents were usually obtained directly from commercial suppliers (and used as supplied) but a limited number of compounds from in-house corporate collections were utilised. In the latter case the reagents are readily accessible using routine synthetic steps that are either reported in the scientific literature or are known to those skilled in the art. 1H nmr spectra were recorded on Bruker AM series spectrometers operating at (reported) frequencies between 300 and 600 MHz. Chemical shifts (δ) for signals corresponding to non- exchangeable protons (and exchangeable protons where visible) are recorded in parts per million (ppm) relative to tetramethylsilane and are measured using the residual solvent peak as reference. Signals are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad, and combinations thereof); coupling constant(s) in hertz; number of protons. Mass spectral (MS) data were obtained on a Perkin Elmer API 100 operating in negative (ES") or positive (ES+) ionization mode and results are reported as the ratio of mass over charge (m/z) for the parent ion only. Preparative scale HPLC separations were carried out on a Waters Delta Prep 4000 separation module, equipped with a Waters 486 absorption detector or on a Gilson preparative system. In all cases compounds were eluted with linear gradients of water and acetonitrile both containing 0.1% TFA using flow rates between 15 and 25 mL/min. LC-MS; Conditions 1 : Waters X-TERRA MS C 18, 8 micron, 4.6 x 100 mm; flow: 1 mL/min; Gradient: A: H2O + 0.1% HCO2H; B: MeCN + 0.1% HCO2H; linear from 90% to 10% A in 7.5 min. Conditions 2: Waters X-TERRA MS C 18, 5 micron, 4.6 x 50 mm; flow: 1 mL/min; Gradient: A: H2O + 0.1% HCO2H; B: MeCN + 0.1% HCO2H; linear from 90% to 70% A in 0.5 min, isocratic 70% A for 0.5 min, then linear to 0% A in 6 min. The following abbreviations are used in the examples:
AcOH: acetic acid; BINAP: 2,2'-bis(diphenylphosphino)-l,l '-binaphthyl; DBU: 1,8- Diazabicyclo[5.4.0]undec-7-ene; DIPEA: diisopropylethyl amine; DMF: dimethylformamide; DMSO: dimethylsulfoxide; eq.: equivalent(s); Et2O: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; h: hour(s); HATU: O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; M: molar; MeCN: acetonitrile; MeI: iodomethane; MeOH: methanol; min: minutes; NMP: l-methyl-2- pyrrolidinone; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; RP-HPLC: reversed phase high-pressure liquid chromatography; RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran.
Example 1: benzyl-4-{[3-(3-chlorophenyl)-l-methyl-2,4-dioxo-l,2,3,4-tetrahydroquinazolin-7- yl]amino}piperidinium trifluoroacetate (107)
Step 1: 7-chloro-3-(3-chlorophenyl)quinazoline-2,4(lH,3H)-dione
To a solution (0.3 M) of 2-amino-4-chlorobenzoic acid (1 eq.) in dry TΗF under nitrogen atmosphere cooled to 00C, pyridine (1.4 eq.) and phenyl chloroformate (1.2 eq.) were added dropwise. The reaction mixture was stirred at 00C for 2 h. After dilution with EtOAc the organic phase was filtered and washed with IN HCl, brine, and dried. Evaporation of the solvent afforded a crude (LC-MS (ES+) m/z 291, 293 (M+Η)+. Retention time (conditions 1): 5.84 min) that was disolved in DMF. The resulting solution (0.34 M) was treated with 3-chloroaniline (2 eq.), HATU (1.1 eq.) and DIPEA (2.5 eq.). The reaction mixture was stirred at 600C for 4 h. After cooling down, the reaction was diluted with water and the resulting precipitate was filtered off and washed with Et2O, affording (95%) the title compound as pale yellow powder. 1H NMR (300 MHz, DMSOd6, 300 K) δ 7.25 (m, 3H), 7.51 (m, 3H), 7.93 (d, IH), 11.71 (s, IH); MS (ES+) m/z 307, 309 (M+H)+.
Step 2: 7-chloro-3-(3-chlorophenyl)-l-methylquinazolme-2,4(lH.,3H)-dione A solution (0.26 M) 7-chloro-3-(3-chlorophenyl)quinazoline-2,4(lH,3H)-dione (from Step 1) in DMF was treated with DBU (1.2 eq.) and MeI (1.2 eq.). The reaction mixture was stirred at RT for 1 h. After dilution with water, the resulting precipitate was filtered off affording the title compound (71%) as white solid. 1H NMR (300 MHz, DMSOd6, 300 K) δ 3.53 (s, 3H), 7.32 (m, IH), 7.4 (dd, IH, J 8.4, 1.5), 7.49 (s, IH), 7.52 (m, 2H), 7.65 (d, IH, J 1.5), 8.04 (d, IH, J8.4); MS (ES+) m/z 321, 323 (M+H)+.
Step 3: 1 -benzyl-4- { [3 -(3-chlorophenyl)- 1 -methyl-2,4-dioxo- 1 ,2,3,4-tetrahydroquinazolin-7- vHaminolpiperidinium trifluoroacetate
A solution (0.2 M) of 7-chloro-3-(3-chlorophenyl)-l-methylquinazoline-2,4(lH,3H)-dione (from Step 2) in NMP was treated with 1 -benzylpiperidin-4-amine (7 eq.). The reaction mixture was heated at 2000C under microwave irradiation for 30 min. The solution was purified by RP-ΗPLC (Conditions: Waters X-TERRA
C 18, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 70% A isocratic for 1 min, linear to 30% A in 9 min, then linear to 10% A in 0.2 min and 10% A isocratic for 1.6 min) affording (10%) the title compound as a solid. 1H NMR (300 MHz, DMSOd6, 300 K) δ 1.75 (m, 2H), 2.2 (m, IH), 2.4 (m, IH), 3.25 (m, 2H), 3.75 (m, 5H), 3.93 (m, IH), 4.55 (bs, 2H), 6.75 (s, IH), 6.37 (s, IH), 6.57 (d, IH, J8.8), 6.93 (d, IH, J 13), 7.2 (m, IH), 7.5 (m, 8H), 7.73 (d, IH, J8.6); MS (ES+) m/z 475, 477 (M+H)+.
Example 2: 3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l,8-dimethylquinazoline-2,4(lH,3H)- dione (114)
Step 1: Methyl 2-amino-4-fluoro-3-methylbenzoate
A solution (1.0 M) of 2-amino-4-fluoro-3-methylbenzoic acid in dry MeOH was treated with SOCl2 (1.5 eq.). The reaction mixture was stirred overnight at RT. After evaporation of the solvent the residue was treated with aqueous NaHCθ3 (saturated solution) and extracted with EtOAc. The combined organic layers were dried. Evaporation of the solvent afforded (77%) the title compound as a solid. 1H NMR
(400 MHz, DMSO-dg, 300 K) δ 2.01 (s, 3H), 3.82 (s, 3H), 5.96 (bs, 2H), 6.34 (t, IH, J 8.3), 7.72 (t, IH, J 8.8). MS (ES+) m/z 184 (M+H)+.
Step 2: 3-(3-chlorophenyl)-7-r(2-hvdroxyethyl)aminol- 1 ,8-dimethylquinazoline-2,4(lH,3H)-dione A solution (0.27 M) of methyl 2-amino-4-fluoro-3-methylbenzoate (from Step 1) in dry Et2O was treated with 3-chlorophenyl isocyanate (1.0 eq.). The reaction mixture was stirred at RT for 27 h. Additional 3- chlorophenyl isocyanate (0.5 eq.) was added, and the reaction mixture was stirred additional 24 h at RT. Evaporation of the solvent gave a residue that was disolved in EtOH. The resulting solution (0.27 M) was treated with aqueous NaOH (IN, 2 eq.). The reaction mixture was stirred at RT for 1.5 h. Then, it was diluted with water, treated with 6N HCl and filtered to give a solid (LC-MS (ES+) m/z 305, 307 (M+H)+. Retention time (conditions 2): 4.24 min) that was dissolved in dry DMF. The resulting solution (0.27 M) was treated with DBU (1.2 eq.) and MeI (1.2 eq.). The reaction mixture was stirred at RT for 24 h, while additional amounts of reagents were added periodically (up to 4.8 eq.). The reaction was quenched by addition of water, and the resulting precipitate was collected by filtration. This solid (LC-MS (ES+) m/z 319, 321 (M+H)+. Retention time (conditions 2): 4.59 min) was dissolved in dry NMP and the resulting solution (0.15 M) was treated with 2-aminoethanol (4.0 eq.). The reaction mixture was heated at 2000C under microwave irradiation for 30 min. After cooling down, the reaction mixture was purified by RP- HPLC (Conditions: Waters Symmetry C 18, 7 micron, 19 x 300 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 70% A isocratic for 2 min, linear to 30% A in 14 min) to afford (4%) the title compound as a solid. 1H NMR (400 MHz, DMSO-(I6, 300 K) δ 2.20 (s, 3H), 3.31 (t, 2H, J 6.1), 3.45 (s, 3H), 3.59 (t, 2H, J6.1), 6.65 (d, IH, J8.8), 7.26 (m, IH), 7.46 (m, 2H), 7.70 (d, IH, J 8.8); MS (ES+) m/z 360, 362 (M+H)+.
Example 3 : 3-(3-chlorophenyl)-l-methyl-2,4-dioxo-l,2,3,4-tetrahydroquinazolin-6-aminium trifluoroacetate (117)
Step 1: Methyl 2-amino-5-nitrobenzoate
A suspension (0.55 M) of 2-amino-5-nitrobenzoic acid in MeOH was treated with thionyl chloride (3 eq.).
The reaction mixture was heated to reflux overnight. After cooling down, the reaction was treated with water and extracted with EtOAc. The combined organic layers were washed with NaHCθ3 (saturated solution), brine and dried. Evaporation of the solvent afforded (79%) the title compound as a yellow powder. 1H NMR (300 MHz, DMSO-ds, 300 K) δ 3.88 (s, 3H), 6.89 (d, IH, J 9.3), 7.80 (bs, 2H), 8.08
(dd, IH, J 9.3, 2.8), 8.58 (d, IH, J 2.6) MS (ES+) m/z 197 (M+H)+.
Step 2: 3 -(3 -chlorophenyl)- 1 -methyl-2,4-dioxo- 1 ,2,3 ,4-tetrahvdroquinazolm-6-amimum trifluoroacetate A suspension (1.0 M) of methyl 2-amino-5-nitrobenzoate (from Step 1) in dry Et2O was treated with 3- chlorophenyl isocyanate (5 eq.) and pyridine (4 eq.). The reaction mixture was stirred at RT overnight. After evaporation of the solvent, the resulting residue (LC-MS (ES") m/z 348, 350 (M-H)+. Retention time (conditions 1): 6.43 min) was dissolved in EtOH. The resulting solution (0.2 M) was treated with aqueous NaOH (10% solution, 10 eq.) and heated to reflux for 3 h. After cooling down, the reaction was neutralised with IN HCl and extracted with EtOAc. The combined organic layers were washed with brine and dried.
Evaporation of the solvent gave a crude (LC-MS (ES+) m/z 318, 320 (M+H)+. Retention time (conditions 1): 4.86 min) that was dissolved in DMF. The resulting solution (0.26 M) was treated with DBU (1.2 eq.) and MeI (1.2 eq.). The reaction mixture was stirred at RT for 1 h. then, quenched with IN HCl and extracted with EtOAc. The combined organic layer was washed with brine and dried. Evaporation of the solvent afforded the crude 3-(3-chlorophenyl)-l-methyl-6-nitroquinazoline-2,4(lH,3H)-dione (LC-MS (ES+) m/z 332, 334 (M+Η)+. Retention time (conditions 1): 4.25 min). A solution (0.2 M) of this crude in EtOH was treated with SnCl2-H2O (5 eq.). The reaction mixture was heated at 700C for 4 h. After cooling the reaction was filtered and filtrate was purified by RP-HPLC (Conditions: Waters X-TERRA C18, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 80% A isocratic for 1 min, linear to 20% A in 9 min, then linear to 10% A in 0.2 min and 10% A isocratic for 1.6 min) affording (2%) the title compound as a solid. 1H NMR (400 MHz, DMSO, 300 K) δ 3.47 (s, 3H), 7.21 (m, IH), 7.31 (m, 2H), 7.4 (m, 2H), 7.50 (m, 2H); MS (ES+) m/z 302, 304 (M+H)+.
Example 4: l-benzyl-4-({[3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahydroquinazolin-8- yl]carbonyl}amino)piperidinium trifluoroacetate (119)
Step 1: 2-amino-3-(methoxycarbonyl)benzoic acid
To a solution (0.4 M) of 2,3-dioxoindoline-7-carboxylic acid (1 eq.) in MeOH, HCl gas was bubbled and the reaction mixture was stirred at 800C for 2 h. After evaporation of the solvent, the resulting residue was diluted with CHCI3, washed with aqueous NaHCθ3 (saturated solution), brine and dried. Evaporation of the solvent afforded a crude (MS (ES+) m/z 206 (M+H)+) that was dissolved in H2O2 (10%). To the resulting solution (0.2 M) was added an equal volume of aqueous NaOH (2.5% solution) and the reaction mixture was stirred at RT for 15 min. The reaction mixture was acidified with cone. HCl and the resulting precipitate was filtered off and washed with water to afford (88%) the title compound as white powder. 1H NMR (400 MHz, DMSO-ds, 300K) δ 3.82 (s, 3H), 6.60 (t, IH, J 7.4), 8.04 (m, 3H), 12.94 (bs, IH); MS (ES+) m/z 196 (M+H)+.
Step 2: methyl 3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahvdroquinazoline-8-carboxylate
To a solution (0.17 M) of 2-amino-3-(methoxycarbonyl)benzoic acid (from Step 1) in CH2Cl2 were added 3- chloro-aniline (1.4 eq.), DIPEA (1.4 eq.) and HATU (1.1 eq.). The reaction mixture was stirred at RT for 7 days. After dilution with CH2Cl2, the resulting solution was washed with IN HCl, brine and dried. Evaporation of the solvent gave a crude that was washed with petroleum ether/CH2Cl2 affording a solid (MS (ES+) m/z 305, 307 (M+H)+) that was dissolved in dry 1,2-dichloroethane. The resulting solution (0.3 M) was treated with phenyl chloroformate (1.6 eq.). The reaction mixture was heated at 8O0C for 2 h. After evaporation of the solvent the resulting residue was dissolved in MeOH and treated with Et3N (10 eq.). The reaction mixture was heated at 8O0C for 30 min. After evaporation of the solvent the residue was washed with water and a solution of petroleum ether/Et2O to afford (77%) the title compound. 1H NMR (400 MHz, DMSO-ds, 300K) δ 3.97 (s, 3H), 7.38 (m, 2H), 7.55 (m, 3H), 8.27 (d, IH, J7.8), 8.34 (d, IH, J 7.6), 10.8 (s, IH); MS (ES+) m/z 331, 333 (M+H)+. Step 3: l-benzyl-4-({r3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahydroquinazolin-8- yllcarbonyl} amino)piperidinium trifluoroacetate
To a solution (0.1 M) of methyl 3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-8- carboxylate (from Step 2) in MeOH was added 2N NaOH (2 eq.). The reaction mixture was stirred at RT for 6 h. After evaporation of the solvent the residue was dissolved in EtOAc and the resulting solution washed with IN HCl, dried. Evaporation of the solvent gave a crude (MS (ES+) m/z 317, 319 (M+H)+) that was dissolved in CH2CI2. The resulting solution (0.1 M) was treated with 4-amino benzylpiperidine (1.2 eq.), DIPEA (1.2 eq.) and HATU (1.1 eq.). The reaction mixture was stirred at RT for 48 h. After dilution with DCM, the resulting solution was washed with water, dried and solvent was evaporated. The crude was purified by RP-HPLC (Conditions: Waters Symmetry C 18, 7 micron, 19 x 300 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 80% A isocratic for 2 min, linear to 20% A in 14 min) to afford (31%) the title compound as a solid. 1H NMR (400 MHz, DMSO-(I6, 300K) δ 1.81 (m, 2H), 2.12 (m, 2H), 3.16 (m, 2H), 3.44 (m, 2H), 4.07 (m, IH), 4.32 (d, 2H, J5.0), 7.37 (m, 2H), 7.52 (m, 8H), 8.17 (m, IH), 8.24 (d, IH, J7.8), 9.0 (d, IH, J7.3), 9.54 (bs, IH), 11.6 (s, IH); MS (ES+) m/z 489, 491 (M+H)+.
Example 5: 2-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino]-6,7-dihydro-lH,5H-pyrido[3,2,l- //]quinazoline-l,3(2H)-dione (202)
Step 1: 5-fluoro-8-methylquinoline
A solution of 5-fluoro-2-methylaniline (1.1 M) and sodium 3-nitrobenzenesulfonate (1 eq.) in glycerol/sulphuric acid (1/4, v/v) was refluxed for 5 h. After cooling the reaction mixture to 00C, Et2O and water were carefully added followed by solid NaOH until basic pH. After filtering away the insoluble material, the organic layer was separated, washed with brine, and dried. Evaporation of the solvent afforded (85%) the title compound as a pale brown solid; MS (ES+) m/z 162 (M+H)+.
Step 2: S-fluoroquinoline-S-carboxylic acid
A solution (0.15 M) of 5-fluoro-8-methylquinoline (from Step 1) in sulphuric acid/water (8/5, v/v) was heated at 900C and treated portionwise with Crθ3 (10 eq.) at such a rate to maintain the temperature below 1050C. After cooling the reaction mixture to 00C, CH2Cl2 and water were carefully added. Then, NaOH was added until pH = 5. The organic layer was separated and dried. Evaporation of the solvent afforded (25%) the title compound as a pale brown solid; MS (ES+) m/z 192 (M+H)+.
Step 3: 5-fluoro-l,2,3,4-tetrahvdroquinoline-8-carboxylic acid A solution (0.25 M) of 5-fluoroquinoline-8-carboxylic acid (from Step 2) in acetic acid was treated with PtO2 (0.3 eq.) and stirred under hydrogen at atmospheric pressure for 3 h. The catalyst was filtered off and the solution was concentrated to dryness under reduced pressure to afford a residue, which was redissolved with DMSO and purified by RP-HPLC (Conditions: Waters X-TERRA Cl 8, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 80% A isocratic for 1 min, linear to 20% A in 9 min) affording (40%) the title compound as a white solid; MS (ES+) m/z 196 (M+H)+.
Step 4: methyl 5-fluoro-l,2,3,4-tetrahvdroquinoline-8-carboxylate
A solution (0.04 M) of 5-fluoro-l,2,3,4-tetrahydroquinoline-8-carboxylic acid (from Step 3) in MeOH was treated with SOCl2 (28 eq.) and heated to reflux for 24 h. Volatiles were evaporated under reduced pressure and the residue partitioned between CH2Cl2 and aqueous NaHCθ3 (saturated solution). The organic layer was separated and dried. Evaporation of the solvent afforded (80%) the title compound as a solid; MS (ES+) m/z 210 (M+H)+.
Step 5: 2-(3-chlorophenyl)-8-fluoro-6,7-dihvdro-lH,5H-pyridor3,2,l-//'lquinazoline-l,3(2H)-dione
A solution (0.3 M) of methyl 5-fluoro-l,2,3,4-tetrahydroquinoline-8-carboxylate (from Step 4) in toluene was treated with l-chloro-3-isocyanatobenzene (4.5 eq.) and heated at 900C for 20 h. Solvent was evaporated under reduced pressure to give a residue that was dissolved in ethanol/aqueous NaOH (IN) (2/1, v/v). The resulting solution (0.2 M) was stirred at RT for 3 h. Then, the solution was concentrated to dryness under reduced pressure to afford a residue, which was redissolved with DMSO and purified by RP-ΗPLC (Conditions: Waters SYMMETRY Cl 8, 7 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 60% A isocratic for 2 min, linear to 10% A in 14 min) affording (35%) the title compound as a white solid; MS (ES+) m/z 331, 333 (M+H)+.
Step 6: 2-(3-chlorophenyl)-8-r(2-hvdroxyethyl)aminol-6,7-dihvdro-lH,5H-pyridor3,2,l-//'lquinazoline- l,3(2H)-dione A solution (0.1 M) of 2-(3-chlorophenyl)-8-fluoro-6,7-dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)- dione (from Step 5) in NMP was treated with ethanolamine (6 eq.). The reaction mixture was heated at 2000C under microwave irradiation for 2 h. The solution was purified by RP-ΗPLC (Conditions: Waters X- TERRA C18, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 80% A isocratic for 1 min, linear to 20% A in 9 min) affording (35%) the title compound as a white solid. 1H NMR (300 MHz, DMSO-ds, 300 K) δ 2.01 (m, 2H), 2.50 (m, 2H), 3.30 (m, 2H), 3.59, (m, 2H),
3.90 (m, 2H), 4.79 (bs, IH), 5.90 (bs, IH), 6.62 (d, IH, J 9.0), 7.22-7.30 (m, IH), 7.40-7.54 (m, 3H), 7.72 (d, IH, J 9.0); MS (ES+) m/z 372, 374 (M+H)+.
Example 6: l-benzyl-4-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido [3,2,1- ij]quinazolin-8-yl]amino}piperidinium trifhioroacetate (203) Step 1: 5-bromo-8-methylquinoline
A solution (0.3 M) of 8-methylquinoline in H2SO4 (cone.) was treated with Ag2SC^ (1.5 eq.) and bromine (1.0 eq.) were added. The reaction mixture was stirred at RT for 5 h and then poured into ice. The precipitate was filtrated and discarded. The remaining solution was basified with aqueous Na2CO3 (saturated solution) and the aqueous phase was extracted with EtOAc. The combined organic layers were dried and evaporated affording (71%) the title compound as a solid; MS (ES+) m/z 222, 224 (M+H)+.
Step 2: S-bromoquinoline-S-carboxylic acid
A solution (0.1 M) of 5-bromo-8-methylquinoline (from Step 1) in H2SOzrH2O (3:2) was treated with Crθ3 (10 eq.) at 900C. The reaction mixture was heated at 900C for 2 h. Then, the mixture was poured into ice and the precipitate was filtered affording (62%) the title compound as an orange solid; MS (ES+) m/z 252, 254 (M+H)+.
Step 3: 5-bromo-N-(3-chlorophenyl)-l,2,3,4-tetrahvdroquinoline-8-carboxamide A solution (0.3 M) of 5-bromoquinoline-8-carboxylic acid (from Step 2) in CH2Cl2 was treated with
DIPEA (4.4 eq.), 3-chloroaniline (1.1 eq.), and HATU (1.1 eq.). The reaction mixture was stirred at RT for 16 h. Then, it was treated with IN HCl, the resulting precipitate was filtered and the organic phase separated. The organic phase was then washed with IN HCl, aqueous NaHCθ3 (saturated solution) and dried. Evaporation of the solvent gave a crude that was washed with Et2O and filtered affording a solid that was dissolved in THF. The resulting solution (0.1 M) was treated with NaCNBH3 (2.0 eq) and
BF3. Et2O (1.5 eq.). The reaction mixture was heated at 8O0C for 2 h and then, more NaBH3CN (3.0 eq.) and BF3. Et2O (3.0 eq.) were added. After heating the reaction mixture at 8O0C for another 2 h, it was left to cool down and then treated with NH3 and the aqueous phase extracted with EtOAc. The combined organic layers were dried and evaporated to give a crude which was resubmitted to the same reaction conditions to afford (87%) the title compound as a solid; MS (ES+) m/z 365, 367 (M+H)+.
Step 4: 8-bromo-2-(3-chlorophenyl)-6,7-dihvdro-lH,5H-pyridor3,2,l-//'lquinazoline-l,3(2H)-dione To a solution (0.1 M) of 5-bromo-N-(3-chlorophenyl)-l,2,3,4-tetrahydroquinoline-8-carboxamide (from Step 3) in 1 ,2-dicloroethane was added phenyl chloroformate (1.0 eq.) and the reaction mixture was stirred at 8O0C. After 1 h the solvent was evaporated and the crude (MS (ES+) m/z 507, 509 (M+Η)+) was dissolved in MeOH. The resulting solution (0.1 M) was treated with Et3N (10 eq.). The reaction mixture was heated at 8O0C for 30 min. Then, the solvent was evaporated and the crude washed with Et2O and filtered off affording (30%) the title compound as a solid; MS (ES+) m/z 391, 393 (M+H)+.
Step 5: l-benzyl-4-{r2-(3-chlorophenyl)-l,3-dioxo-2,3,6J-tetrahvdro-lH5H-pyridor3,2,l-//lquinazolin-8- yllaminolpiperidinium trifluoroacetate To a solution (0.05 M) of 8-bromo-2 -(3-chlorophenyl)-6,7-dihydro-lH, 5H-pyrido [3,2,1-//] quinazoline- l,3(2H)-dione (from Step 4) in toluene, 4-amino-benzyl piperidine (1.2 eq.), NaO1Bu (1.4 eq.), BINAP (0.03 eq.) and Pd2(dba)3 (0.02 eq.) were added. The reaction mixture was heated at 800C for 16 h. The solvent was evaporated and the residue purified by RP-ΗPLC (Conditions: Waters X-TERRA Cl 8, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 90% A isocratic for 1 min, linear to 10% A in 20 min and 10% A isocratic for 2 min) affording (20%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-ds, 300 K) δ 1.78 (m, 2H), 2.0 (m, 2H), 2.13 (m, 2H), 3.10, (m, 2H), 3.36 (m, 3H), 3.70 (bs, IH), 3.91 (m, 3H), 4.33 (d, 2H, J 4.2), 5.77 (d, 1 R, J 13), 6.71 (d, IH, J 9.1), 7.25 (m, IH), 7.48-7.50 (m, 8H), 7.71 (d, IH, J 9.1), 9.54 (bs, IH); MS (ES+) m/z 501, 503 (M+H)+.
Example 7: l-benzyl-4-{[2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H- pyrido[3,2,l-//]quinazolin-8-yl]amino}piperidinium trifluoroacetate (207)
Step 1: methyl 3-chloro-5-nitrobenzoate A solution (0.96 M) OfNaNO2 (7.0 eq.) in water was added to a solution (0.09 M) of 3-amino-5-nitrobenzoic acid in HCl (cone.) at 00C. The reaction mixture was left to warm up to RT over a period of 30 min and then was added to a solution (1.37 M) of CuCl (10.0 eq.) in water. The reaction mixture was stirred at RT for 3 h and then heated to 700C for 30 min. After addition Of Et2O and water, the organic phase was separated and the aqueous phase extracted with Et2O. The combined organic layers were dried and evaporated to give a solid (MS (ES+) m/z 200, 202 (M+H)+), which was dissolved in MeOH. The resulting solution (0.1 M) was treated with SOCl2 (20 eq.) and the reaction mixture was heated at 800C for 16 h. After evaporation of the solvent, the resulting residue was dissolved in EtOAc and aqueous NaHCO3 (saturated solution). The aqueous phase was separated and the organic phase washed with aqueous NaHCO3 (saturated solution) and brine and dried. Evaporation of the solvent afforded (95%) the title compound as a white solid; MS (ES+) m/z 216, 218 (M+H)+.
Step 2: methyl 3-amino-5-chlorobenzoate
A solution (0.13 M) of methyl 3-chloro-5-nitrobenzoate (from Step 1) in dioxane was treated with SnCl2 (3.9 eq.). The reaction mixture was stirred at 700C for 2 h. After cooling down, EtOAc and aqueous NaHCO3 (saturated solution) were added, the precipitate formed was filtered, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried and evaporation of the solvent afforded (88%) the title compound as a yellow solid; MS (ES+) m/z 186, 188 (M+H)+.
Step 3: 5-bromo-l,2,3,4-tetrahvdroquinoline-8-carboxylic acid To a solution (0.2 M) of 5-bromoquinoline-8-carboxylic acid (prepared as in Example 6, Step 2) in
MeOH/HCl (4 M in dioxane) (1 :1, v/v), PtO2 (0.3 eq.) was added. The reaction mixture was stirred under H2 atmosphere for 30 min. The reaction mixture was filtered over celite. After evaporation of the solvent the residue was purified on flash column chromatography reverse phase (MeCN/water, 1 :1) affording (20%) of the title compound as a solid; MS (ES+) m/z 256, 258 (M+H)+.
Step 4: 8-bromo-6,7-dihvdro-lH,5H-ri,31oxazinor5,4,3-//'lquinoline-l,3-dione
A solution (0.1 M) of 5-bromo-l,2,3,4-tetrahydroquinoline-8-carboxylic acid (from Step 3) in TΗF was treated with COCl2 (0.3 eq.). The reaction mixture was stirred at RT for 16 h. The resulting solution was diluted with EtOAc and washed with aqueous NaΗCθ3 (saturated solution). The organic phase was dried and evaporation of the solvent afforded (80%) the title compound as a yellow solid; MS (ES+) m/z 282, 284 (M+H)+.
Step 5: l-benzyl-4-{r2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahvdro-lH5H-pyridor3,2,l-
//'lquinazolin-8-yllaminolpiperidinium trifluoroacetate
To a solution (0.1 M) of 8-bromo-6,7-dihydro-lH,5H-[l,3]oxazino[5,4,3-z/] quinoline-l,3-dione (from Step 4) in NMP, methyl 3-amino-5-chlorobenzoate (3.0 eq.) (prepared as in Example 7, Step 2) was added. The reaction mixture was heated to 1700C for 16 h. After cooling down, the reaction mixture was diluted with EtOAc and the organic phase was washed with IN HCl, aqueous NaΗCθ3 (saturated solution) and brine. The combined organic layers were dried and evaporated and Et2O was added to the residue. The resulting precipitate (MS (ES+) m/z 423, 425 (M+H)+) was filtered and dissolved in 1 ,2-dichloroethane. The resulting solution (0.2 M) was treated with phenyl chloroformate (1.0 eq.). The reaction mixture was heated to 800C for 30 min. Then, the solvent was evaporated and the crude dissolved in MeOH. The resulting solution (0.2 M) was treated with Et3N (10 eq.) and the reaction mixture was heated to 800C for 30 min. After cooling down, solvent was evaporated and Et2O was added. The resulting precipitate was filtered and washed with water giving a crude (MS (ES+) m/z 449, 451 (M+H)+) that was dissolved in toluene. The resulting solution (0.05 M) was treated with 4-amino-benzylpiperidine (1.2 eq.), BINAP (0.06 eq.), NaO1Bu (2.4 eq.) and Pd2(dba)3 (0.04 eq.). The reaction mixture was stirred at 800C for 2 h. Evaporation of the solvent gave a residue that was purified by RP-HPLC (Conditions: Waters X-TERRA C 18, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 90% A isocratic for 1 min, linear to 10% A in 20 min and 10% A isocratic for 2 min) affording (20%) the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-ds, 300 K) δ 1.78 (m, 2H), 1.90-2.13 (m, 5H), 3.07 (m, 2H), 3.34-3.43 (m, 3H), 3.69 (m, IH), 3.90 (m, 2H), 4.31 (m, 2H), 5.76 (m, IH), 6.70 (d, 1 H, J 8.8 Hz), 7.52 (m, 5H), 7.71 (m, 2H), 7.78 (s, 1 H), 7.93 (s, 1 H), 9.54 (bs, IH), 13.46 (bs, IH); MS (ES+) m/z 545, 547 (M+H)+.
Example 8: 3-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-ij]quinazolin-l- yl]methyl}benzoic acid (213) Step 1: N-Q-chlorophenvDquinoxalme-S-carboxamide
A solution (0.1 M) of quinoxaline-5-carboxylic acid in CH2Ck was treated with DIPEA (2.2 eq.), 3- chloroaniline (1.1 eq.) and HATU (1.1 eq.). The reaction mixture was stirred at RT overnight. The solution was diluted with EtOAc and the organic phase was washed with aqueous NaHCθ3 (saturated solution) and dried. Evaporation of the solvent gave a crude that was washed with MeCN and filtered off affording (93%) the title compound as a solid; MS (ES+) m/z 284, 286 (M+H)+.
Step 2: N-(3-chlorophenyl)-l,2,3,4-tetrahvdroquinoxaline-5-carboxamide
A solution (0.1 M) of N-(3-chlorophenyl)quinoxaline-5-carboxamide (from Step 1) in AcOH was treated with NaBH4 (2.0 eq.). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with EtOAc and IN HCl. The aqueous phase was separated and the organic phase washed with brine and dried. Evaporation of the solvent afforded (78%) the title compound as an orange solid; MS (ES+) m/z 287, 289 (M+H)+.
Step 3: methyl 3-{r6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahvdro-lH,5H-pyrazinor3,2,l-//'lquinazolin-l- yllmethyllbenzoate
A solution (0.06 M) of N-(3-chlorophenyl)-l,2,3,4-tetrahydroquinoxaline-5-carboxamide (from Step 2) in MeOH was treated with methyl 3-formylbenzoate (1.0 eq.), NaBH3CN (1.0 eq.) and AcOH. The reaction mixture was stirred at RT overnight. Then, aqueous NaHCO3 (saturated solution) was added and the aqueous phase extracted with EtOAc. The combined organic layers were dried and evaporated to give a solid (LC-
MS (ES+) m/z 436, 438 (M+H)+ that was dissolved in 1,2-dichloroethane. The resulting solution (0.1 M) was treated with phenyl chloroformate (1.0 eq.). The reaction mixture was stirred at 800C for 2 h. Evaporation of the solvent gave a crude (MS (ES+) m/z 556, 558 (M+H)+) which was dissolved in MeOH. The resulting solution (0.1 M) was treated with Et3N (10 eq.). The reaction mixture was heated to 800C for 30 min. The solvent was evaporated and the residue purified by RP-HPLC (Conditions: Waters X-TERRA Cl 8, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 90% A isocratic for 1 min, linear to 10% A in 20 min and 10% A isocratic for 2 min) affording (20%) the title compound as a white solid; MS (ES+) m/z 462, 464 (M+H)+.
Step 4: 3-{r6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahvdro-lH,5H-pyrazinor3,2,l-//'lquinazolin-l- yllmethyl} benzoic acid
A solution (0.05 M) of methyl 3-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l- z/]quinazolin-l-yl]methyl}benzoate (from Step 3) in dioxane was treated with aqueous NaOH (2N, 4.0 eq.). The reaction mixture was stirred at RT for 8 h. The solvent was evaporated and the residue purified by RP- ΗPLC (Conditions: Waters X-TERRA Cl 8, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 90% A isocratic for 1 min, linear to 10% A in 20 min and 10% A isocratic for 2 min) affording (80%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-(I6, 300 K) δ 3.57 (bs, 2H), 4.10 (bs, 2H), 4.69 (bs, 2H), 7.07-6.96 (m, 2H), 7.33 (m, 2H), 7.51-7.60 (m, 5H), 7.85 (m, IH), 7.93 (m, IH), 12.98 (bs, IH); MS (ES+) m/z 448, 450 (M+H)+.
Example 9: l-benzyl-4-{[4-(3-chlorophenyl)-5-oxo-4,5-dihydroimidazo[l,2-α]quinazolin-8- yl]amino}piperidinium trifluoroacetate (302)
Step 1: 4-bromo-N-(3-chlorophenyl)-2-nitrobenzamide
To a solution (0.2 M) of 4-bromo-2-nitrobenzoic acid in CH2CI2, 3-chloro aniline (1.1 eq.), DIPEA (2.2 eq.) and HATU (1.1 eq.) were added. The reaction mixture was stirred at RT for 16 h. Then, it was treated with aqueous NaHCθ3 (saturated solution) and the organic phase was separated and washed with IN HCl and dried. Evaporation of the solvent gave a solid that was washed with Et2O affording (67%) the title compound as a white solid. 1H NMR (400 MHz, DMSOd6, 300 K) δ 7.21 (d, IH, ./ 8.1), 7.41 (t, IH, J8.1), 7.51 (d, IH, J 8.8), 7.77 (d, IH, J 8.1), 7.85 (s, IH), 8.13 (d, IH, J 8.1), 8.40 (s, IH), 10.89 (s, IH); MS (ES+) m/z 355, 357, 359 (M+H)+.
Step 2: 7-bromo-3-(3-chlorophenyl)-2-thioxo-2,3-dihvdroquinazolin-4(lH)-one
To a solution (0.05 M) of 4-bromo-N-(3-chlorophenyl)-2-nitrobenzamide (from Step 1) in EtOΗ/Η2O/AcOΗ (12:1 :0.008), iron (20 eq.) was added and the resulting suspension was heated to 660C for 5 h. The resulting precipitated was filtered and the filtrated concentrated. The residue was dissolved in EtOAc and the resulting organic phase was washed with aqueous NaHCθ3 (saturated solution), brine and dried. Evaporation of the solvent gave a solid (LC-MS (ES+) m/z 325, 327, 329 (M+H)+) which was added slowly to a solution (0.2 M) Of CS2 (20 eq.) and DBU (1 eq.) in THF at RT. The resulting suspension was heated at 45°C for 30 min and then at RT for 16 h. The reaction mixture was poured in IN HCl and the resulting precipitated was collected and washed with EtOH and petroleum ether affording (45%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-ds, 300 K) δ 7.30 (d, IH, J 6.8), 7.53-7.47 (m, 4H), 7.62 (s, IH), 7.87 (d, IH, J 8.3), 13.11 (s, IH); MS (ES+) m/z 367, 369, 371 (M+H)+.
Step 3: 8-bromo-4-(3-chlorophenyl)-imidazori,2-α1 quinazolin-5(4H)-one
To a solution (0.2 M) of 7-bromo-3-(3-chlorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(lH)-one (from Step 2) in CHCl3 at RT, SO2Cl2 was added and the resulting solution was heated at 80 0C for 3 h. Then, the solution was poured into ice and CH2Cl2 was added and the organic phase was separated, washed with water and dried. Evaporation of the solvent gave a crude (LC-MS (ES+) m/z 369, 371, 373 (M+H)+) which was dissolved in EtOH. The resulting solution (0.2 M) was treated with 2,2-dimethoxyethanamine (6 eq.) and Et3N (6 eq.). The reaction mixture was heated at 8O0C for 30 min. After evaporation of the solvent, water was added and was extracted with EtOAc. The combined organic phase was dried and evaporated giving a residue which was dissolved in DMF/conc. HCl (2:1). The resulting solution (0.2 M) was heated at 80 0C for 1 h. After cooling down it was purified by RP-HPLC (Conditions: Waters X-TERRA Cl 8, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 90% A isocratic for 1 min, linear to 10% A in 20 min and 10% A isocratic for 2 min) affording (40%) the title compound as a white solid. 1H NMR (400 MHz, DMSOd6, 300 K) δ 7.03 (s, IH), 7.48 (m, IH), 7.60 (m, 2H), 7.64 (s, IH), 7.73 (d, IH, J 8.6), 8.12 (d, IH, J 8.3), 8.22 (s, IH), 8.52 (s, IH); MS (ES+) m/z 374, 376, 378 (M+H)+.
Step 4: l-benzyl-4-{r4-(3-chlorophenyl)-5-oxo-4,5-dihvdroimidazori,2-αlquinazolin-8- vHaminolpiperidinium trifluoroacetate
To a solution (0.2 M) of 8-bromo-4-(3-chlorophenyl)-imidazo[l,2-α] quinazolin-5(4H)-one (from Step 3) in toluene were added 4-amino-benzylpiperidine (1.2 eq.), NaO1Bu (1.4 eq.), XANTPΗOS (0.3 eq.) and Pd2(dba)3 (0.2 eq.). The reaction mixture was heated at 800C for 2 h. After evaporation of the solvent the residue was purified by RP-ΗPLC (Conditions: Waters X-TERRA C18, 5 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 90% A isocratic for 1 min, linear to 10% A in 20 min and 10% A isocratic for 2 min) affording (70%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-ds, 300 K) δ 1.67 (m, 2H), 2.23 (m, 2H), 3.05 (m, 2H), 3.53 (m, 2H), 3.7 (bs, IH), 4.38 (s, 2H), 6.75 (d, IH, J8.8), 6.91 (s, IH), 7.04 (s, IH), 7.14 (m, IH), 7.59-7.41 (m, 7H), 7.86 (d, IH, J 8.8), 8.04 (s, IH), 9.72 (bs, IH); MS (ES+) m/z 484, 486 (M+H)+.
Example 10: 4-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino][l,2,4]triazolo[4,3-α]quinazolin-5(4H)-one (304)
Step 1: 7-bromo-3-(3-chlorophenyl)-2-hvdrazinoquinazolin-4(3H)-one
To a solution (0.5 M) of 7-bromo-3-(3-chlorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(lH)-one (from Example 9, Step 2) in EtOH at RT, hydrazine (1 M solution in TΗF, 6.5 eq.) was added. The reaction mixture was heated at 800C for 12 h. Then, more hydrazine (1 M solution in TΗF, 6.5 eq.) was added and the reaction heated at 800C for another 12 h. After evaporation of the solvent, the resulting crude was purified by RP-ΗPLC (Conditions: Waters SYMMETRY Cl 8, 7 micron, 19 x 100 mm; flow: 20 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 80% A isocratic for 2 min, linear to 10% A in 15 min) affording (40%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-(I6, 300 K) δ 7.13 (d, IH, J 12.0), 7.35-7.42 (m, 2H), 7.62 (s, IH), 7.90 (d, 2H, J 12.0), 8.14 (s, IH), 8.65 (bs, IH), 9.65 (bs, IH); MS (ES+) m/z 365, 367, 369 (M+H)+.
Step 2: 8-bromo-4-(3-chlorophenyl)ri,2,41triazolor4,3-αlquinazolin-5(4H)-one
A solution (0.2 M) of 7-bromo-3-(3-chlorophenyl)-2-hydrazinoquinazolin-4(3H)-one (from Step 1) in formic acid was heated at 1400C for 2 h. After cooling, it was purified by RP-ΗPLC (Conditions: Waters X-TERRA C18, 5 micron, 19 x 100 mm; flow: 15 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 80% A isocratic for 2 min, linear to 20% A in 12 min) affording (40%) the title compound as a white solid. 1H NMR (300 MHz, DMSO-Cl6, 400 K) δ 7.50-7.53 (m, IH), 7.61-7.67 (m, 3H) 7.82 (dd, IH, J 9.3, 2.1), 8.13 (d, IH, J 9.3), 8.65 (d, IH, J 2.1), 9.57 (s, IH); MS (ES+) m/z 375, 377, 379 (M+H)+.
Step 3: 4-(3-chlorophenyl)-8-r(2-hvdroxyethyl)aminoiri,2,41triazolor4,3-αlquinazolin-5(4H)-one To a solution (0.6 M) of 8-bromo-4-(3-chlorophenyl)[l,2,4]triazolo[4,3-α]quinazolin-5(4H)-one (from Step 2) in NMP at RT, ethanolamine (10 eq.) was added. The reaction mixture was irradiated with a MW apparatus at 1500C for 15 min. After cooling down, it was purified by RP-ΗPLC (Conditions: Waters X- TERRA C18, 5 micron, 19 x 100 mm; flow: 15 mL/min; Gradient: A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 80% A isocratic for 2 min, linear to 20% A in 12 min) affording (25%) the title compound as a white solid. 1H NMR (300 MHz, DMSO-ds, 400 K) δ 3.34 (t, 2H, J 6.0), 3.65 (t, 2H, J 6.0), 6.86 (dd, IH, J 9.2, 1.5), 7.15 (d, IH, J 1.5), 7.46-7.51 (m, IH), 7.58-7.60 (m, 2H), 7.63-7.65 (m, IH), 7.84 (d, IH, J9.2), 9.45 (s, IH); MS (ES+) m/z 356, 358 (M+H)+.
The following tables contain further examples:
Table 1 : Examples of compounds of formula (Ii)
Figure imgf000041_0001
Figure imgf000042_0001
Table 2: Examples of 6,7-dihvdro-lH,5H-pyridor3,2,l-//'lquinazoline-l,3(2H)-diones i.e. compounds of formula (Iii)
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001

Claims

Claims
1. Use of a compound of formula (I):
Figure imgf000045_0001
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein
A and B are each independently CH2, C=O or C=S, with the proviso that A and B are not both CH2;
R1 is Ci.galkyl, C2.galkenyl, C2.galkynyl or (CH2)0_3Ra, optionally substituted by Q1 and Q2; Q1 and Q2 are independently selected from hydrogen, halo, hydroxy,
Figure imgf000045_0002
C2.6alkenyl, CN, S(O)0.2Rb, SO2NR5R6, NR7SO2NR5R6, CO2R5, CONR5R6, NR5COR6, NR5SO2R6, NR5CONR6, NR5CO2R6, OCONR5R6, CONR5SO2R6 or CONR7SO2NR5R6, optionally substituted by 1 to 8 halogen atoms;
Ra is Cs.γcycloalkyl, Het, aryl or heteroaryl; Rb is C i-βalkyl, heteroaryl or aryl;
R5, R6 and R7 are independently selected from hydrogen, C^alkyl, (CH2)i_3OH, (CH2)0_3Het, (CH2)o_3aryl and (CH2)0.3heteroaryl;
R is hydrogen,
Figure imgf000045_0003
C2_6alkenyl, C2_6alkynyl, C3.gcycloalkyl, (CH2)0_3Het, (CH2)0.3aryl, (CH2)o_3heteroaryl or (CH2)o.3θ(CH2)0.3aryl, optionally substituted by hydroxy, CN or 1 to 8 halogen atoms;
R3 is hydrogen, d.6alkyL C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl, CO2R5, CONR5R6, NR5COR6,
NR5SO2R6 Or NR7CONR5R6, optionally substituted by hydroxy or 1 to 8 halogen atoms; or R2 and R3, together with the C=C-N group to which they are attached, form a 5-, 6- or 7- membered nitrogen-containing heterocyclic ring, which heterocyclic ring optionally contains 1 or 2 further heteroatoms selected from N and O, and which hetorcyclic ring is optionally substituted by Q3;
Q3 is hydrogen, halo,
Figure imgf000045_0004
(CH2)0.3aryl, (CH2)0_3Het, (CH2)0.3heteroaryl or (CH2)o.3C3-8cycloalkyl, which Ci.ealkyl, (CH2)0.3aryl, (CH2)0.3Het, (CH2)0.3heteroaryl and (CH2)o_3C3_8cycloalkyl groups are optionally substituted by hydroxy, CO2H or CO2Ci_6alkyl; R4 is hydrogen, Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl, (CH2)0_3aryl, Het, (CH2)o.3heteroaryl, hydroxy, d.6alkoxy, halo, d.6alkylene-SH, NRcRd, NRcC0Rd, NReC0NRcRd,
NRcC02Rd, NRcS02Rd or NReS02NRcRd, where said Ci.ealkyl, C2.6alkenyl, C2-6alkynyl, C3.8cycloalkyl and Ci-βalkoxy groups are optionally substituted by hydroxy or 1 to 8 halogen atoms; Rc, Rd and Re are independently selected from hydrogen,
Figure imgf000046_0001
C2-6alkenyl, C2-6alkynyl, Cs.gcycloalkyl, (CH2)o-2aryl, (CH2)o-3Het and (CH2)o-3heteroaryl, optionally substituted by one to three substituents independently selected from halo, hydroxy, Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, CO2H, (CH2)o-3aryl and (CH2)o-3heteroaryl; or B and R2 are joined to form a 5-, 6- or 7- membered nitrogen-containing heterocycle, which heterocycle optionally contains 1, 2 or 3 further heteroatoms selected from N, O and S, and which heterocycle is optionally substituted by Q4;
Q4 is hydrogen, halo, hydroxy,
Figure imgf000046_0002
(CH2)o-3aryl or (CH2)o-3C3_8cycloalkyl, optionally substituted by hydroxy, CO2H or CO2Ci.6alkyl.
2. Use of a compound according to Claim 1 of formula (Ii):
Figure imgf000046_0003
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein A, B and R3 are as defined in Claim 1 ;
R1 is Ci-galkyl, C2.8alkenyl, C2.8alkynyl or (CH2)0.3Ra, optionally substituted by Q1 and Q2;
Q1 and Q2 are independently selected from hydrogen, halo, hydroxy, C
Figure imgf000046_0004
^alkyl, C2.6alkenyl, CN, S(O)0.2Rb, SO2NR5R6, NR7SO2NR5R6, CO2R5, CONR5R6, NR5COR6, NR5SO2R6, NR5CONR6, NR5CO2R6, OCONR5R6, CONR5SO2R6 or CONR7SO2NR5R6, optionally substituted by 1 to 8 halogen atoms;
Ra is C3.7cycloalkyl, Het, aryl or heteroaryl;
Rb is Ci-βalkyl, heteroaryl or aryl;
R5, R6 and R7 are independently selected from hydrogen, C^alkyl, (CH2)0_3Het, (CH2)0_3aryl and (CH2)o_3heteroaryl; R2 is hydrogen, Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C3_8cycloalkyl, (CH2)0.3Het, (CH2)0_3aryl or
(CH2)o-3θ(CH2)o_3aryl, optionally substituted by hydroxy or 1 to 8 halogen atoms;
R4 is hydrogen, Ci_6alkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl, (CH2)0.3aryl, (CH2)o.3heteroaryl, hydroxy, d.6alkoxy, halo, d.6SH, NRcRd, NRcC0Rd, NReC0NRcRd, NRcCO2Rd, NRcS02Rd or NReS02NRcRd, where said Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl and d.6alkoxy groups are optionally substituted by hydroxy or 1 to 8 halogen atoms;
Rc, Rd and Re are independently selected from hydrogen,
Figure imgf000046_0005
C2.6alkenyl, C2.6alkynyl, C3_8cycloalkyl, (CH2)0.3aryl, (CH2)0.3Het and (CH2)0.3heteroaryl, optionally substituted by one to three substituents independently selected from halo, hydroxy, C2-6alkenyl, C2-6alkynyl and (CH2)0.3aryl.
3. Use of a compound according to Claim 2 of formula (Iia):
Figure imgf000047_0001
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
R2, R3 and R4 are as defined in Claim 2, and
Q1 and Q2 are independently selected from hydrogen, halo, hydroxy,
Figure imgf000047_0002
CN, CO2H, CO2(C i-6alkyl) and CONHR5 where R5 is as defined in Claim 2.
4. Use of a compound according to Claim 2 of formula (lib):
Figure imgf000047_0003
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
Q1 and Q2 are independently selected from hydrogen, CO2H, halo,
Figure imgf000047_0004
or S(O)L2R8;
R »2 : is Ci-βalkyl, C2.6alkenyl, C2.6alkynyl or C3.8cycloalkyl, optionally substituted by hydroxy or
OR8
R )3 i :s as defined in Claim 2;
R4 is halo or a group NRcRd, OR9 or Het, which Het group is optionally substituted by Rd; Rc and Re are hydrogen or
Figure imgf000047_0005
optionally substituted by hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group;
R > d i:s a Ci-βalkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl or piperidinyl, optionally substituted by hydroxy, halo, CMalkyl, benzyl, OR9, NReRf, S(O)i.2R8 or COR9; Rf is hydrogen or an
Figure imgf000048_0001
group substituted by phenyl, hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group;
R8 is phenyl or
Figure imgf000048_0002
optionally substituted by phenyl;
R9 is Ci_4alkyl group optionally substituted by hydroxy, halo or a group NReRf or a N-linked 5- or 6-membered heterocyclic ring optionally containing a further nitrogen atom and optionally substituted by R8.
5. Use of a compound according to Claim 2 selected from Group (II), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein Group (II) is:
3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l-methylquinazoline-2,4(lH,3H)-dione, 7-chloro-3-(3-chlorophenyl)quinazoline-2,4(lH,3H)-dione, 7-chloro-3-(3-chlorophenyl)-l-methylquinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-7-(isobutylamino)-l-methylquinazoline-2,4(lH,3H)-dione, l-benzyl-3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione,
7-[(l -benzylpiperidin-4-yl)amino]-3-(3-chlorophenyl)- 1 -methylquinazoline-2,4(lH,3H)-dione,
3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l-(3-methylbut-2-en-l-yl)quinazoline-2,4(lH,3H)-dione, l-[2-(benzyloxy)ethyl]-3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-l-(2-hydroxyethyl)-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-l-ethyl-7-[(2-hydroxyethyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l-isobutylquinazoline-2,4(lH,3H)-dione, 3-(5-chloro-2-fluorophenyl)-7-[(2-hydroxyethyl)amino]-l-methylquinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-7-[(2-hydroxyethyl)amino]-l,8-dimethylquinazoline-2,4(lH,3H)-dione, 3-(3-chlorophenyl)-l-methyl-7-[(4-methylcyclohexyl)amino]quinazoline-2,4(lH,3H)-dione, 3-(2-chlorophenyl)-l-methyl-7-(piperidin-4-ylamino)quinazoline-2,4(lH,3H)-dione, 6-amino-3-(3-chlorophenyl)-l-methylquinazoline-2,4(lH,3H)-dione,
2-[7-[(l-benzylpiperidin-4-yl)amino]-l-methyl-2,4-dioxo-l,4-dihydroquinazolin-3(2H)-yl]-4- chlorobenzoic acid, and N-(l-benzylpiperidin-4-yl)-3-(3-chlorophenyl)-2,4-dioxo-l,2,3,4-tetrahydroquinazoline-8-carboxamide.
6. Use of a compound according to Claim 1 of formula (Iii):
(Iii)
Figure imgf000048_0003
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein A, B, R1 and R2 are as defined in Claim 1 ; or R2 and R3, together with the C=C-N group to which they are attached, form a 5-, 6- or 7- membered nitrogen-containing heterocyclic ring, which heterocyclic ring optionally contains 1 or 2 further heteroatoms selected from N and O, and which heterocyclic ring is optionally substituted by Q3;
Q3 is hydrogen, halo, Ci_6alkyl, Ci_6alkoxy, (CH2)o-3aryl, (CH2)o-3Het, (CH2)o-3heteroaryl or (CH2)o.3C3.gcycloalkyl, which Ci.6alkyl, (CH2)0.3aryl, (CH2)0.3Het, (CH2)0.3heteroaryl and (CH2)o-3C3_8cycloalkyl groups are optionally substituted by hydroxy, CO2H or CO2Ci_6alkyl; R4 is hydrogen,
Figure imgf000049_0001
C2_6alkenyl, C2_6alkynyl, Cs.gcycloalkyl, (CH2)0.3aryl,
(CH2)o.3heteroaryl, hydroxy, d.6alkoxy, halo, d.6alkylene-SH, NRcRd, NRcC0Rd, NReC0NRcRd, NRcC02Rd, NRcSO2Rd or NReSO2NRcRd, where said Ci.6alkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl and Ci-βalkoxy groups are optionally substituted by hydroxy or 1 to 8 halogen atoms;
Rc, Rd and Re are independently selected from hydrogen,
Figure imgf000049_0002
C2_6alkenyl, C2.6alkynyl, Cs.gcycloalkyl, (CH2)0.3aryl, (CH2)0.3Het and (CH2)0.3heteroaryl, optionally substituted by one to three substituents independently selected from halo, hydroxy, C^alkyl, C2_6alkenyl, C2.6alkynyl, CO2H, (CH2)o_3aryl and(CH2)0.3heteroaryl.
7. Use of a compound according to Claim 6 of formula (Iiia):
Figure imgf000049_0003
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
R2, R3 and R4 are as defined in Claim 6; and
Q1 and Q2 are independently selected from hydrogen, halo, hydroxy, C
Figure imgf000049_0004
^alkyl, CN, CO2H, CO2(C i.6alkyl) and CONHR5 where R5 is as defined in Claim 1.
8. Use of a compound according to Claim 6 of formula (Iiib):
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein
Q1 and Q2 are independently selected from hydrogen, CO2H, halo, C
Figure imgf000050_0002
^haloalkyl, or
R »2 : is Ci-βalkyl, C2-6alkenyl, C2-6alkynyl or C3.8cycloalkyl, optionally substituted by hydroxy or
OR8
R )3 i :s as defined in Claim 6;
R4 is halo or a group NRcRd, OR9 or Het, which Het group is optionally substituted by Rd;
Rc and Re are hydrogen or
Figure imgf000050_0003
optionally substituted by hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group;
Rd is a Ci-βalkyl, C2.6alkenyl, C2.6alkynyl, C3.8cycloalkyl or piperidinyl, optionally substituted by hydroxy, halo, CMalkyl, benzyl, OR9, NReRf, S(O)L2R8 or COR9;
Rf is hydrogen or an
Figure imgf000050_0004
group substituted by phenyl, hydroxy, halo, amino or a mono- or di-Ci_4alkyl substituted amino group;
R8 is phenyl or
Figure imgf000050_0005
optionally substituted by phenyl;
R9 is Ci_4alkyl group optionally substituted by hydroxy, halo or a group NReRf or a N-linked 5- or 6-membered heterocyclic ring optionally containing a further nitrogen atom and optionally substituted by R8.
9. Use of a compound according to Claim 6 of formula (Iiic):
Figure imgf000050_0006
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein Q1, Q2, R4 and Q3 are as defined in Claim 6 and A is CH or N.
10. Use of a compound according to Claim 6 selected from Group (III), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein Group (III) is:
2-(3-chlorophenyl)-8-fluoro-6,7-dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)-dione, 2-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino]-6,7-dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)- dione, l-benzyl-4-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}piperidinium trifluoroacetate, cώ-4-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}cyclohexanecarboxylic acid, frα«s-4-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid,
4-({[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}methyl)benzoic acid, l-benzyl-4-{[2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l- ij] quinazolin- 8 -yl] amino } piperidinium trifluoroacetate,
3-chloro-N-(2-hydroxyethyl)-5-[8-[(2-hydroxyethyl)amino]-l,3-dioxo-6,7-dihydro-lH,5H-pyrido[3,2,l- z/]quinazolin-2(3H)-yl]benzamide,
4-{[2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}piperidinium trifluoroacetate,
4-{[2-(3-carboxy-5-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}-l-(pyridin-4-ylmethyl)piperidinium trifluoroacetate,
3-({[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino}methyl)benzoic acid, 6-(3-chlorophenyl)-l-(2-hydroxyethyl)-2,3-dihydro-lH,5H-pyrazino[3,2,l-//]quinazoline-5,7(6H)-dione,
3-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl} benzoic acid, ethyl 2-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl}cyclopropanecarboxylate, methyl 3-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl}benzoate,
2-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl} cyclopropanecarboxylic acid,
6-(3-chlorophenyl)-l-(3-hydroxypropyl)-2,3-dihydro-lH,5H-pyrazino[3,2,l-//]quinazoline-5,7(6H)- dione,
4-{[6-(3-chlorophenyl)-5,7-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrazino[3,2,l-//]quinazolin-l- yl]methyl} benzoic acid, 2-(3-chlorophenyl)-8-hydroxy-6,7-dihydro-lH,5H-pyrido[3,2,l-//]quinazoline-l,3(2H)-dione, 3-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid, cώ-3-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid, and cώ-3-{[2-(3-chlorophenyl)-l,3-dioxo-2,3,6,7-tetrahydro-lH,5H-pyrido[3,2,l-//]quinazolin-8- yl]amino} cyclohexanecarboxylic acid.
11. Use of a compound according to Claim 1 of formula (Iiii):
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein
A, R1, R3 and R4 are defined in Claim 1;
B and R2 are joined to form a 5-, 6- or 7-membered nitrogen- containing heterocycle, which heterocycle optionally contains 1, 2 or 3 further heteroatoms selected from N, O and S, and which heterocycle is optionally substituted by Q4;
Q4 is hydrogen, halo, hydroxy,
Figure imgf000052_0002
(CΗ2)o-3aryl or (CH2)o-3C3_8cycloalkyl, optionally substituted by hydroxy, CO2H or CO2Ci_6alkyl.
12. Use of a compound according to Claim 11 of formula (Iiiia):
(liiia)
Figure imgf000052_0003
or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of prevention or infection by hepatitis C virus, wherein
Q1, Q4, R3 and R4 are as defined in Claim 11; and D is N, CH or C(d.6alkyl).
13. Use of a compound according to Claim 11 selected from Group (IV), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, wherein Group (IV) is: 4-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino]imidazo [l,2-α]quinazolin-5(4H)-one, l-benzyl-4-{[4-(3-chlorophenyl)-5-oxo-4,5-dihydroimidazo[l,2-α]quinazolin-8-yl]amino}piperidinium trifluoroacetate,
8-bromo-4-(3-chlorophenyl)-l-methyl[l,2,4]triazolo [4,3-α]quinazolin-5(4H)-one, 4-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino][l,2,4] triazolo[4,3-α]quinazolin-5(4H)-one,
4-(3-chlorophenyl)-8-[(2-hydroxyethyl)amino]-9-methyl[l,2,4]triazolo[4,3-α]quinazolin-5(4H)-one, l-benzyl-4-{[4-(3-chlorophenyl)-9-methyl-5-oxo-4,5-dihydro[l,2,4]triazolo[4,3-α]quinazolin-8- yl]amino}piperidinium trifluoroacetate, cώ-4-{[4-(3-chlorophenyl)-9-methyl-5-oxo-4,5-dihydro[l,2,4]triazolo[4,3-α]quinazolin-8- yl]amino}cyclohexanecarboxylic acid.
14. A method of inhibiting hepatitis C virus polymerase and/or of treating or preventing an illness due to hepatitis C virus, the method involving administering to a human or animal subject suffering from the condition a therapeutically or prophylactically effective amount of a compound as defined in any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof.
15. Use of a compound as defined in any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of infection by hepatitis C virus, in combination with one or more other agents for the treatment of viral infections such as an antiviral agent, and/or an immunomodulatory agent such as OC-, β- or γ-interferon.
16. A pharmaceutical composition comprising a compound as defined in any one of Claims 4, 5 and 8 to 13, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
17. A compound as defined in any one of Claims 4, 5 and 8 to 13 or a pharmaceutically acceptable salt thereof for use in therapy.
18. A compound as defined in any one of Claims 4, 5 and 8 to 13 or a pharmaceutically acceptable salt thereof.
PCT/EP2006/066002 2005-09-07 2006-09-05 Quinazoline derivatives as antiviral agents Ceased WO2007028789A1 (en)

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Publication number Priority date Publication date Assignee Title
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US7767660B2 (en) 2006-12-20 2010-08-03 Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
US7781422B2 (en) 2006-12-20 2010-08-24 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Antiviral indoles
US7879797B2 (en) 2005-05-02 2011-02-01 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US7973040B2 (en) 2008-07-22 2011-07-05 Merck Sharp & Dohme Corp. Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors
US7989438B2 (en) 2007-07-17 2011-08-02 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Therapeutic compounds
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US8278322B2 (en) 2005-08-01 2012-10-02 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8309540B2 (en) 2006-10-24 2012-11-13 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8314062B2 (en) 2006-06-23 2012-11-20 Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Macrocyclic compounds as antiviral agents
US8377873B2 (en) 2006-10-24 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8377874B2 (en) 2006-10-27 2013-02-19 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
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US8461107B2 (en) 2008-04-28 2013-06-11 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
US8541404B2 (en) 2009-11-09 2013-09-24 Elexopharm Gmbh Inhibitors of the human aldosterone synthase CYP11B2
US8828930B2 (en) 2009-07-30 2014-09-09 Merck Sharp & Dohme Corp. Hepatitis C virus NS3 protease inhibitors
US8927569B2 (en) 2007-07-19 2015-01-06 Merck Sharp & Dohme Corp. Macrocyclic compounds as antiviral agents
US9738661B2 (en) 2006-10-27 2017-08-22 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
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WO2025193760A1 (en) * 2024-03-11 2025-09-18 Door Pharmaceuticals Llc Quinazolinone compounds for treatment of hbv

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006027628A2 (en) * 2004-09-07 2006-03-16 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Naphthalimide derivatives as antiviral agents
EP1700850A1 (en) * 2003-12-22 2006-09-13 Ajinomoto Co., Inc. Novel phenylalanine derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1700850A1 (en) * 2003-12-22 2006-09-13 Ajinomoto Co., Inc. Novel phenylalanine derivative
WO2006027628A2 (en) * 2004-09-07 2006-03-16 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Naphthalimide derivatives as antiviral agents

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