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WO2012085003A1 - 2-hydroxyisoquinoline-1,3(2h,4h)-diones and related compounds useful as hiv replication inhibitors - Google Patents

2-hydroxyisoquinoline-1,3(2h,4h)-diones and related compounds useful as hiv replication inhibitors Download PDF

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Publication number
WO2012085003A1
WO2012085003A1 PCT/EP2011/073480 EP2011073480W WO2012085003A1 WO 2012085003 A1 WO2012085003 A1 WO 2012085003A1 EP 2011073480 W EP2011073480 W EP 2011073480W WO 2012085003 A1 WO2012085003 A1 WO 2012085003A1
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WO
WIPO (PCT)
Prior art keywords
het
civ
alkyl
halo
carboxamide
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PCT/EP2011/073480
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French (fr)
Inventor
Fabrice BAILLY
Muriel BILLAMBOZ
Frauke Christ
Philippe COTELLE
Zeger Debyser
Cédric LION
Virginie SUCHAUD
Original Assignee
Katholieke Universiteit Leuven, K.U. Leuven R&D
Universite De Lille
Centre National De Recherche Scientifique
Ecole Nationale Superieure De Chimie De Lille
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Application filed by Katholieke Universiteit Leuven, K.U. Leuven R&D, Universite De Lille, Centre National De Recherche Scientifique, Ecole Nationale Superieure De Chimie De Lille filed Critical Katholieke Universiteit Leuven, K.U. Leuven R&D
Publication of WO2012085003A1 publication Critical patent/WO2012085003A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds and compositions containing said compounds acting as inhibitors of HIV integrase.
  • the invention also provides processes for the preparation of the disclosed compounds and compositions and methods of using them, for instance as a medicine. BACKGROUND OF THE INVENTION
  • HIV-1 Human immunodeficiency virus type 1
  • NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
  • NRTIs non- nucleoside reverse transcriptase inhibitors
  • protease inhibitors Pis
  • entry inhibitors NRTIs
  • the standard combination therapy consists of a PI compound or a NNRTI compound combined with two NRTIs compounds.
  • HAART can suppress virus titers to undetectable levels but the virus persists in reservoirs such as peripheral blood mononuclear cells or resting T-lymphocytes. While HAART is undeniably effective, it is strongly limited by several factors like lack of therapy adherence, occurrence of important side effects and the development of resistance (multidrug resistance and cross-resistance) causing the loss of drug effectiveness. In the last decade, viral entry inhibitors and, most importantly, HIV-1 integrase inhibitors have been pursued as novel anti-HIV agents.
  • HIV-1 integrase has emerged as an attractive target since it is necessary for stable infection and has no cellular equivalent.
  • This enzyme is essential for viral replication, and mediates the insertion of viral DNA within the host cell genome via a multistep process that occurs in discrete biochemical stages: (i) assembly of a stable-DNA enzyme complex with specific DNA sequences at the end of the HIV-1 long terminal repeat (LTR) regions, (ii) endonucleolytic process of the viral DNA to remove the terminal dinucleotide from each 3 '-end (3 '-processing), (iii) strand transfer in which the viral DNA 3 '-ends are covalently linked to the cellular DNA, (iv) removal of the two unpaired nucleotides at the 3 '-ends of the viral DNA and (v) gap-filling, probably accomplished by cellular enzymes.
  • LTR long terminal repeat
  • WO200400472 published on 15 January 2004 discloses 3,4-dihydroisoquinolin-l-one derivatives as inducers of apoptosis.
  • WO200707578 published on 5 July 2005 discloses substituted isoquinoline-l,3(2H, 4H> diones for the prevention of cancer.
  • Billamboz et al. J. Med. Chem. 2008, 51, 7717-7730 disclose the design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-l,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain.
  • the present novel hydroxyisoquinolineidiones derivatives act as selective inhibitors of HIV- 1 integrase. They inhibit the overall catalytic activity of HIV-integrase and act as inhibitors of HIV- 1 replication. More in particular they act as strand transfer inhibitors.
  • the present compounds act as 3 'processing inhibitors. Thus they have a strong activity against both strand transfer activity and 3 'processing and inhibit the viral integrase in a unique way.
  • the compounds inhibit the overall integrase reaction, the strand transfer reaction and the 3 'processing reaction with similar potency.
  • the present invention satisfies the urgent need for efficient and non-harmful pharmaceutically compounds and combinations for the treatment of retroviral infections, in particular lentiviral infections, and more particularly HIV infections, in mammals and in humans.
  • new anti-viral, more in particular anti-HIV compounds are provided.
  • the compounds are novel hydroxyisoquinolinediones derivatives of formula (I) and it has been shown that they possess anti-viral activity, more specifically against HIV.
  • the present invention demonstrates that the compounds inhibit the replication of HIV. Therefore, these compounds constitute a new potent class of anti-viral agents that can be used in the treatment and prevention of viral infections in animals, mammals and humans, more specifically for the treatment and prevention of HIV.
  • the present invention relates to novel hydroxyisoquinolinediones derivatives of formula (I).
  • the invention further relates to compounds having anti-viral activity, more specifically to novel hydroxyisoquinolinediones derivatives of formula (I) thereof having viral replication inhibitory properties, more in particular of HIV (Human Immunodeficiency Virus), which is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans, and consequently may be useful for the treatment of individuals infected by HIV.
  • HIV Human Immunodeficiency Virus
  • the present invention also relates to compounds of formula (I) having antiviral activities with respect to other viruses, such as Hepatitis C Virus.
  • Present invention furthermore relates to the use of the compounds of formula (I) as a medicine and more specifically to the use of the compounds of formula (I) as an anti-viral agent.
  • the invention also relates to methods for preparation of all such compounds and pharmaceutical compositions comprising them.
  • the invention further relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection, as well as for treatment of other viral, retroviral or lentiviral infections, treatment of animals suffering from FIV, viral, retroviral, lentiviral infections or treatment of tumour or cancer cells.
  • the present invention also relates to a method of treatment or prevention of viral infections, by using said compounds.
  • One aspect of the present invention is the provision of hydroxyisoquinolinediones derivatives and analogues thereof.
  • the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I),
  • R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • R 1 and R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each Ar 1 , Ar 2 , Ar 3 ; or Ar 4 is independently phenyl or naphtyl and is optionally substituted with 1 to 5 substituents each of which is independently halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 or CF 3 ;
  • each Het 1 , Het 2 , Het 3 or Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S and is optionally substituted with 1 to 4 substituents each of which is independently halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 or CF 3 .
  • the present invention also relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I),
  • R 1 and R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • Ci -6 alkyl optionally substituted with halo, Ci -6 alkyl, -OH, -SH, -CN, -N0 2 ,
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 ;
  • One embodiment of the present invention relates to the compounds of formula (I) or ( ⁇ ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, or for use as a treatment of infection by HIV, or for treating AIDS.
  • One embodiment of the present invention relates to the compounds of formula (I) or ( ⁇ ) as defined just hereinbefore or 2-Hydroxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide, or 2-Hydroxy-6,7-dimethyl-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide for use as an antiviral agent, or for use as a treatment of infection by HIV, or for treating AIDS.
  • One aspect of the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I), or a tautomer ( ⁇ ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
  • R 1 is selected from:
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • One embodiment of the present invention relates to the compounds of formula (I) or ( ⁇ ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (X),
  • R 1 is selected from:
  • R 2 is selected from:
  • R 5 is selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ; and
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • substituents for example 1, 2, 3 or 4 substituents
  • One embodiment of the present invention relates to the compounds of formula (X) or ( ⁇ ') as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention is the provision of 2-benzyloxy-4- carboxamidoisoquinoline-l ,3(2H,4H)-diones of formula (II) or ( ⁇ ) wherein the substituents R 1 , R 2 , R 3 , R 4 , R s and R 6 , are as defined above.
  • One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-l,3(2H,4H)- dioxoisoquinoline-4-carboxamides of formula (II) or (IF) wherein the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , are as defined above, provided that the following compounds are excluded:
  • One embodiment of the present invention relates to the compounds of formula (II) or (II ') as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-4-carboxamidoisoquinoline- l,3(2H,4H)-diones of formula (II) or a tautomer ( ⁇ ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof,
  • R 1 is selected from:
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and - CF 3 .
  • substituents for example 1, 2, 3 or 4 substituents
  • One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-4-carboxamidoisoquinoline- l,3(2H,4H)-diones of formula (II) or a tautomer (IF) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each R 9 is hydrogen; OH; C
  • each R 10 , R U , and R 12 is independently selected from hydrogen; OH; Cuealkyl optionally substituted with halo, C
  • each of Ar 1 , Ar 2 , Ar 3 , and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, OH, Ci-6alkyloxy, N0 2 , -OCF3, and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-ealkyl, OH, Ci-ealkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • Another aspect of the present invention relates to 2-benzyloxy-l ,3(2/ ,4/_')- dioxoisoquinoline-4-carboxamides of formula (XI)
  • R 1 is selected from:
  • R 2 is selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • Ar 1 Het 1 ;
  • R 1 and R 2 together form a bivalent radical of formula
  • R 5 is selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 .
  • One embodiment of the present invention relates to the compounds of formula (XI) or ( ⁇ ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • R 2 is hydrogen or Ci- 6 alkyl
  • R 1 and R 2 together form the bivalent radical of formula (a-3);
  • R 7 and R 8 are each, independently, hydrogen or Ci- 6 alkyl
  • R 9 is Ci -6 alkoxy
  • Ar 1 and Ar 3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci-6alkyl, OH, and Ci-6alkyloxy;
  • Het 2 is pyridinyl
  • Het 3 is thienyl.
  • interesting group of compounds are those compounds of formula (I), (F), (II), or (IF) wherein
  • substituents for example 1, 2, 3 or 4 substituents
  • R 2 is hydrogen, methyl, or ethyl
  • R 1 and R 2 together form the bivalent radical of formula (a-3);
  • R 3 , R 4 , R 5 and R 6 are each, independently, hydrogen, N0 2 , or H 2 , methyloxy, - HCOCH 3 , - HCOCH 2 phenyl, - HCOphenyl, - HCOpyridinyl, or - HCOCH 2 thienyl; and
  • each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy.
  • One embodiment of the present invention relates to the compounds of formula (I), ( ⁇ ), (II), or ( ⁇ ), as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • R 1 is hydrogen, Ci-i 2 alkyl, phenylmethyl, phenylethyl, or phenyl;
  • R 2 is hydrogen
  • R 5 is hydrogen, methyloxy, - HCOCH 2 phenyl, -NHCOphenyl, -NHCOpyridinyl, or -NHCOCH 2 thienyl;
  • each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy.
  • One embodiment of the present invention relates to the compounds of formula (I), ( ⁇ ), (X), ( ⁇ '), (II), (IF), (XI), or (XT), as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
  • R 2 is hydrogen or Ci- 6 alkyl
  • R 3 , R 4 , R 5 and R 6 are each hydrogen, halo, N0 2 or -NR 7 R 8 ;
  • R 7 andR 8 are each Ci -6 alkyl
  • R 9 is Ci-6 alkoxy
  • Ar 1 and Ar 3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci- 6 alkyl, OH, or Ci- 6 alkyloxy.
  • R 2 is hydrogen or ethyl
  • R 3 , R 4 , R 5 and R 6 are each hydrogen, halo, N0 2 or H 2 ;
  • R 9 is ethyl oxy
  • each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, or methyloxy.
  • R 1 is hydrogen
  • R 2 is halophenylmethyl
  • R 5 is hydrogen or N0 2 .
  • Preferred compounds are those compounds of formula (I), (F), (II), or (IF) wherein
  • R 2 is hydrogen or Ci -6 alkyl;
  • R 1 and R 2 together form the bivalent radical of formula (a-3);
  • R 3 , R 4 , R 5 and R 6 are each hydrogen, N0 2 or - R 7 R 8 ;
  • R 7 and R 8 are each Ci -6 alkyl;
  • R 9 is Ci -6 alkoxy;
  • Ar 1 and Ar 3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci- 6 alkyl, OH, or Ci- 6 alkyloxy.
  • the most preferred compounds are selected from:
  • One embodiment of the present invention relates to a compound of formula (I),
  • R 1 and R 2 are each independently selected from:
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and -CF 3 ;
  • R 1 and R 2 are each independently selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 3 , R 4 , R 5 and R 6 are each independently selected from:
  • each R 9 is hydrogen; OH; Ci- 6 alkyl optionally substituted with halo, -OH, -SH, -CN, -N0 2 ,
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ;
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1 , 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci- 6 alkyl, OH, Ci- 6 alkyloxy, N0 2 , -OCF 3 , and
  • the invention relates the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, for use as a medicine, more particularly as antiviral compounds, even more particularly as compounds active against HIV.
  • the invention also relates to the use of the compounds of the formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, for the manufacture of a medicament or as a pharmaceutically active ingredient, especially as a virus replication inhibitor, preferably a retrovirus replication inhibitor, for instance for the manufacture of a medicament or pharmaceutical composition having antiviral activity for the prevention and/or treatment of viral, preferably retroviral, infections in humans and mammals.
  • a virus replication inhibitor preferably a retrovirus replication inhibitor
  • the present invention further relates to a method of treatment of a viral infection, preferably a retroviral infection in a mammal, including a human, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, as an active ingredient, preferably in admixture with at least a pharmaceutically acceptable carrier.
  • a viral infection preferably a retroviral infection in a mammal, including a human
  • the invention further relates to methods for the preparation of compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof.
  • the invention also relates to pharmaceutical compositions comprising the compounds of the invention according to formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, in admixture with at least a pharmaceutically acceptable carrier, the active ingredient preferably being in a concentration range of about 0.1 to 100% by weight, and to the use of these derivatives namely as drugs useful for the treatment of subjects suffering from HIV infection.
  • the invention further relates to the use of a composition
  • a composition comprising (a) one or more derivatives of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, and (b) one or more viral inhibitors as biologically active agents in respective proportions such as to provide a synergistic effect against a viral infection, preferably a lentiviral infection and more preferably a retroviral infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in retroviral infection therapy.
  • the retroviral enzyme inhibitors used as a therapeutically active ingredients (b) may belong to categories already known in the art and include, among others,
  • HIV integrase inhibitors such as for instance, elvitegravir and raltegravir,
  • nucleoside, non-nucleoside and nucleotide reverse transcriptase inhibitors such as for instance, dideoxyadenosine, stavudine, zalcitabine, zidovudine, lamivudine, didanosine, nevirapine, delavirdine, efavirenz, tenofovir, foscamet sodium and the like,
  • HIV protease inhibitors such as for instance saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and the like,
  • the present invention also relates to a pharmaceutical composition according to the invention further comprising a therapeutically effective amount of an HIV/ AIDS treatment agent selected from the group consisting of: an HIV/ AIDS antiviral agent; an anti-infective agent; and an immunomodulator.
  • an HIV/ AIDS treatment agent selected from the group consisting of: an HIV/ AIDS antiviral agent; an anti-infective agent; and an immunomodulator.
  • the invention also relates to a process for preparing a pharmaceutical composition of the invention wherein a therapeutically effective amount of a compound of formula (I) is intimately mixed with a pharmaceutically acceptable carrier.
  • the invention also relates to a process for preparing a pharmaceutical composition of the invention wherein a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of an HIV/AIDS treatment agent as defined herein are intimately mixed with a pharmaceutically acceptable carrier
  • the invention also relates to the compounds of the invention according to formula (I) being used for inhibition of the proliferation of other viruses than HIV, preferably the inhibition of viral activity of hepatitis B virus, hepatitis C virus or flaviviruses, with in particular yellow fever virus or Dengue virus. More generally, the invention relates to the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, being useful as agents having biological activity (preferably antiviral or antitumoral activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, more in particular having antiviral activity, yet more in particular against HIV.
  • a further aspect of the invention provides for a method of treatment or prevention of a viral infection in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the compounds of the present invention can act as inhibitors of HIV- 1 integrase, strand transfer inhibitors and/or 3 'processing inhibitors. Accordingly the present invention includes a method of inhibiting HIV- 1 integrase in a subject in need of such inhibition which comprises administering to the subject an effective amount of a compound of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof.
  • the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
  • Ci- 6 alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • Representative examples of Ci- 6 alkyl include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.
  • C 7- nalkyr refers to a straight or branched chain hydrocarbon containing from 7 to 11 carbon atoms.
  • C 7- nalkyl include, but are not limited to 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undyl, and the like.
  • Ci-nalkyl refers to a straight or branched chain hydrocarbon containing from 1 to 12 carbon atoms and includes but is not limited to Ci- 6 alkyl, the examples given under these definitions, include, but are not limited to, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undyl, and the like.
  • C2- 6 alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbons, and containing at least one carbon-carbon double bond, formed structurally, for example, by the replacement of two hydrogens.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, and the like.
  • C 2 - 6 alkynyl refers to a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms, and containing at least one carbon- carbon triple bond.
  • alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
  • C3-iocycloalkyl means a monocyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkylene refers to a cyclic hydrocarbon radical of 3-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane; i.e.
  • C 3- iocycloalkenyl refers to a cyclic hydrocarbon having 3 to 10 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp2 double bond.
  • monocyclic heterocyclic ring system refers to any 5 or 6 member ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S.
  • the 5 member ring has from 0 to 2 double bonds, and the 6 member ring has from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,
  • bicyclic heterocyclic ring system refers to any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxane, 1,3- benzodioxane, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like.
  • C 1-6 alkoxy refers to substituents wherein a Ci -6 alkyl radical Ar or Het radical (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
  • halo means any atom selected from the group consisting of fluorine (F), chlorine (CI), bromine (Br) and iodine (I).
  • Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
  • the compounds of the invention optionally are bound covalently to an insoluble matrix and used for affinity chromatography separations, depending on the nature of the groups of the compounds, for example compounds with aryl are useful in hydrophobic affinity separations.
  • the present invention encompasses compounds of formula (I) or ( ⁇ ), wherein
  • R 1 and R 2 are each independently selected from:
  • substituents for example 1, 2, 3 or 4 substituents
  • R 1 and R 2 are each independently selected from:
  • C 3 -iocycloalkyl or C 3 -iocycloalkenyl which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci -6 alkyl, -OH, and Ar 3 ;
  • R 1 and R 2 together form a bivalent radical of formula
  • R 3 , R 4 , and R 6 are each independently selected from:
  • R 5 is selected from: hydrogen; halo; -OH; -SH; -CN; -N0 2 ; -NR 7 R 8 ; -OCF 3 ; CF 3 ;
  • each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents independently selected from halo, Ci-6alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and CF 3 ; preferably each of Ar 1 , Ar 2 , Ar 3 ; and Ar 4 , is independently phenyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl,
  • each of Het 1 , Het 2 , Het 3 , and Het 4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 , -OCF 3 , and - CF 3 ; preferably each of Het 1 , Het 2 , Het 3 , and Het 4 , is independently a mono- or bicyclic heterocyclic ring system containing 1 or 2 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents independently selected from halo, Ci -6 alkyl, OH, Ci -6 alkyloxy, N0 2 ,
  • Another embodiment of the present invention is a process for preparing compounds of formula (I). They can be readily prepared according to the following reaction scheme and examples, or modifications thereof, using readily available starting materials and reagents. In the reactions below, it is possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction scheme and examples.
  • Bn benzyl
  • BOP (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate
  • DMSO dimethyl sulfoxide
  • ESI-MS electrospray ionization mass spectrometry
  • EtOAc ethyl acetate
  • h hour(s)
  • LDA lithium diisopropyl amide
  • MeOH methanol
  • MM 4- methylmorpholine
  • MR nuclear magnetic resonance
  • rt room temperature
  • THF tetrahydrofuran.
  • the present invention encompasses a process for making a compound of formula (I) wherein
  • the 4-carboxamido-2-hydroxyisoquinoline-l,3(2H,4H)-diones of formula (I) can be prepared by reacting an intermediate of formula (II) with a boron halide (BX 3 ) such as for example boron tribromide or boron trichloride at room or low temperature.
  • BX 3 boron halide
  • Use of boron tribromide allows for a complete deprotection of the intermediates of formula (II) (deprotection of the benzyloxy function as well as of the alkoxy functions in aromatic rings) whereas boron trichloride only affects the benzyloxy function. Deprotection may also be performed by catalytic hydrogenation on Pd/C 5%.
  • the 4-carboxamido-2-hydroxyisoquinoline-l,3(2H,4H)-diones of formula (I) wherein R 3 , R 4 and R 6 are hydrogen and R 5 is aminated herein referred to as compounds of formula (I- b) can be prepared by catalytic hydrogenation on Pd/C of an intermediate of formula (Il-a).
  • the basic treatment of an intermediate of formula (IV) does not yield an homophthalic acid derivative but a cyclized 2-benzyloxy-4-methoxycarbonylisoquinoline- l,3(2H,4H)-dione of formula (III).
  • the intermediates of formula (III) can be prepared by cyclization of an intermediate of formula (IV). This cyclization can be performed quantitatively using 2.5 M potassium hydroxide in a suitable solvent such as aqueous methanol, at room temperature for 5 min.
  • he benzyloxycarboxamide of formula (IV) can be prepared by coupling the intermediate of formula (V) with O-benzylhydroxylamine, after activation with the BOP reagent and N- methylmorpholine.
  • the coupling can be performed in a suitable solvent such as CH 2 CI 2 .
  • ⁇ he benzyloxycarboxamide of formula (IV) wherein R 3 , R 4 and R 6 are hydrogen and R 5 is a nitro function herein referred to as compounds of formula (IV-a) can be prepared by coupling the intermediate of formula (VIII), wherein R 3 , R 4 and R 6 are hydrogen and R 5 is a nitro function with O-benzylhydroxylamine by refluxing in toluene using a Dean Stark apparatus.
  • the methyl 2-(2-methoxycarbonylphenyl) malonate monoester of formula (V) can be prepared by reacting the anion of the homophthalic diester of formula (VI) with carbon dioxide. This reaction is possible after treatment of the homophthalic diester of formula
  • reaction can be performed in a suitable solvent such as for example tetrahydrofuran.
  • the triester of formula (VIII) can be prepared by aromatic nucleophilic substitution of intermediate (IX) with methylmalonate in the presence of NaH and under reflux in a suitable solvent such as, for example, THF.
  • he methyl diester of formula (VI) can be prepared by reacting the commercially available homophthalic acid of formula (VII) with thionyl chloride in a suitable solvent such as, for example, methanol.
  • the intermediate of formula (IX) can be prepared by esterifi cation of 2-fluoro-5- nitrobenzoic acid with thionyl chloride in a suitable solvent such as, for example, methanol.
  • 2-fluoro-5-nitrobenzoic acid can be prepared by nitrating the commercial 2- fluorobenzoic acid in a mixture of sulfuric acid and nitric acid.
  • the present invention also encompasses an intermediate of formula (II) wherein the substituents R 1 , R 2 , R 3 , 4 , R 5 and R 6 , are as defined hereinabove.
  • the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state, any and all protonated forms of the compounds are intended to fall within the scope of the invention.
  • the resulting compounds may be optionally converted into a pharmaceutically acceptable salt or vice versa according to the methods known by the skilled in the art. Further, the resulting compounds may be converted into each other following art-known functional group transformation reactions. For example, amino groups may be N-alkylated, nitro groups reduced to amino groups, a halo atom may be exchanged for another halo.
  • salts as used herein means the therapeutically active non-toxic salt forms which the compounds according to the formulas of the application like (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + , Ca 2+ and Mg 2+ . Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges.
  • the net charge of the compounds of the invention may be either positive or negative.
  • Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion.
  • the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li + , Na + , and K + . A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups.
  • acids include, for instance, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the salts of the parental compounds with one or more amino acids especially the naturally-occurring amino acids found as protein components.
  • the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the compounds of the invention also include physiologically acceptable salts thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NXf (wherein X is Cl-C4alkyl).
  • an appropriate base such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NXf (wherein X is Cl-C4alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X typically is independently selected from H or a Ci -4 alkyl group).
  • a suitable cation such as Na + and NX 4 + (wherein X typically is independently selected from H or a Ci -4 alkyl group).
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%) and more preferably at least 98%>.
  • isomers as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, may possess, but not including position isomers.
  • the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
  • the compounds of the present invention may also occur as tautomers thereof, such as the following tautomer ( ⁇ ) of a compound of formula (I):
  • the present invention includes all tautomers of 2-hydroxyisoquinoline- l,3(2H,4H)-dione compounds of Formula I (or ⁇ ), as well as the tautomers of its intermediates of Formula II (or ⁇ ), both singly and in mixtures.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds according to the formulas of the application like (I) may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or transconfiguration.
  • stereoisomerically pure or “chirally pure” relates to compounds having a stereoisomeric excess of at least about 80% (i.e. at least 90% of one isomer and at most 10%) of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%.
  • enantiomerically pure and “diastereomerically pure” should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.
  • stereoisomers Separation of stereoisomers is accomplished by standard methods known to those in the art.
  • One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113 :(3) 283-302).
  • Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compounds of the invention.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers can be separated and isolated by normal- and reverse- phase chromatography following methods for separation of atropisomeric naphthyl- isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase.
  • Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives.
  • Commercially available polysaccharide based chiral stationary phases are ChiralCelTM CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP(+) and OT(+).
  • Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.
  • the active ingredients of the compound(s) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra- arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of viral infections in humans and other mammals preferably is a retroviral enzyme inhibiting amount. More preferably, it is a retroviral replication inhibiting amount or a retroviral enzyme inhibiting amount of the derivative(s) of formula (I) as defined herein corresponds to an amount which ensures a plasma level of between ⁇ g/ml and 100 mg/ml, optionally of 10 mg/ml. This can be achieved by administration of a dosage of in the range of 0.001 mg to 2000 mg, in particular 0.01 mg to 1000 mg, more in particular O.
  • the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • the present invention further relates to a method for preventing or treating a viral infection in a subject or patient by administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I).
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of viral infections in humans and other mammals preferably is HIV protein/enzyme inhibiting amount. More preferably, it is a HIV replication inhibiting amount or a HIV enzyme inhibiting amount of the derivative(s) of the formulas as defined herein.
  • Suitable dosage is usually in the range of 0.001 mg to 20 mg, in particular 0.01 mg to 5 mg, more in particular O. lmg to 1 mg per day per kg bodyweight for humans.
  • the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
  • the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27 ' . Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as CI) defined by the following equation:
  • ED x is the dose of the first or respectively second drug used alone (la, 2a), or in combination with the second or respectively first drug (lc, 2c), which is needed to produce a given effect.
  • Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against viral infection may also be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC 50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC).
  • FIC fractional inhibitory concentration
  • the combination When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FIC X + FIC y ) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as sub synergistic, and when it is lower than 0.5, the combination is defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as sub antagonistic and, when it is higher than 2.0, the combination is defined as antagonistic.
  • This principle may be applied to a combination of different antiviral drugs of the invention or to a combination of the antiviral drugs of the invention with other drugs that exhibit anti-HIV activity.
  • Suitable anti-viral agents for inclusion into the synergistic antiviral compositions or combined preparations of this invention include practically all known anti-HIV compounds known at this moment such as nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors.
  • the pharmaceutical composition or combined preparation with synergistic activity against viral infection may contain the compounds of the present invention over a broad content range depending on the contemplated use and the expected effect of the preparation.
  • the content of the compounds of formula (I) of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.
  • the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of HIV infections.
  • the invention therefore relates to the use of a composition comprising:
  • the active ingredients (f) and (g) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the combined preparation of (f) and (g), especially for the treatment of viral infections in humans and other mammals particularly is a HIV enzyme inhibiting amount. More particularly, it is a HIV replication inhibiting amount of derivative (f) and a HIV enzyme inhibiting amount of inhibitor (g). Still more particularly when the said HIV enzyme inhibitor (g) is a reverse transcriptase inhibitor, its effective amount is a reverse transcriptase inhibiting amount. When the said HIV enzyme inhibitor (g) is a protease inhibitor, its effective amount is a protease inhibiting amount. When the said HIV enzyme inhibitor (g) is an integrase inhibitor, its effective amount is a integrase inhibiting amount.
  • the invention also relates to the compounds of the invention, for inhibition of the proliferation of other viruses than HIV, particularly for the inhibition of other retroviruses and lentiviruses and also for the inhibition of flaviviruses or picornaviruses such as BVDV, HCV, HBV or Coxsackie virus, with in particular yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus.
  • Other viruses may be inhibited such as HSV, CMV and Sars-virus.
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. More generally, the invention relates to the compounds of formula (I) being useful as agents having biological activity (particularly antiviral activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non- medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • the compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the term "pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
  • Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface- active agents may also be prepared by inicronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
  • Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties.
  • Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface- active agents.
  • Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C 10 - 22 ), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil.
  • Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates.
  • Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts.
  • alkaline or alkaline-earth metal salts unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulph
  • Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
  • alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product.
  • phosphates e.g. salts of phosphoric acid ester and an adduct of p- nonylphenol with ethylene and/or propylene oxide, or phospholipids.
  • Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.
  • cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.
  • Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol.
  • non-ionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups.
  • Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
  • non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, poly ethyleneglycol and octylphenoxypolyethoxyethanol.
  • Fatty acid esters of polyethylene sorbitan such as polyoxyethylene sorbitan trioleate
  • glycerol glycerol
  • sorbitan sucrose and pentaerythritol are also suitable non-ionic surfactants.
  • Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy- lower alkyl radicals.
  • C8C22 alkyl radical e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like
  • Compounds of the invention and their physiologically acceptable salts may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration may vary with for example the condition of the recipient.
  • the formulations both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients.
  • the carrier(s) optimally are "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g.
  • the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7%) w/w, etc), preferably 0.2 to 15%> w/w and most preferably 0.5 to 10%> w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30%> w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
  • Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like.
  • the rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers.
  • Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on.
  • the pharmaceutical composition may require protective coatings.
  • Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
  • each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
  • Al-b intermediate 2 3-Methoxy-2 -(methoxycarbonyl)phenyl1-3-oxopropanoic acid
  • the mixture was acidified with 2.0 M HCl and then extracted with CHC1 3 .
  • the combined organic extracts were extracted with 10% Na 2 C0 3 .
  • the basic extracts were made acidic by the careful addition of 2.0 M HCl and the product was extracted into CHCI 3 (3 x 100 mL).
  • the combined CHCI 3 extracts were dried over Na 2 S0 4 .
  • the solvent was removed under reduced pressure to give an oily residue intermediate 2 which crystallized on cooling.
  • Al-d intermediate 4 Methyl 2-(benzyloxy)-L3-dioxo-L2,3,4-tetrahydroisoquinoline
  • Al-e intermediate 5 N-(3-Chloropropyl)-2-benzyloxy-l,3-dioxo-l,2,3,4
  • A2-e intermediate 6 N-Propyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline -4-carboxamide
  • A3-e intermediate 7 N-Butyl-2-benzyloxy-1.3-dioxo-1.2.3.4-tetrahvdroisoquinoline-4- carboxamide
  • A4-e intermediate 8 N-Pentyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A6-e intermediate 10 N-Nonyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A7-e intermediate 11 N-Isopropyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-
  • A8-e intermediate 12 N-7ert-butyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline
  • A9-e intermediate 13 N-Cvclopentyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • AlO-e intermediate 14 N-Allyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A12-e intermediate 16 N-(3-Fluorophenyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A13-e intermediate 17 N-(3-Chloro-4-methoxyphenyl)-2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
  • A14-e intermediate 18 N-(4-Fluorobenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A16-e intermediate 20 N-(2,4-Dimethoxybenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4 tetrahydroisoquinoline-4-carboxamide
  • A18-e intermediate 21 N-(3,4-Dimethoxybenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A20-e intermediate 22 N-((Thiophen-2-vnmethylV2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
  • A21-e intermediate 23 N-r2-(3.4-Dimethoxyphenyl)ethyl1-2-benzyloxy-1.3-dioxo- 1.2.3.4-tetrahydroisoquinoline-4-carboxamide
  • A23-e intermediate 24 (2-Benzylox -l -dioxoisoquinolin-4-yl)(piperidin-l-yl)methanone
  • A24-e intermediate 25 N,N-Diethyl-2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
  • A25-e intermediate 26 N-Butyl-N-methyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A26-e intermediate 27 N-Heptyl-2-benzyloxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A27-e intermediate 28 N-Octyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A29-e intermediate 30 /V-Phenyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A30-e intermediate 31 N-Methyl-N-phenyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A31-e intermediate 32 N-(4-Fluorophenyl)-2-benzyloxy-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A32-e intermediate 33 N-Benzyl-2-benzyloxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide
  • A33-e intermediate 34 N-4-Methoxybenzyl-2-benzyloxy-l,3-dioxo-l,2,3,4
  • A34-e intermediate 35 N-(4-Fluorophenethyl)-2-benzyloxy-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
  • A35-a intermediate 36 2-Fluoro- -nitrobenzoic acid
  • Nitric acid 50% solution, 5.0 mL was carefully added to a cooled solution of concentrate sulfuric acid (5.0 mL) so that the temperature did not exceed 10 °C.
  • 2-f uorobenzoic acid 2.1 g, 15.0 mmol was added by small portions while maintaining temperature between 15 and 25 °C. The mixture was stirred for 2 h at room temperature. Ice was added and the precipitate was filtered. After drying at room temperature, intermediate 36 was obtained as a white powder.
  • A35-c intermediate 38 Methyl 2- ⁇ -dimethoxy-L3-dioxopropan-2-yl
  • A35-d intermediate 39 Methyl 2- ⁇ l-r(benzyloxy)amino1-3-methoxy-l -dioxopropan-2- yl I - 5 -nitrob enzoate
  • A35-f intermediate 41 N-(4-Fluorobenzyl)-2-benzyloxy-3-hvdroxy-7-nitro-l-oxo-L2- dihydro- isoquinoline-4-carboxamide
  • A37-a intermediate 42 N-Hexyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
  • A38-a intermediate 43 N-Phenyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-l,2- dihydroisoquinoline-4-carboxamide
  • A40-a intermediate 45 N-Benzyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
  • A41-a intermediate 46 N-(4-Methoxybenzyl)-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
  • A43-a intermediate 48 Methyl 5-amino-2- ⁇ L3-dimethoxy-L3-dioxopropan-2-yl
  • A43-b intermediate 49 Methyl 5-acetamido-2- ⁇ l,3-dimethoxy-l,3-dioxopropan-2- yllbenzoate
  • Acetyl chloride (1.1 mL, 16.0 mmol) was added to a solution of intermediate 48 (3.0 g, 10.7 mmol) in dichloromethane (50 mL). After stirring for 4 h at room temperature, the solution was washed with aqueous 1.0 M HCl. The organic phase was dried over Na 2 S0 4 .
  • A43-c intermediate 50 Methyl 5-acetamido-2- ⁇ 1 (benzyloxy)amino1-3-methoxy-l,3- dioxopropan-2-yl Ibenzoate
  • A43-d intermediate 51 Methyl 7-acetamido-2-(benzyloxy)-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxylate
  • A44-b intermediate 54 Methyl 2- ⁇ l-r(benzyloxy)amino1-3-methoxy-1.3-dioxopropan-2- yl
  • A44-c intermediate 55 Methyl 2-(benzyloxy)- 7-phenylacetamido -1.3-dioxo-l.2.3.4- tetrahydroisoquinoline-4-carboxylate
  • A44-d intermediate 56 N-(4-fluorobenzyl)-2-(benzyloxy)-l,3-dioxo-7-phenylacetamido- 1,2,3, 4-tetrahydroisoquinoline-4-carboxamide
  • A45-b intermediate 58 Methyl 5-benzamido-2- ⁇ l-r(benzyloxy)amino1-3-methoxy-L3- dioxopropan-2-yl Ibenzoate
  • A45-d intermediate 60 N-(4-fluorobenzyl)-7-benzamido-2-(benzyloxy)-L3-dioxo-L2,3,4- tetrah droiso uinoline-4-carboxamide
  • A46-b intermediate 62 Methyl 2- ⁇ l-r(benzyloxy)aminol-3-methoxy-1.3-dioxopropan-2- yll-5-picolinamidobenzoate
  • A46-d intermediate 64 N-(4-fluorobenzyl)- 2-(benzyloxy)-l,3-dioxo-7-picolinamido-
  • A47a intermediate 65 Methyl 2- ⁇ l,3-dimethoxy-l,3-dioxopropan-2-yl
  • A47-b intermediate 66 Methyl 2- ⁇ l-r(benzyloxy)amino1-3-methoxy-L3-dioxopropan-2- yl
  • A47-d intermediate 68 N-(4-fluorobenzyl)- 2-(benzyloxy)-l,3-dioxo-7-(2-(thiophen-2- yl)acetamido)-l,2,3,4-tetrahvdroisoquinoline-4-carboxamide
  • A48-b intermediate 70 Methyl 2- ⁇ l-r(benzyloxy)amino1 -3-methoxy-L3-dioxopropan-2- yll-5-chlorobenzoate
  • A48-d intermediate 72 N-(4-fluorobenzyl)- 2-(benzyloxy -7-chloro-l,3-dioxo-l,2,3,4- tetrah droiso uinoline-4-carboxamide
  • A49-b intermediate 74 Methyl 2- ⁇ l-r(benzyloxy)amino1 -3-methoxy-l,3-dioxopropan-2- yl
  • A49-c intermediate 75 Methyl 2-(benzyloxyV7-bromo-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxylate
  • A49-d intermediate 76 N-(4-fluorobenzyl)- 2-(benzyloxy)-7-bromo-L3-dioxo-L2,3,4- tetrah droiso uinoline-4-carboxamide
  • A50-b intermediate 78 Methyl 2- ⁇ 1 (benzyloxy)amino1-3-methoxy-L3-dioxopropan-2- yll-5 -fluorob enzoate
  • A50-C intermediate 79 Methyl 2-(benzyloxy)-7-fruoro-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxylate
  • A50-d intermediate 80 N-(4-fluorobenzyl)- 2-(benzyloxy)-7-fruoro-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
  • Fuming nitric acid (20.0 mL) was cooled to 0 °C and 6.25 g of homophthalic acid (35.0 mmol) was carefully added while maintaining temperature below 22 °C. After 2 h, ice (20 g) was added. The precipitate was filtered and washed several times with distilled water.
  • A51e intermediate 85 Methyl 2- ⁇ 1 (benzyloxy)amino1 -3-methoxy-L3-dioxopropan-2- yll-5 -methoxyb enzoate
  • A51-f intermediate 86 Methyl 2-(benzyloxy)-7-methoxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxylate

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Abstract

The present invention relates to compounds and compositions acting as inhibitors of HIV integrase. The compound of the invention is of Formula (I), or a tautomer (I') thereof, or a pharmaceutically acceptable salt, or solvate of said compound or tautomer thereof, wherein R1, R2, R3, R4, R5 and R6 have defined meanings.

Description

2 -HYDROXYISOQUINOLINE- 1 , 3 ( 2H , 4H) - DIONES AND RELATED COMPOUNDS USEFUL AS HIV REPLICATION INHIBITORS
FIELD OF THE INVENTION The present invention relates to compounds and compositions containing said compounds acting as inhibitors of HIV integrase. The invention also provides processes for the preparation of the disclosed compounds and compositions and methods of using them, for instance as a medicine. BACKGROUND OF THE INVENTION
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immune deficiency syndrome (AIDS). Despite decades of research and the successful development of combination therapies known as highly active antiretroviral therapy (HAART), HIV-1 remains one of the most serious health problems in the world. Currently, 22 drugs are approved by FDA for the treatment of HIV infection. These compounds that have been licensed for clinical use for the treatment of HIV infections fall into one of the following four categories: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), (ii) non- nucleoside reverse transcriptase inhibitors (NNRTIs), (iii) protease inhibitors (Pis), and (iv) entry inhibitors. The standard combination therapy consists of a PI compound or a NNRTI compound combined with two NRTIs compounds. HAART can suppress virus titers to undetectable levels but the virus persists in reservoirs such as peripheral blood mononuclear cells or resting T-lymphocytes. While HAART is undeniably effective, it is strongly limited by several factors like lack of therapy adherence, occurrence of important side effects and the development of resistance (multidrug resistance and cross-resistance) causing the loss of drug effectiveness. In the last decade, viral entry inhibitors and, most importantly, HIV-1 integrase inhibitors have been pursued as novel anti-HIV agents.
HIV-1 integrase (IN) has emerged as an attractive target since it is necessary for stable infection and has no cellular equivalent. This enzyme is essential for viral replication, and mediates the insertion of viral DNA within the host cell genome via a multistep process that occurs in discrete biochemical stages: (i) assembly of a stable-DNA enzyme complex with specific DNA sequences at the end of the HIV-1 long terminal repeat (LTR) regions, (ii) endonucleolytic process of the viral DNA to remove the terminal dinucleotide from each 3 '-end (3 '-processing), (iii) strand transfer in which the viral DNA 3 '-ends are covalently linked to the cellular DNA, (iv) removal of the two unpaired nucleotides at the 3 '-ends of the viral DNA and (v) gap-filling, probably accomplished by cellular enzymes. Structural studies showed that the IN catalytic domain contains a triad of invariant carboxylate residues, D64, D116 and E152 (the so-called DDE motif), which are required for catalysis. One Mg2+ ion is coordinated by D64 and D116 along with water molecules whereas El 52 that lies closely to D64 does not participate in metal binding. However it is largely accepted that this enzyme requires two metal divalent ions for catalysis. A great number of HIV-1 IN inhibitors have been described. Two IN inhibitors, GS-9137 (Elvitegravir) and MK-0518 (Raltegravir), demonstrated promising clinical trial results and advanced into later stage trials, the latter being the first US FDA-approved drug targeting IN. Raltegravir is the successful result of continued efforts to optimise HIV-1 IN inhibitory properties of the /?-diketo acid class of compounds directed to two-metal ion enzyme catalytic sites.
US3726875 issued on 10 April 1973 discloses isoquinoline-l,3(2H,4H)-diones with antiinflammatory activity.
US3886163 issued on 27 May 1975 discloses isoquinoline-l,3(2H,4H)-diones with antiinflammatory activity.
WO200400472 published on 15 January 2004 discloses 3,4-dihydroisoquinolin-l-one derivatives as inducers of apoptosis.
WO200707578 published on 5 July 2005 discloses substituted isoquinoline-l,3(2H, 4H> diones for the prevention of cancer.
Billamboz et al. (J. Med. Chem. 2008, 51, 7717-7730) disclose the design, synthesis, and biological evaluation of a series of 2-hydroxyisoquinoline-l,3(2H,4H)-diones as dual inhibitors of human immunodeficiency virus type 1 integrase and the reverse transcriptase RNase H domain.
Billamboz et al. (European Journal of Medicinal Chemistry, 2011, 46, 535-546; available online 27 November 2010) disclose 2-hydroxyisoquinoline-l,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain and the influence of the alkylation of position 4. There is a stringent need in the art for potent inhibitors of HIV. In particular, there is a need for compounds which either complement existing drugs such that the resulting cocktail has improved activity or resistance to virus mutation or compounds which are themselves effective against many or all viable mutations of a virus.
Unexpectedly the present novel hydroxyisoquinolineidiones derivatives act as selective inhibitors of HIV- 1 integrase. They inhibit the overall catalytic activity of HIV-integrase and act as inhibitors of HIV- 1 replication. More in particular they act as strand transfer inhibitors.
Even more unexpectedly the present compounds act as 3 'processing inhibitors. Thus they have a strong activity against both strand transfer activity and 3 'processing and inhibit the viral integrase in a unique way. The compounds inhibit the overall integrase reaction, the strand transfer reaction and the 3 'processing reaction with similar potency.
Hence, the present invention satisfies the urgent need for efficient and non-harmful pharmaceutically compounds and combinations for the treatment of retroviral infections, in particular lentiviral infections, and more particularly HIV infections, in mammals and in humans.
SUMMARY OF THE INVENTION
In the present invention, new anti-viral, more in particular anti-HIV compounds are provided. The compounds are novel hydroxyisoquinolinediones derivatives of formula (I) and it has been shown that they possess anti-viral activity, more specifically against HIV. The present invention demonstrates that the compounds inhibit the replication of HIV. Therefore, these compounds constitute a new potent class of anti-viral agents that can be used in the treatment and prevention of viral infections in animals, mammals and humans, more specifically for the treatment and prevention of HIV.
The present invention relates to novel hydroxyisoquinolinediones derivatives of formula (I). The invention further relates to compounds having anti-viral activity, more specifically to novel hydroxyisoquinolinediones derivatives of formula (I) thereof having viral replication inhibitory properties, more in particular of HIV (Human Immunodeficiency Virus), which is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans, and consequently may be useful for the treatment of individuals infected by HIV. The present invention also relates to compounds of formula (I) having antiviral activities with respect to other viruses, such as Hepatitis C Virus. Present invention furthermore relates to the use of the compounds of formula (I) as a medicine and more specifically to the use of the compounds of formula (I) as an anti-viral agent. The invention also relates to methods for preparation of all such compounds and pharmaceutical compositions comprising them. The invention further relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection, as well as for treatment of other viral, retroviral or lentiviral infections, treatment of animals suffering from FIV, viral, retroviral, lentiviral infections or treatment of tumour or cancer cells. The present invention also relates to a method of treatment or prevention of viral infections, by using said compounds.
One aspect of the present invention is the provision of hydroxyisoquinolinediones derivatives and analogues thereof.
The present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I),
Figure imgf000005_0001
or a tautomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein and R2 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S) R9;
Ci.i2alkyl, C2-i2alkenyl or C2-i2alkynyl which are optionally substituted with halo, -OH, -SH, -CN, -NO2, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3 ;
C3-iocycloalkyl or C3-iocycloalkenyl which are optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S) R9 or Ar3; Ar1; Het1; or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S) R9;
Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -NO2, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6cycloalkyl; NHC(=0)Ci-6alkyl, which is optionally substituted with halo, -OH, -SH, -CN, -N02, -NR7R8, C(=0)OCi-6alkyl, Het1 or Ar3; NHC(=0)Ar2 or NHC(=0)Het2; each R7 and R8 is independently selected from hydrogen; Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; or C(=0)R9;
each R9 is hydrogen; OH; Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -NO2, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; Ci-6 alkoxy; NR10RU; Ar4; or Het4;
each R10 and R11 is independently selected from hydrogen; OH; Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; Ci-6 alkoxy; Ar4; or Het4; each Ar1, Ar2, Ar3 ; or Ar4 is independently phenyl or naphthyl and is optionally substituted with 1 to 5 substituents each of which is independently halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3 or CF3; each Het1, Het2, Het3 or Het4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S and is optionally substituted with 1 to 4 substituents each of which is independently halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3 or CF3. In an embodiment, the present invention also relates to a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof,
wherein
R1 and R2 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S) R9;
Ci-i2alkyl, Ci-i2alkenyl or Ci-i2alkynyl which are optionally substituted with halo, -OH, -SH, -CN, -NO2, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3 ;
C3-iocycloalkyl or C3-iocycloalkenyl which are optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S) R9 or Ar3; Ar1; Het1; or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S) R9; Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -NO2, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6cycloalkyl; NHC(=0)Ci-6alkyl, which is optionally substituted with halogen, C(=0)OCi-6alkyl or Ar3;
NHC(=0)Ar2 or NHC(=0)Het2; each R and R is independently selected from hydrogen; Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, - R7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; or C(=0)R9;
each R9 is hydrogen; OH; Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -NO2, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; Ci-6 alkoxy; NR10Ru; Ar4; or Het4;
each R10 and R11 is independently selected from hydrogen; OH; Ci-6alkyl which is optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S) R9, Ar3 or Het3; Ci-6 alkoxy; Ar4; or Het4;
each Ar1, Ar2, Ar3 ; or Ar4 is independently phenyl or naphtyl and is optionally substituted with 1 to 5 substituents each of which is independently halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3 or CF3;
each Het1, Het2, Het3 or Het4 is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S and is optionally substituted with 1 to 4 substituents each of which is independently halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3 or CF3.
The present invention also relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I),
Figure imgf000008_0001
or a tautomer (Γ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof,
wherein
R1 and R2 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; C(=0)R9; C(=S)R9; C2-i2 lkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo,
Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1; or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02,
-NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3; -NHC(=0)Ar2; or -NHC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or
Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and CF3;
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3;
provided that the following compounds are excluded:
Figure imgf000010_0001
2-Hydroxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4-carboxamide,
Figure imgf000010_0002
2-Hydroxy-6,7-dimethyl-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4-carboxamide.
One embodiment of the present invention relates to the compounds of formula (I) or (Γ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, or for use as a treatment of infection by HIV, or for treating AIDS.
One embodiment of the present invention relates to the compounds of formula (I) or (Γ) as defined just hereinbefore or 2-Hydroxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide, or 2-Hydroxy-6,7-dimethyl-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide for use as an antiviral agent, or for use as a treatment of infection by HIV, or for treating AIDS. One aspect of the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (I), or a tautomer (Γ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
R1 is selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci.i2alkyl, C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
R2 is selected from:
halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci-i2alkyl, C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; Ci-ealkyl optionally substituted with halo, C1-6alkyl, -OH, -SH, -CN, -N02, - R7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6cycloalkyl;
Figure imgf000012_0001
optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3;
- HC(=0)Ar2; or - HC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; C1-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and CF3;
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3.
One embodiment of the present invention relates to the compounds of formula (I) or (Γ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Another aspect of the present invention relates to hydroxyisoquinolinediones and derivatives or analogues thereof, corresponding to the formula (X),
Figure imgf000013_0001
(X) (Χ') or a tautomer (Χ') thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
R1 is selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9;
C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
R2 is selected from:
halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci.i2alkyl, C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo,
-OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo,
Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3;
Ar1;
Het1; R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R5 is selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; C1-6alkyl optionally substituted with halo, C1-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio;
C3-6cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3;
-NHC(=0)Ar2; or -NHC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and CF3; and
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3. One embodiment of the present invention relates to the compounds of formula (X) or (Χ') as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Another aspect of the present invention is the provision of 2-benzyloxy-4- carboxamidoisoquinoline-l ,3(2H,4H)-diones of formula (II) or (Ι ) wherein the substituents R1, R2, R3, R4, Rs and R6, are as defined above.
Figure imgf000015_0001
One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Another aspect of the present invention relates to 2-benzyloxy-l,3(2H,4H)- dioxoisoquinoline-4-carboxamides of formula (II) or (IF) wherein the substituents R1, R2, R3, R4, R5 and R6, are as defined above, provided that the following compounds are excluded:
Figure imgf000015_0002
2-Benzyloxy- 1 ,3-dioxo- 1 ,2,3,4-tetrahydro-isoquinoline-4-carboxamide,
14
RECTIFIED SHEET (RULE 91)
ISA/EP
Figure imgf000016_0001
N-( 1 , 1 -dimethyl-but-2-ynyl)-2-benzyloxy- 1 ,3 -dioxo- 1,2,3 ,4-tetrahydroisoquinoline-4- carboxamide,
Figure imgf000016_0002
2-Benzyloxy-7-chloro- 1 ,3-dioxo-l ,2,3,4-tetrahydro-isoquinoline-4-carboxamide,
Figure imgf000016_0003
N-(l , 1 -dimethyl-but-2-ynyl)-2-benzyloxy-6,7-dimethoxy-l ,3 -dioxo- 1 ,2,3,4-tetrahydro- isoquinoline-4-carboxamide. One embodiment of the present invention relates to the compounds of formula (II) or (II ') as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Another aspect of the present invention relates to 2-benzyloxy-4-carboxamidoisoquinoline- l,3(2H,4H)-diones of formula (II) or a tautomer (ΙΓ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof,
15
RECTIFIED SHEET (RULE 91)
ISA/EP wherein
R1 is selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9;
C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-i0cycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
R2 is selected from:
halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci-i2alkyl, C2-i2alkenyl, C2-5alkynyl, or C7-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3; Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6cycloalkyl;
Figure imgf000018_0001
optionally substituted with halogen, -C(=0)OC1-6alkyl, or Ar3;
- HC(=0)Ar2; or - HC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, - R10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H,
C(=S)H, Ar3, or Het3; Ci-6alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and
CF3;
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and - CF3. One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Another aspect of the present invention relates to 2-benzyloxy-4-carboxamidoisoquinoline- l,3(2H,4H)-diones of formula (II) or a tautomer (IF) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
R1 is selected from: hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9;
C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
R2 is selected from:
halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci-i2alkyl or C2-i2alkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-i0cycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar
-NHC(=0)Ar2; or -NHC(=0)Het2; li each R7 and R8 is independently selected from hydrogen; C[.6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RN, -OCF3, C(=0)R12, C(=S)R12,
Figure imgf000020_0001
or Het3; or C(=0)R12;
each R9 is hydrogen; OH; C|-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NRIOR", -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci.6 alkoxy; -NR10RU ; Ar4; or
Het4;
each R10, RU, and R12 is independently selected from hydrogen; OH; Cuealkyl optionally substituted with halo, C|.6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; C|-6 alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3, and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo,
Figure imgf000020_0002
OH, Ci-6alkyloxy, N02, -OCF3, and CF3;
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-ealkyl, OH, Ci-ealkyloxy, N02, -OCF3, and -CF3.
One embodiment of the present invention relates to the compounds of formula (II) or (IF) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS. Another aspect of the present invention relates to 2-benzyloxy-l ,3(2/ ,4/_')- dioxoisoquinoline-4-carboxamides of formula (XI)
Figure imgf000021_0001
(XI) (XT) or a tautomer (ΧΓ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof,
wherein
R1 is selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9;
C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1;
R2 is selected from:
halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci-i2alkyl, C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-i0cycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1: Het1;
or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)s- (a-3);
R5 is selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; C1-6alkyl optionally substituted with halo, C1-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3;
-NHC(=0)Ar2; or -NHC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H,
C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and
CF3; and
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3.
One embodiment of the present invention relates to the compounds of formula (XI) or (ΧΓ) as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Interesting group of compounds are those compounds of formula (I), (Γ), (II), or (IF), wherein
R1 is hydrogen; Ci-i2alkyl or C2-i2alkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, C(=0)R9, Ar3, and Het3; C3.10cycloalkyl; or Ar1;
R2 is hydrogen or Ci-6alkyl; or
R1 and R2 together form the bivalent radical of formula (a-3);
R3, R4, R5 and R6 are each, independently, hydrogen, N02, - R7R8, Ci-6 alkoxy,
Figure imgf000023_0001
optionally substituted with -C(=0)OCi-6alkyl or Ar3,
- HC(=0)Ar2, or - HC(=0)Het2;
R7 and R8 are each, independently, hydrogen or Ci-6alkyl;
R9 is Ci-6 alkoxy; and
Ar1 and Ar3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci-6alkyl, OH, and Ci-6alkyloxy;
Het2 is pyridinyl; and
Het3 is thienyl. Interesting group of compounds are those compounds of formula (I), (F), (II), or (IF) wherein
R1 is hydrogen; Ci.i2alkyl or C2-i2alkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -C(=0)OC2H5, phenyl, and thienyl; C5cycloalkyl; or phenyl;
R2 is hydrogen, methyl, or ethyl; or
R1 and R2 together form the bivalent radical of formula (a-3); R3, R4, R5 and R6 are each, independently, hydrogen, N02, or H2, methyloxy, - HCOCH3, - HCOCH2phenyl, - HCOphenyl, - HCOpyridinyl, or - HCOCH2thienyl; and
each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy.
One embodiment of the present invention relates to the compounds of formula (I), (Γ), (II), or (ΙΓ), as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Interesting group of compounds are those compounds of formula (I), (Γ), (X), (Χ'), (II), (ΙΓ), (XI), or (ΧΓ), wherein
R1 is hydrogen, Ci-i2alkyl, phenylmethyl, phenylethyl, or phenyl;
R2 is hydrogen; and
R5 is hydrogen, methyloxy, - HCOCH2phenyl, -NHCOphenyl, -NHCOpyridinyl, or -NHCOCH2thienyl; and
each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy. One embodiment of the present invention relates to the compounds of formula (I), (Γ), (X), (Χ'), (II), (IF), (XI), or (XT), as defined just hereinbefore for use as a medicine, or for use as an antiviral agent, for treating infection by HIV, or for treating AIDS.
Interesting group of compounds are those compounds of formula (I), (Γ), (II), or (IF), wherein one or more of the following restrictions apply:
a) R1 is hydrogen; Ci-i2alkyl or C2-i2alkenyl which are optionally substituted with halo, C(=0)R9, Ar3 or Het3; C3-iocycloalkyl; or Ar1;
b) R2 is hydrogen or Ci-6alkyl;
b) R1 and R2 together form the bivalent radical of formula (a-3);
c) R3, R4, R5 and R6 are each hydrogen, halo, N02 or -NR7R8 ;
d) R7 andR8 are each Ci-6alkyl;
e) R9 is Ci-6 alkoxy; f) Ar1 and Ar3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci-6alkyl, OH, or Ci-6alkyloxy.
Further interesting compounds are those interesting compounds of formula (I), (Γ), (II), or (IF), wherein one or more of the following restrictions apply:
a) R1 is hydrogen; Ci-i2alkyl or C2-i2 lkenyl which are optionally substituted with halo, C(=0)OC2H5, phenyl or thienyl; C5cycloalkyl; or phenyl;
b) R2 is hydrogen or ethyl;
b) R1 and R2 together form the bivalent radical of formula (a-3);
c) R3, R4, R5 and R6 are each hydrogen, halo, N02 or H2 ;
e) R9 is ethyl oxy;
f) each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, or methyloxy.
Even further interesting compounds are those interesting and further interesting compounds of formula (I), (F), (X), (Χ'), (II), (IF), (XI), or (XT), wherein one or more of the following restrictions apply:
a) R1 is hydrogen;
b) R2 is halophenylmethyl;
c) and R5 is hydrogen or N02.
Preferred compounds are those compounds of formula (I), (F), (II), or (IF) wherein
R1 is hydrogen; Ci.i2alkyl or C2-i2alkenyl which are optionally substituted with halo, C(=0)R9, Ar3 or Het3; C3-iocycloalkyl; or Ar1; R2 is hydrogen or Ci-6alkyl; R1 and R2 together form the bivalent radical of formula (a-3); R3, R4, R5 and R6 are each hydrogen, N02 or - R7R8 ; R7 and R8 are each Ci-6alkyl; R9 is Ci-6 alkoxy; and Ar1 and Ar3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci-6alkyl, OH, or Ci-6alkyloxy.
More preferred compounds are those compounds of formula (I), (F), (II), or (IF) wherein R1 is hydrogen; Ci.i2alkyl or C2-i2alkenyl which are optionally substituted with halo, C(=0)OC2H5, phenyl or thienyl; C5cycloalkyl; or phenyl; R2 is hydrogen or ethyl; R1 and R2 together form the bivalent radical of formula (a-3); R3, R4, R5 and R6 are each hydrogen, N02 or H2 ; R9 is ethyloxy; and each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, or methyloxy. Even more preferred compounds are compounds of formula (I), (Γ), (II), or (ΙΓ) wherein R1 is hydrogen; R2 is halophenylmethyl; and R5 is hydrogen or N02.
Even more preferred compounds are those selected from
N-(3-Chloropropyl)-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4-carboxamide, N-Hexyl-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4-carboxamide,
N-(3-Fluorophenyl)-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4-carboxamide, N-(3-Chloro-4-methoxyphenyl)-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4-carboxamide, N-(2,4-Dimethoxybenzyl)-2 -hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4- carboxamide,
N-(2,4-Dihydroxybenzyl)-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4- carboxamide,
N-(3,4-Dihydroxybenzyl)-2-hydroxy-l,3-dioxoisoquinoline-4-carboxamide,
N-Dodecyl-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4-carboxamide,
N-Benzyl-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4-carboxamide,
N-(4-Fluorobenzyl)-2,3-dihydroxy-7-nitro-l-oxo-l,2-dihydroisoquinoline-4-carboxamide, N-(4-Fluorobenzyl)-7-amino-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide,
N-Phenyl-2,3-dihydroxy -7-nitro -l-oxo-l,2-dihydroisoquinoline-4-carboxamide,
N-(4-Fluorophenyl)-2,3 -dihydroxy -7-nitro - 1 -oxo- 1 ,2-dihydroisoquinoline-4- carboxamide,
N-Benzyl-2,3-dihydroxy -7-nitro -l-oxo-l,2-dihydroisoquinoline-4-carboxamide,
N-(4-Methoxybenzyl)-2,3-dihydroxy -7-nitro -l-oxo-l,2-dihydroisoquinoline-4- carboxamide,
N-(4-Fluorophenethyl)-2,3 -dihydroxy -7-nitro - 1 -oxo- 1 ,2-dihydroisoquinoline-4- carboxamide, N-(4-Fluorobenzyl)-7-acetamido-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-2-hydroxy- 1 ,3 -dioxo-7-phenylacetamido- 1 ,2,3,4- tetrahydroisoquinoline-4-carboxamide,
N-(4-Fluorobenzyl)- 7-benzamido-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-2-hydroxy-l,3-dioxo-7-picolinamido-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-2-hydroxy- 1 ,3 -dioxo-7-(2-(thiophen-2-yl)acetamido- 1 ,2,3,4- tetrahydroisoquinoline-4-carboxamide, and
N-(4-Fluorobenzyl)-2-hydroxy-7-methoxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide.
The most preferred compounds are selected from
N-(4-Fluorobenzyl)-2-hydroxy-l,3-dioxo-isoquinoline-4-carboxamide, or
N-(4-Fluorobenzyl)-2-hydroxy-7-nitro-l,3-dioxo-isoquinoline-4-carboxamide .
One embodiment of the present invention relates to a compound of formula (I),
Figure imgf000027_0001
or a tautomer (Γ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
R1 and R2 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9; C2-i2 lkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1; or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3;
-NHC(=0)Ar2; or -NHC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and CF3;
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3;
for use as an antiviral agent or for treating AIDS.
One embodiment of the present invention relates to the use of a com ound of formula
Figure imgf000029_0001
or a tautomer (Γ) thereof, or a pharmaceutically acceptable salt, solvate or prodrug of said compound or tautomer thereof, wherein
R1 and R2 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci-i2alkyl, C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-i0cycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1;
Het1; or R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)s- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; C1-6alkyl optionally substituted with halo, C1-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OC1-6alkyl, or Ar3;
-NHC(=0)Ar2; or -NHC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02,
-NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or
Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H,
C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and CF3;
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1 , 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and
-CF3; for the manufacture of a medicament for the prevention or treatment of viral infections in mammals.
According to a second aspect, the invention relates the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, for use as a medicine, more particularly as antiviral compounds, even more particularly as compounds active against HIV. The invention also relates to the use of the compounds of the formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, for the manufacture of a medicament or as a pharmaceutically active ingredient, especially as a virus replication inhibitor, preferably a retrovirus replication inhibitor, for instance for the manufacture of a medicament or pharmaceutical composition having antiviral activity for the prevention and/or treatment of viral, preferably retroviral, infections in humans and mammals. The present invention further relates to a method of treatment of a viral infection, preferably a retroviral infection in a mammal, including a human, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, as an active ingredient, preferably in admixture with at least a pharmaceutically acceptable carrier.
The invention further relates to methods for the preparation of compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof. The invention also relates to pharmaceutical compositions comprising the compounds of the invention according to formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, in admixture with at least a pharmaceutically acceptable carrier, the active ingredient preferably being in a concentration range of about 0.1 to 100% by weight, and to the use of these derivatives namely as drugs useful for the treatment of subjects suffering from HIV infection. The invention further relates to the use of a composition comprising (a) one or more derivatives of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, and (b) one or more viral inhibitors as biologically active agents in respective proportions such as to provide a synergistic effect against a viral infection, preferably a lentiviral infection and more preferably a retroviral infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in retroviral infection therapy. Within the framework of this embodiment of the invention, the retroviral enzyme inhibitors used as a therapeutically active ingredients (b) may belong to categories already known in the art and include, among others,
- HIV integrase inhibitors such as for instance, elvitegravir and raltegravir,
- Nucleoside, non-nucleoside and nucleotide reverse transcriptase inhibitors such as for instance, dideoxyadenosine, stavudine, zalcitabine, zidovudine, lamivudine, didanosine, nevirapine, delavirdine, efavirenz, tenofovir, foscamet sodium and the like,
- HIV protease inhibitors such as for instance saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and the like,
- HIV fusion inhibitors such as enfevurtide. Hence the present invention also relates to a pharmaceutical composition according to the invention further comprising a therapeutically effective amount of an HIV/ AIDS treatment agent selected from the group consisting of: an HIV/ AIDS antiviral agent; an anti-infective agent; and an immunomodulator. The invention also relates to a process for preparing a pharmaceutical composition of the invention wherein a therapeutically effective amount of a compound of formula (I) is intimately mixed with a pharmaceutically acceptable carrier.
The invention also relates to a process for preparing a pharmaceutical composition of the invention wherein a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of an HIV/AIDS treatment agent as defined herein are intimately mixed with a pharmaceutically acceptable carrier
The invention also relates to the compounds of the invention according to formula (I) being used for inhibition of the proliferation of other viruses than HIV, preferably the inhibition of viral activity of hepatitis B virus, hepatitis C virus or flaviviruses, with in particular yellow fever virus or Dengue virus. More generally, the invention relates to the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, being useful as agents having biological activity (preferably antiviral or antitumoral activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, more in particular having antiviral activity, yet more in particular against HIV.
A further aspect of the invention provides for a method of treatment or prevention of a viral infection in a mammal, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the invention.
The compounds of the present invention can act as inhibitors of HIV- 1 integrase, strand transfer inhibitors and/or 3 'processing inhibitors. Accordingly the present invention includes a method of inhibiting HIV- 1 integrase in a subject in need of such inhibition which comprises administering to the subject an effective amount of a compound of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof. DETAILED DESCRIPTION OF THE INVENTION
Definitions
In each of the following definitions, the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
"Ci-6alkyl" as used herein refers to a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of Ci-6alkyl include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. "C7-nalkyr as used herein refers to a straight or branched chain hydrocarbon containing from 7 to 11 carbon atoms. Representative examples of C7-nalkyl include, but are not limited to 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undyl, and the like.
"Ci-nalkyl", as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 12 carbon atoms and includes but is not limited to Ci-6alkyl, the examples given under these definitions, include, but are not limited to, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undyl, and the like.
"C2-6alkenyl" as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 6 carbons, and containing at least one carbon-carbon double bond, formed structurally, for example, by the replacement of two hydrogens. Representative examples of "alkenyl" include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3- butenyl, 4-pentenyl, 5-hexenyl, and the like.
"C2-6alkynyl" as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms, and containing at least one carbon- carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
As used herein and unless otherwise stated, the term "C3-iocycloalkyl" means a monocyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. As used herein and unless otherwise stated, the term "cycloalkylene" refers to a cyclic hydrocarbon radical of 3-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane; i.e. the divalent hydrocarbon radical corresponding to the above defined C3-iocycloalkyl. The term "C3-iocycloalkenyl" as used herein refers to a cyclic hydrocarbon having 3 to 10 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, i.e. a carbon-carbon, sp2 double bond.
The term "monocyclic heterocyclic ring system" refers to any 5 or 6 member ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S. The 5 member ring has from 0 to 2 double bonds, and the 6 member ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, sulfoxide, thiopyran, triazine, triazole, trithiane, and the like.
The term "bicyclic heterocyclic ring system" refers to any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxane, 1,3- benzodioxane, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. As used herein and unless otherwise stated, the terms "C1-6 alkoxy", "Ci-6alkylthio", "Aroxy", "Arthio", "Hetoxy", "Hetthio", "thio C3-10 cycloalkyl", "arylthio", "arylalkylthio" and "thioheterocyclic ring" refer to substituents wherein a Ci-6alkyl radical Ar or Het radical (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
As used herein and unless otherwise stated, the term halo means any atom selected from the group consisting of fluorine (F), chlorine (CI), bromine (Br) and iodine (I).
Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.
Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
The compounds of the invention optionally are bound covalently to an insoluble matrix and used for affinity chromatography separations, depending on the nature of the groups of the compounds, for example compounds with aryl are useful in hydrophobic affinity separations.
In an embodiment, the present invention encompasses compounds of formula (I) or (Γ), wherein
R1 and R2 are each independently selected from:
hydrogen; C(=0)R9; C(=S)R9;
Ci-i2alkyl, C2-i2 lkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, -SH, -CN, -NO2, - R7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo,
Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3; Ar1; Het1;
preferably R1 and R2 are each independently selected from:
hydrogen; Ci.i2alkyl, C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, -OH, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents (for example 1, 2, 3 or 4 substituents) selected from halo, Ci-6alkyl, -OH, and Ar3;
Ar1; and Het1;
or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3); preferably (a-2) or (a-3); preferably (a-3); R3, R4, and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3;
-NHC(=0)Ar2; or -NHC(=0)Het2;
preferably R3, R4, and R6 are each independently selected from hydrogen; halo; -OH; -CN; -N02; -OCF3; CF3; Ci-6alkyl ;Ci-6alkyloxy; Ar2; Ar2oxy; Het2; Het2oxy; C3-6Cycloalkyl; -NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3; -NHC(=0)Ar2; or -NHC(=0)Het2; preferably R3, R4, and R6 are each independently selected from: hydrogen; halo; -OH; -N02; -OCF3; CF3; Ci-6alkyl ;Ci-6alkyloxy; Ar2; preferably R3, R4, and R6 are each independently selected from: hydrogen;
R5 is selected from: hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3;
C(=0)R9; C(=S)R9; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3; Ci-6alkyloxy; Ci-ealkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6cycloalkyl;
Figure imgf000038_0001
optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3;or Het3; - HC(=0)Ar2; or - HC(=0)Het2; preferably R5 is selected from: hydrogen; halo; -OH; -SH; -CN; -N02; - H2; -OCF3; CF3; Ci-6alkyl; Ci-6alkyloxy; Ar2; Ar2oxy; Het2; Het2oxy; C3 -6Cycloalkyl;
Figure imgf000038_0002
optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3; or Het3; - HC(=0)Ar2; or - HC(=0)Het2; preferably R5 is selected from: hydrogen; halo; -OH; -N02;- H2; CF3; Ci-4alkyl; Ci-4alkyloxy; C3 -6Cycloalkyl;
Figure imgf000038_0003
optionally substituted with halogen, C(=0)OCi-6alkyl, or phenyl; or Het3; - HC(=0)phenyl; or - HC(=0)Het2;
each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12; preferably R7 and R8 is independently selected from hydrogen; or Ci-6alkyl ;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or
Het4; preferably R9 is selected from hydrogen; OH; or Ci-6alkyl or Ci_6 alkoxy; each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4; preferably each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl; Ci_6 alkoxy;
each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and CF3; preferably each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl, and is optionally substituted with 1 to 5 substituents (for example 1, 2, 3, 4 or 5 substituents) independently selected from halo, Ci-6alkyl,
OH, Ci-6alkyloxy, N02, -OCF3, and CF3;
each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents (for example 1, 2, 3 or 4 substituents) independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and - CF3; preferably each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1 or 2 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3;
with the proviso that said compound is not 2-Hydroxy-l,3-dioxo-l,2,3,4-tetrahydro- isoquinoline-4-carboxamide, or 2-Hydroxy-6,7-dimethyl-l,3-dioxo-l,2,3,4-tetrahydro- isoquinoline-4-carboxamide.
Another embodiment of the present invention is a process for preparing compounds of formula (I). They can be readily prepared according to the following reaction scheme and examples, or modifications thereof, using readily available starting materials and reagents. In the reactions below, it is possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction scheme and examples.
Abbreviations used in the instant specification, particularly the Scheme and Examples, include the following: Bn = benzyl, BOP = (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, DMSO = dimethyl sulfoxide, ESI-MS = electrospray ionization mass spectrometry, EtOAc = ethyl acetate, h = hour(s); LDA = lithium diisopropyl amide, MeOH = methanol, MM = 4- methylmorpholine, MR = nuclear magnetic resonance, rt = room temperature, THF = tetrahydrofuran.
The present invention encompasses a process for making a compound of formula (I) wherein
a) the intermediate of formula (II) is reacted with a boron halide or is deprotected by catalytic dehydrogenation with the formation of a compound of formula (I),
Figure imgf000040_0001
(Π) (I) b) wherein the intermediate of formula (II) is obtained by reacting the intermediate of formula (III) with a suitable amine with the formation of an intermediate of formula II)
Figure imgf000040_0002
(III) (II)
The 4-carboxamido-2-hydroxyisoquinoline-l,3(2H,4H)-diones of formula (I) can be prepared by reacting an intermediate of formula (II) with a boron halide (BX3) such as for example boron tribromide or boron trichloride at room or low temperature. Use of boron tribromide allows for a complete deprotection of the intermediates of formula (II) (deprotection of the benzyloxy function as well as of the alkoxy functions in aromatic rings) whereas boron trichloride only affects the benzyloxy function. Deprotection may also be performed by catalytic hydrogenation on Pd/C 5%.
Figure imgf000041_0001
(Π) (I) The 4-carboxamido-2-hydroxyisoquinoline-l,3(2H,4H)-diones of formula (I) wherein R3, R4 and R6 are hydrogen and R5 is a nitro function herein referred to as compounds of formula (I-a) can be prepared by deprotecting an intermediate of formula (II) wherein R3, R4 and R6 are hydrogen and R5 is a nitro function, herein referred to as an intermediate of formula (Il-a) with boron trichloride or tribromide.
The 4-carboxamido-2-hydroxyisoquinoline-l,3(2H,4H)-diones of formula (I) wherein R3, R4 and R6 are hydrogen and R5 is aminated herein referred to as compounds of formula (I- b) can be prepared by catalytic hydrogenation on Pd/C of an intermediate of formula (Il-a).
Figure imgf000041_0002
(Il-a) (I-b) The 2-benzyloxy-4-carboxamidoisoquinoline-l,3(2H,4H)-diones of formula (II) can be prepared by reacting the methyl esters of formula (III) with variously suitable amines of formula R1 HR2 for example, by refluxing in toluene using a Dean Stark apparatus.
Figure imgf000042_0001
(III) (II) Surprisingly, the basic treatment of an intermediate of formula (IV) does not yield an homophthalic acid derivative but a cyclized 2-benzyloxy-4-methoxycarbonylisoquinoline- l,3(2H,4H)-dione of formula (III). Hence, the intermediates of formula (III) can be prepared by cyclization of an intermediate of formula (IV). This cyclization can be performed quantitatively using 2.5 M potassium hydroxide in a suitable solvent such as aqueous methanol, at room temperature for 5 min.
Figure imgf000042_0002
he benzyloxycarboxamide of formula (IV) can be prepared by coupling the intermediate of formula (V) with O-benzylhydroxylamine, after activation with the BOP reagent and N- methylmorpholine. The coupling can be performed in a suitable solvent such as CH2CI2.
Figure imgf000043_0001
τ he benzyloxycarboxamide of formula (IV) wherein R3, R4 and R6 are hydrogen and R5 is a nitro function herein referred to as compounds of formula (IV-a) can be prepared by coupling the intermediate of formula (VIII), wherein R3, R4 and R6 are hydrogen and R5 is a nitro function with O-benzylhydroxylamine by refluxing in toluene using a Dean Stark apparatus.
Figure imgf000043_0002
C m) (IV-a)
The methyl 2-(2-methoxycarbonylphenyl) malonate monoester of formula (V) can be prepared by reacting the anion of the homophthalic diester of formula (VI) with carbon dioxide. This reaction is possible after treatment of the homophthalic diester of formula
(VI) with LDA according to the method described in Lazer et al., J. Med. Chem. 1979, 22,
845. The reaction can be performed in a suitable solvent such as for example tetrahydrofuran. COOCH
COOCH
Figure imgf000044_0001
(VI) (V) The triester of formula (VIII) can be prepared by aromatic nucleophilic substitution of intermediate (IX) with methylmalonate in the presence of NaH and under reflux in a suitable solvent such as, for example, THF.
COOCH3
"COOCH3
Figure imgf000044_0002
"COOCH3
(IX) (VIII) he methyl diester of formula (VI) can be prepared by reacting the commercially available homophthalic acid of formula (VII) with thionyl chloride in a suitable solvent such as, for example, methanol.
Figure imgf000044_0003
(VII) (VI) The intermediate of formula (IX) can be prepared by esterifi cation of 2-fluoro-5- nitrobenzoic acid with thionyl chloride in a suitable solvent such as, for example, methanol. 2-fluoro-5-nitrobenzoic acid can be prepared by nitrating the commercial 2- fluorobenzoic acid in a mixture of sulfuric acid and nitric acid.
Figure imgf000045_0001
(IX) T
The above described reactions that can be applied to homophthalic acids containing substituents at any ring position, like the homophthalic acid derivatives previously described in Billamboz et al., J. Med. Chem. 2008, 24, 7717 are exemplified in Examples 1-24. The more specific reactions described for compounds being only nitrated or aminated at position 7 are exemplified in Examples B35-B47.
The present invention also encompasses an intermediate of formula (II) wherein the substituents R1, R2, R3, 4, R5 and R6, are as defined hereinabove.
Figure imgf000045_0002
(II)
Those of skill in the art will also recognize that the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state, any and all protonated forms of the compounds are intended to fall within the scope of the invention. The resulting compounds may be optionally converted into a pharmaceutically acceptable salt or vice versa according to the methods known by the skilled in the art. Further, the resulting compounds may be converted into each other following art-known functional group transformation reactions. For example, amino groups may be N-alkylated, nitro groups reduced to amino groups, a halo atom may be exchanged for another halo.
The term "pharmaceutically acceptable salts" as used herein means the therapeutically active non-toxic salt forms which the compounds according to the formulas of the application like (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+, Ca2+ and Mg2+. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained. Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic and the like. Furthermore, this term also includes the solvates which the compounds according to the formulas of the application like (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, as well as their salts are able to form, such as for example hydrates, alcoholates and the like. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids, especially the naturally-occurring amino acids found as protein components. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine. The compounds of the invention also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NXf (wherein X is Cl-C4alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX4 + (wherein X typically is independently selected from H or a Ci-4alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
As used herein and unless otherwise stated, the term "enantiomer" means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%) and more preferably at least 98%>.
The term "isomers" as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formula (I), (X), (II), (XI), or any other compounds disclosed herein, groups, subgroups, and tautomers thereof, may possess, but not including position isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
The compounds of the present invention may also occur as tautomers thereof, such as the following tautomer (Γ) of a compound of formula (I):
Figure imgf000048_0001
It is understood that the present invention includes all tautomers of 2-hydroxyisoquinoline- l,3(2H,4H)-dione compounds of Formula I (or Γ), as well as the tautomers of its intermediates of Formula II (or ΙΓ), both singly and in mixtures. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds according to the formulas of the application like (I) may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or transconfiguration.
Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term "stereoisomerically pure" or "chirally pure" relates to compounds having a stereoisomeric excess of at least about 80% (i.e. at least 90% of one isomer and at most 10%) of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.
Separation of stereoisomers is accomplished by standard methods known to those in the art. One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113 :(3) 283-302). Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compounds of the invention. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reverse- phase chromatography following methods for separation of atropisomeric naphthyl- isoquinolines (Hoye, T., WO 96/15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCel™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like. ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. of Chromatogr. 513 :375-378).
The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of the substituents on a ring moiety. The absolute stereochemical configuration of the compounds according to the formulas of the application like (I) or (II) may easily be determined by those skilled in the art while using well-known methods such as, for example, X-ray diffraction or NMR. The compounds of the invention are employed for the treatment or prophylaxis of viral infections, more particularly HIV infections. When using one or more compounds of formula (I) as defined herein:
- the active ingredients of the compound(s) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra- arterially, parenterally or by catheterization.
- the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of viral infections in humans and other mammals, preferably is a retroviral enzyme inhibiting amount. More preferably, it is a retroviral replication inhibiting amount or a retroviral enzyme inhibiting amount of the derivative(s) of formula (I) as defined herein corresponds to an amount which ensures a plasma level of between ^g/ml and 100 mg/ml, optionally of 10 mg/ml. This can be achieved by administration of a dosage of in the range of 0.001 mg to 2000 mg, in particular 0.01 mg to 1000 mg, more in particular O. lmg to 500 mg, or 0.1 mg to 100 mg, or 0.1 mg to 20 mg, or 0.1 mg to 5 mg, or 0.1 to 1 mg per day per kg bodyweight for humans. Depending upon the pathologic condition to be treated and the patient's condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.
The present invention further relates to a method for preventing or treating a viral infection in a subject or patient by administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I). The therapeutically effective amount of the preparation of the compound(s), especially for the treatment of viral infections in humans and other mammals, preferably is HIV protein/enzyme inhibiting amount. More preferably, it is a HIV replication inhibiting amount or a HIV enzyme inhibiting amount of the derivative(s) of the formulas as defined herein. Suitable dosage is usually in the range of 0.001 mg to 20 mg, in particular 0.01 mg to 5 mg, more in particular O. lmg to 1 mg per day per kg bodyweight for humans. Depending upon the pathologic condition to be treated and the patient's condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals. As is conventional in the art, the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27 '. Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as CI) defined by the following equation:
Figure imgf000052_0001
wherein EDx is the dose of the first or respectively second drug used alone (la, 2a), or in combination with the second or respectively first drug (lc, 2c), which is needed to produce a given effect. The said first and second drug have synergistic or additive or antagonistic effects depending upon CI < 1, CI = 1, or CI > 1, respectively.
Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against viral infection may also be readily determined by means of one or more tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC50 for calculating the fractional inhibitory concentration (hereinafter referred as FIC). When the minimum FIC index corresponding to the FIC of combined compounds (e.g., FICX + FICy) is equal to 1.0, the combination is said to be additive; when it is between 1.0 and 0.5, the combination is defined as sub synergistic, and when it is lower than 0.5, the combination is defined as synergistic. When the minimum FIC index is between 1.0 and 2.0, the combination is defined as sub antagonistic and, when it is higher than 2.0, the combination is defined as antagonistic.
This principle may be applied to a combination of different antiviral drugs of the invention or to a combination of the antiviral drugs of the invention with other drugs that exhibit anti-HIV activity.
The invention thus relates to a pharmaceutical composition or combined preparation having synergistic effects against a viral infection and containing:
(a) a combination of two or more of the compounds of formula (I), and (b) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers,
for simultaneous, separate or sequential use in the treatment or prevention of a viral infection, or
(c) one or more anti-viral agents, and
(d) at least one of the compounds of formula (I), and
(e) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers,
for simultaneous, separate or sequential use in the treatment or prevention of a viral infection.
Suitable anti-viral agents for inclusion into the synergistic antiviral compositions or combined preparations of this invention include practically all known anti-HIV compounds known at this moment such as nucleoside and non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase inhibitors.
The pharmaceutical composition or combined preparation with synergistic activity against viral infection according to this invention may contain the compounds of the present invention over a broad content range depending on the contemplated use and the expected effect of the preparation. Generally, the content of the compounds of formula (I) of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.
According to a particular embodiment of the invention, the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of HIV infections. The invention therefore relates to the use of a composition comprising:
(f) one or more compounds of formula (I), and
(g) one or more HIV /protein-enzyme inhibitors as biologically active agents in respective proportions such as to provide a synergistic effect against a viral infection, particularly a HIV infection in a mammal, for instance in the form of a combined preparation for simultaneous, separate or sequential use in viral infection therapy, such as HIV. When using a combined preparation of (f) and (g):
- the active ingredients (f) and (g) may be administered to the mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
- the therapeutically effective amount of the combined preparation of (f) and (g), especially for the treatment of viral infections in humans and other mammals, particularly is a HIV enzyme inhibiting amount. More particularly, it is a HIV replication inhibiting amount of derivative (f) and a HIV enzyme inhibiting amount of inhibitor (g). Still more particularly when the said HIV enzyme inhibitor (g) is a reverse transcriptase inhibitor, its effective amount is a reverse transcriptase inhibiting amount. When the said HIV enzyme inhibitor (g) is a protease inhibitor, its effective amount is a protease inhibiting amount. When the said HIV enzyme inhibitor (g) is an integrase inhibitor, its effective amount is a integrase inhibiting amount.
- ingredients (f) and (g) may be administered simultaneously but it is also beneficial to administer them separately or sequentially, for instance within a relatively short period of time (e.g. within about 24 hours) in order to achieve their functional fusion in the body to be treated. The invention also relates to the compounds of the invention, for inhibition of the proliferation of other viruses than HIV, particularly for the inhibition of other retroviruses and lentiviruses and also for the inhibition of flaviviruses or picornaviruses such as BVDV, HCV, HBV or Coxsackie virus, with in particular yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus. Other viruses may be inhibited such as HSV, CMV and Sars-virus.
The present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. More generally, the invention relates to the compounds of formula (I) being useful as agents having biological activity (particularly antiviral activity) or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non- medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
The compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
Subsequently, the term "pharmaceutically acceptable carrier" as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface- active agents may also be prepared by inicronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients. Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface- active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10-22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acid or dibutyl-naphtalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p- nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures. Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, poly ethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.
Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy- lower alkyl radicals. A more detailed description of surface-active agents suitable for this purpose may be found for instance in "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw1, 2 d ed. (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants, (Chemical Publishing Co., New York, 1981).
Compounds of the invention and their physiologically acceptable salts (hereafter collectively referred to as the active ingredients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration may vary with for example the condition of the recipient.
While it is possible for the active ingredients to be administered alone it is preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients. The carrier(s) optimally are "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g. mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7%) w/w, etc), preferably 0.2 to 15%> w/w and most preferably 0.5 to 10%> w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30%> w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2- ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition may require protective coatings. Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof. In view of the fact that, when several active ingredients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
Examples
The following examples are provided for the purpose of illustrating the present invention and should in no way be interpreted as limiting the scope thereof. A INTERMEDIATES
EXAMPLE Al
Al -a intermediate 1 Methyl 2-(2-methoxy-2-oxoethyl)benzoate
Figure imgf000063_0001
2-Carboxymethyl-benzoic acid (5 g, 28.0 mmol) was dissolved in MeOH (100 mL) and thionyl chloride (5.5 mL, 62.0 mmol) was added dropwise. The solution was heated under reflux for 2 h and concentrated in vacuo. The residue was dissolved in AcOEt and washed several times with 10% NaHC03. After drying over Na2S04, the solvent was evaporated in vacuo to yield intermediate 1 as a yellow oil (99%). 1H NMR (300 MHz, DMSO-<¾): δ = 3.60 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.00 (s, 2 H, CH2), 7.36 (m, 3 H, HAr), 7.92 (1 H, HAr, dd, 3J = 8.2 Hz, 4J = 2.0 Hz); 13C NMR (75 MHz, DMSO-i¾): δ= 36.7 (CH2), 51.4 (OCH3), 51.8 (OCH3), 127.4 (CH), 129.5 (C), 130.3 (CH), 132.4 (CH), 132.6 (CH), 135.9 (C), 166.9 (CO), 172.4 (CO).
Al-b intermediate 2: 3-Methoxy-2 -(methoxycarbonyl)phenyl1-3-oxopropanoic acid
Figure imgf000063_0002
A solution of freshly distilled diisopropylamine (0.75 mL, 5.35 mmol) in 10.0 mL of dry THF under an argon atmosphere was cooled to -78 °C and 3.34 mL of 1.6 M n- butyllithium (5.35 mmol) was added. After 30 min reaction at -78 °C, a solution of intermediate 1(0.79 g, 3.8 mmol) in 10.0 mL of THF was added dropwise. After stirring the solution for 30 min, temperature was risen to -5 °C and the argon inlet was removed. C02 formed from addition of sulfuric acid on anhydrous barium carbonate was bubbled through the reaction mixture for 20 min. The mixture was acidified with 2.0 M HCl and then extracted with CHC13. The combined organic extracts were extracted with 10% Na2C03. The basic extracts were made acidic by the careful addition of 2.0 M HCl and the product was extracted into CHCI3 (3 x 100 mL). The combined CHCI3 extracts were dried over Na2S04. The solvent was removed under reduced pressure to give an oily residue intermediate 2 which crystallized on cooling. Orange solid (0.49 g; 62%); mp 100 °C; 1H NMR (300 MHz, CDC13): δ = 3.75 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 5.16 (s, 1 H, CH), 7.38 (1 H, HAr, dd, 3J= 7.7 Hz, 4J= 1.2 Hz), 7.44 (1 H, HAr, td, 3J= 7.7 Hz, 4J= 1.2 Hz), 7.57 (1 H, HAr, td, 3J= 7.7 Hz, 4J= 1.2 Hz), 8.07 (1 H, HAr, dd, 3J= 7.7 Hz, 4J= 1.2 Hz), 11.22 (br s, 1 H, COOH); 13C NMR (75 MHz, CDC13): δ= 52.5 (OCH3), 53.3 (OCH3), 55.5 (CH), 128.5 (CH), 128.6 (C), 131.3 (CH), 132.3 (CH), 132.9 (CH), 134.4 (C), 167.7 (CO), 170.6 (CO), 170.8 (CO).
Al-c intermediate 3 : Methyl 2-{ 1 (benzyloxy)amino1-3-methoxy-l -dioxopropan-2-yl| benzoate
Figure imgf000064_0001
BOP (1.69 g, 4.0 mmol) was added at -25 °C to a solution of intermediate 2 (1.00 g, 4.0 mmol) and 4-methylmorpholine (2.2 mL, 20.0 mmol) in a minimum of CH2CI2. After 30 min stirring at -25 °C, O-benzylhydroxylamine hydrochloride (0.64 g, 4.0 mmol) was added and after 12 h stirring at room temperature, the mixture was washed with 1.0 M HCl, 1.0 M NaHC03 solutions and brine. The organic layer was dried over Na2S04 and concentrated in vacuo. After column chromatography of the residue (eluent: petroleum ether/ AcOEt, 70/30), intermediate 3 was obtained as a yellow oil (69%); 1H NMR (300 MHz, CDCI3): δ = 3.63 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 4.79 (s, 2 H, CH2), 5.20 (s, 1 H, CH), 7.18-7.28 (m, 5 H, HAr), 7.33 (1 H, HAr, td, 3J= 7.5 Hz, 4J= 1.2 Hz), 7.48 (1 H, HAr, td, 3J= 7.5 Hz, 4J= 1.2 Hz), 7.57 (1 H, HAr, dd, 3J= 7.5 Hz, 4J= 1.2 Hz,), 7.87 (1 H, HAr, dd, 3J= 7.5 Hz, 4J= 1.2 Hz), 9.64 (s, 1 H, NH); 13C NMR (75 MHz, CDC13): δ= 52.5 (OCH3), 52.7 (OCH3), 52.8 (CH), 78.0 (OCH2), 116.7 (C), 128.1 (CH), 128.5 (2CH), 128.6 (CH), 128.8 (C), 129.3 (2CH), 130.8 (CH), 131.9 (CH), 132.8 (CH), 134.5 (C), 165.4 (CO), 168.3 (CO), 169.3 (CO); ESI-MS: m/z = 358 (M+H)+
Al-d intermediate 4: Methyl 2-(benzyloxy)-L3-dioxo-L2,3,4-tetrahydroisoquinoline
-4-carboxylate
Figure imgf000065_0001
Intermediate 3 (0.337 g, 1.0 mmol) was dissolved in a solution of methanol (10.0 mL) and 2.0 M KOH (10.0 mL). After 5 min stirring, the solution was acidified with 2.0 M HCl and extracted three times with ether (20.0 mL). The combined organic extracts were dried over Na2S04 and concentrated in vacuo to intermediate 4 as white crystals (0.323 g, 99%); mp 126 °C; 82% enol, 18% keto form. We give the 1H NMR data of the keto/enol mixture since the contributions of the two forms exhibited strong overlaps. 1H NMR (300 MHz, CDC13): δ = 3.77 (s, 3 H, OCH3), 4.11 (s, 3 H, OCH3), 5.03 (s, 1 H, CH), 7.29-7.65 (m, 7 H, HAT), 5.29 (s, 2 H, CH2), 6.37 (1 H, HAr, dd, 3J= 8.5 Hz, 4J= 1.5 Hz), 7.25 (1 H, HAr, dd, 3J = 7.7 Hz, 4J = 1.5 Hz), 8.45 (m, 2 H, HAr); Enol form; 13C NMR (75 MHz, CDCI3): δ= 53.1 (CH3), 79.0 (CH2), 84.3 (C), 121.2 (C), 124.3 (CH), 124.6 (CH), 128.3 (CH), 128.6 (2CH), 129.4 (CH), 130.1 (2CH), 132.9 (C), 133.5 (C), 133.8 (CH), 158.8 (CO), 163.0 (CO), 173.5 (CO); Keto form; 13C NMR (75 MHz, CDC13): δ= 53.8 (CH3), 54.8 (CH), 78.5 (CH2), 119.3 (C), 123.5 (C), 127.3 (CH), 128.5 (2CH), 129.2 (CH), 129.3 (CH), 129.5 (CH), 130.0 (2CH), 131.4 (C), 133.5 (C), 134.4 (CH), 160.7 (CO), 162.9 (CO), 171.6 (CO); ESI-MS: m/z = 326 (M+H)+.
Al-e intermediate 5: N-(3-Chloropropyl)-2-benzyloxy-l,3-dioxo-l,2,3,4
tetrahydroisoquinoline-4-carboxamide
Figure imgf000065_0002
Intermediate 4 (0.325 g, 1.0 mmol) and 3-chloropropylamine hydrochloride (0.26 g, 2.0 mmol) were dissolved in toluene (100 mL). The mixture was refluxed for 12 h using a Dean Stark apparatus. After cooling, the solution was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with 2.0 M HCl and dried over Na2S04. After concentration in vacuo, the residue was triturated with ether and the precipitate was filtered and dried at room temperature giving intermediate 5. White crystals (82%); mp 126 °C; 100% enol form; 1H NMR (300 MHz, DMSO-i¾): δ = 2.08 (quin, 2 H, CH2, J = 7.0 Hz), 3.60 (t, 2 H, CH2, J = 7.0 Hz), 4.67 (t, 2 H, CH2, V = 7.0 Hz), 5.05 (s, 2 H, OCH2), 7.15 (td, 1 H, HAr , 5J = 8.0 Hz, 4J = 1.5 Hz), 7.39-7.50 (m, 3 H, HAT), 7.54 (td, 1 H, HAr, 3J = 8.0 Hz, 4J = 1.5 Hz), Ί .59-1.61 (m, 2 H, HAr), 8.11 (dd, 1 H, HAr, 3J = 8.0 Hz, 4J = 1.5 Hz), 8.22 (dd, 1 H, HAr, 5J = 8.0 Hz, 4J = 1.5 Hz), 12.05 (s, 1 H, H); 13C NMR (75 MHz, OMSO-d6): δ = 20.1 (CH2), 37.9 (CH2), 67.6 (CH2), 77.4 (OCH2), 88.8 (Civ, C4), 119.9 (Civ), 122.2 (CH), 123.8 (CH), 128.0 (CH), 128.8 (2CH), 129.1 (CH), 129.8 (2CH), 133.2 (CH), 135.5 (Civ), 135.6 (Civ), 161.0 (CO), 164.2 (CO), 166.8 (CO); ESI-MS: m/z = 387 ((M+H)+ , 100%, 35C1); 389 ((M+H)+, 32%, 37C1).
EXAMPLE A2
The process followed in this example is the same as described in example Al
A2-e intermediate 6: N-Propyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline -4-carboxamide
Figure imgf000066_0001
Intermediate 6: white solid (80%); mp 166 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 0.86 (t, 3 H, CH3, 3J = 13 Hz), 1.45 (sext, 2 H, CH2, 3J = 7.1 Hz), 3.06 (q, 2 H, NH-CHz, 3J = 6.3 Hz), 4.98 (d, 1 H, OCH2, 2J = 9.8 Hz), 5.03 (d, 1 H, OCH2, 2J= 9.8 Hz), 5.12 (s, 1 H, CH), 7.38-7.45 (m, 4 H, HAr), 8.10 (d, 1 H, HAr, 3J = 7.8 Hz), 8.80 (t, 1 H, NH, 3J = 5.4 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 11.3 (CH3), 22.2 (CH2), 40.9 (CH2), 55.8 (CH), 77.4 (OCH2), 125.3 (Civ), 126.6 (CH), 128.1 (CH), 128.3 (CH), 128.4 (2 CH), 128.9 (CH), 129.4 (2 CH), 134.2 (CH), 134.5 (Civ), 133.9 (Civ), 161.1 (CO), 164.6 (CO), 167.0 (CO); ESI-MS: m/z = 353 (M+H)+; Anal. (C20H20N2O4) C, H, N.
EXAMPLE A3
The process followed in this example is the same as described in example Al
A3-e intermediate 7: N-Butyl-2-benzyloxy-1.3-dioxo-1.2.3.4-tetrahvdroisoquinoline-4- carboxamide
Figure imgf000067_0001
Intermediate 7: white solid (83%); mp 166 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 0.85 (t, 3 H, CH3, 3J = 7.0 Hz), 1.12-1.40 (m, 4 H, 2 CH2), 3.28 (q, 2 H, NH- CH2, 3J = 6.9 Hz), 4.80 (s, 1 H, CH), 5.14 (s, 2 H, OCH2), 6.47 (t, 1 H, NH, 3J = 7.0 Hz), 7.40 (d, 1 H, HAr, 3J = 7.7 Hz), 7.52 (t, 1 H, HAr, 3J = 7.6 Hz), 7.69 (t, 1 H, HAr, 3J = 7.4 Hz), 8.07 (d, 1 H, ¾, 3J = 6.8 Hz); 13C NMR (75 MHz, CDC13): δ = 13.7 (CH3), 20.0 (CH2), 31.3 (CH2), 40.3 (CH2), 55.7 (CH), 78.5 (OCH2), 125.3 (Civ), 128.1 (CH), 128.5 (2 CH), 128.7 (CH), 129.0 (CH), 129.2 (CH), 130.0 (2CH), 133.0 (Civ), 133.8 (Civ), 134.0 (CH), 161.1 (CO), 164.6 (CO), 165.1 (CO); ESI-MS: m/z = 367 (M+H)+; Anal.
Figure imgf000067_0002
EXAMPLE A4
The process followed in this example is the same as described in example Al
A4-e intermediate 8: N-Pentyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000067_0003
Intermediate 8: white solid (45%); mp 134 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 0.90 (t, 3 H, CH3, 3J = 6.4 Hz), 1.32-1.65 (m, 6 H, 3 CH2), 3.25 (q, 2 H, NH- CHz, 3J= 7.0 Hz), 4.79 (s, 1 H, CH), 5.11 (d, 1 H, OCH2, 2J = 9.0 Hz), 5.15 (d, 1 H, OCH2, 2J= 9.0 Hz), 6.50 (s, 1 H, NH), 7.34-7.66 (m, 8 H, HAr), 8.24 (d, 1 H, ¾, 3J= 7.3 Hz); 13C NMR (75 MHz, CDC13): δ = 13.9 (CH3), 22.2 (CH2), 28.9 (2 CH2), 40.5 (CH2), 55.7 (CH), 78.5 (OCH2), 125.3 (Civ), 127.8 (CH), 128.5 (2 CH), 128.6 (CH), 128.9 (CH), 129.1 (CH), 129.9 (2 CH), 133.1 (Civ), 133.8 (Civ), 134.0 (CH), 161.1 (CO), 164.9 (CO), 165.0 (CO); ESI-MS: m/z = 381 (M+H)+; Anal. (C22H24N204) C, H, N.
EXAMPLE A5
The process followed in this example is the same as described in example Al A5-e intermediate 9: N-Hexyl-2-benzyloxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4 carboxamide
Figure imgf000068_0001
Intermediate 9: white crystals (83%); mp 139-140 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 0.88 (t, 3 H, CH3, 3J = 7.0 Hz), 1.29 (m, 6 H, CH2), 1.51 (quin, 2 H, CH2, 3J = 7.0 Hz), 3.25 (t, 2 H, CH2, 3J = 7.0 Hz), 4.80 (s, 1 H, CH), 5.12 (d, 1 H, OCH2, 2J = 9.2 Hz), 5.16 (d, 1 H, OCH2, 2J = 9.2 Hz), 6.51 (t, 1 H, NH, 3J = 6.0 Hz), 7.28 (dd, 1 H, H5, 3J= 8.0 Hz, 4J= 1.5 Hz), 7.30-7.40 (m, 3 H, HAr), 7.51-7.68 (m, 4 H, HAr), 8.23 (dd, 1 H, ¾, 3 J = 8.0 Hz, 4 J = 1.5 Hz); 13C NMR (75 MHz, CDC13): δ = 14.0 (CH3), 22.5 (CH2), 26.4 (CH2), 29.2 (CH2), 31.4 (CH2), 40.6 (CH2), 55.5 (CH), 78.6 (OCH2), 125.2 (Civ), 128.5 (2CH), 128.6 (CH), 128.8 (CH), 129.0 (CH), 129.2 (CH), 130.0 (2CH), 132.7 (Civ), 133.7 (Civ), 133.9 (CH), 160.5 (CO), 164.0 (CO), 165.1 (CO); ESI-MS: m/z = 395 (M+H)+.
EXAMPLE A6
The process followed in this example is the same as described in example Al
A6-e intermediate 10: N-Nonyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000068_0002
Intermediate 10: white solid (65%); mp 146 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 0.89 (t, 3 H, CH3, 3J= 7.0 Hz), 1.28-1.60 (m, 14 H, 7 CH2), 3.28 (q, 2 H, NH- CHz, 3J = 6.0 Hz), 4.78 (s, 1 H, CH), 5.14 (m, 2 H, OCH2), 6.43 (m, 1 H, NH), 7.30-7.68 (m, 8 H, HAr), 8.25 (d, 1 H, ¾, 3J = 7.6 Hz); 13C NMR (75 MHz, CDC13): δ = 14.1 (CH3), 22.6 (CH2), 26.8 (2 CH2), 29.2 (3 CH2), 29.5 (CH2), 31.8 (CH2), 40.5 (CH2), 55.7 (CH), 78.5 (OCH2), 125.3 (Civ), 127.9 (CH), 128.5 (2 CH), 128.6 (CH), 128.9 (CH), 129.1 (CH), 129.9 (2 CH), 133.1 (Civ), 133.8 (Civ), 134.0 (CH), 161.1 (CO), 164.8 (CO), 165.0 (CO); ESI-MS: m/z = 437 (M+H)+; Anal. (C26H32N204) C, H, N. EXAMPLE A7
The process followed in this example is the same as described in example Al
A7-e intermediate 11 : N-Isopropyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-
4-carboxamide
Figure imgf000069_0001
Intermediate 11: white solid (74%); mp 158 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 1.07 (d, 3 H, CH3, 3J = 6.4 Hz), 1.14 (d, 3 H, CH3, 3J = 6.4 Hz), 3.76 (sext, 1 H, CH, 3J = 6.6 Hz), 4.99 (d, 1 H, OCH2, 2J = 9.6 Hz), 5.04 (d, 1 H, OCH2, 2J= 9.6 Hz), 5.08 (s, 1 H, CH), 7.42-7.45 (m, 4 H, HAr), 7.57-7.60 (m, 3 H, HAr), 7.74 (t, 1 H, HAr, 3J = 7.2 Hz), 8.10 (d, 1 H, ¾, 3 J = 7.7 Hz), 8.74 (dapp, 1 H, NH, 3 J = 7.4 Hz); 13C NMR (75 MHz, DMSO-i¾): 6 = 22.0 (2 CH3), 41.3 (CH), 55.7 (CH), 77.3 (OCH2), 125.2 (CH),
128.0 (CH), 128.3 (3 CH), 128.8 (CH), 129.4 (2 CH), 134.1 (CH), 134.4 (Civ), 134.9 (Civ),
161.1 (CO), 164.5 (CO), 165.0 (CO); ESI-MS: m/z = 353 (M+H)+; Anal. (Ci2oH20N204) C, H, N.
EXAMPLE A8
The process followed in this example is the same as described in example Al
A8-e intermediate 12: N-7ert-butyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline
-4-carboxamide
Figure imgf000069_0002
Intermediate 12: beige solid (70%); mp 143 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 1.31 (s, 9 H, 3 CH3), 5.04 (d, 1 H, OCH2, 2J = 9.3 Hz), 5.08 (d, 1 H, OCH2, 2J = 9.3 Hz), 5.19 (s, 1 H, CH), 7.48 (m, 3 H, HAr), 7.51 (d, 1 H, HAr, 3J = 7.7 Hz), 7.60- 7.65 (m, 3 H, HAr), 7.80 (t, 1 H, HAr, 3J= 7.7 Hz), 8.15 (d, 1 H, ¾, 3J = 7.7 Hz), 8.55 (s, 1 H, H); 13C NMR (75 MHz, OMSO-d6): δ = 28.1 (3 CH3), 50.9 (Civ), 56.2 (CH), 77.3 (OCH2), 125.2 (Civ), 126.4 (CH), 128.0 (CH), 128.3 (2 CH), 128.8 (CH), 129.3 (2 CH), 134.0 (CH), 134.5 (Civ), 135.1 (Civ), 161.1 (CO), 164.6 (CO), 165.2 (CO); ESI-MS: m/z = 367 (M+H)+; Anal. (C21H22N204) C, H, N.
EXAMPLE A9
The process followed in this example is the same as described in example Al
A9-e intermediate 13 : N-Cvclopentyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000070_0001
Intermediate 13: white solid (77%); mp 188 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 1.40- 1.90 (m, 8 H, 4 CH2), 3.95 (sext, 1 H, CH, 3J = 6.3 Hz), 4.99 (d, 1 H, OCH2, 2J = 9.6 Hz), 5.04 (d, 1 H, OCH2, 2J = 9.6 Hz), 5.10 (s, 1 H, CH), 7.40-7.43 (m, 4 H, HAT), 7.55-7.59 (m, 3 H, HAr), 7.74 (t, 1 H, HAr, 3J = 7.6 Hz), 8.09 (d, 1 H, ¾, 3J = 7.9 Hz), 8.79 (dapp, 1 H, NH, 3J = 7.3 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 23.4 (CH2), 23.5 (CH2), 32. 1 (CH2), 32.2 (CH2), 50.9 (CH), 55.6 (CH), 77.3 (OCH2), 125.2 (Civ), 126.4 (CH), 128.0 (CH), 128.2 (CH), 128.3 (2 CH), 128.8 (CH), 129.3 (2 CH), 134. 1 (CH), 134.4 (Civ), 134.9 (Civ), 161.0 (CO), 164.5 (CO), 165.3 (CO); ESI-MS: m/z = 379 (M+H)+; Anal. (C22H22N204) C, H, N.
EXAMPLE A10
The process followed in this example is the same as described in example Al
AlO-e intermediate 14: N-Allyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000071_0001
Intermediate 14: white solid (70%); mp 186 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 3.76 (m, 2 H, CH2-CH=CH2), 4.85 (d, 1 H, OCH2, 2J = 9.6 Hz), 4.95 (d, 1 H, OCH2, 2J = 9.6 Hz), 5.02-5.20 (m, 3 H, C4H, CH2-CH=CH2), 5.80 (m, 1 H, CH2- CH=CH2), 7.43 (d, 1 H, HAr, 3J = 7.5 Hz), 7.55 (t, 1 H, HAr, 3J= 7.2 Hz), 7.71 (t, 1 H, HAr, 3J = 7.2 Hz), 8.07 (d, 1 H, ¾, 3J = 7.5 Hz), 9.00 (m, 1 H, NH); 13C NMR (75 MHz, DMSO-i¾): 6 = 41.7 (CH2-CH=CH2), 55.7 (CH), 77.3 (OCH2), 115.4 (CH2-CH=CH2), 125.3 (Civ), 126.7 (CH), 128.0 (CH), 128.3 (CH), 128.4 (2 CH), 128.8 (CH), 129.3 (2 CH), 134.1 (CH), 134.3 (CH), 134.4 (Civ), 134.7 (Civ), 161.0 (CO), 164.4 (CO), 165.9 (CO); ESI-MS: m/z = 351.1 (M+H)+; Anal. (C20Hi8N2O4) C, H, N.
EXAMPLE All
The process followed in this example is the same as described in example Al
Al l-e intermediate 15 : Ethyl 2-r(2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinolin-4- vPformamidolacetate
Figure imgf000071_0002
Intermediate 15: orange oil (78%); 100% keto form; 1H NMR (300 MHz, CDC13): δ = 1.22 (t, 3 H, CH3, 3J = 7.0 Hz), 4.01-4.12 (m, 4 H, CH2), 5.10 (m, 3 H, CH, OCH2), 7.28- 7.40 (m, 4 H, NH, 3 HAr) 7.43-7.70 (m, 5 H, HAr), 8.22 (dd, 1 H, H8, 3J = 8.0 Hz, 4J = 1.5 Hz); 13C NMR (75 MHz, CDC13): δ = 14.1 (CH3), 42.0 (CH2), 55.3 (CH), 61.7 (OCH2), 78.5 (OCH2), 125.3 (Civ), 127.0 (CH), 128.1 (CH), 128.7 (2CH), 129.0 (CH), 129.1 (CH), 130.0 (2CH), 132.8 (Crv), 133.8 (Crv), 134.1 (CH), 161.1 (CO), 164.8 (CO), 165.6 (CO), 169.4 (CO); ESI-MS: m/z = 397 (M+H)+; Anal. (C21H20N2O6) C, H, N.
EXAMPLE A12
The process followed in this example is the same as described in example Al
A12-e intermediate 16 : N-(3-Fluorophenyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000072_0001
Intermediate 16: green oil (78%); 100% keto form; 1H MR (300 MHz, CDC13): δ = 4.17 (s, 1 H, CH), 5.16 (s, 2 H, OCH2), 6.82 (t, 1 H, HAr, 3J = 7.6 Hz), 7.00-7.59 (m, 12 H, NH, 11 HAT), 8.23 (dd, 1 H, ¾, 3J = 8.0 Hz, 4J = 1.5 Hz); 13C MR (75 MHz, CDC13): δ = 55.9 (CH), 78.5 (OCH2), 109.1 (d, CH, C2-, 2JC-F = 28.0 Hz), 110.7 (d, CH, C4 », 2JC-F = 28.0 Hz), 118.4 (d, CH, C6 », 4JC-F = 3.0 Hz), 126.9 (Crv), 127.0 (CH), 127.6 (CH), 128.1 (CH), 128.6 (d, CH, C5», 3JC- F = 8.0 Hz), 128.7 (2CH), 129.0 (CH), 129.1 (CH), 130.0 (2CH), 131.6 (Civ), 134.8 (Crv), 136.1 (d, Crv, Ci», 3JC-F = 10.0 Hz), 161.1 (d, Crv, C3 », 1JC-F = 255.0 Hz), 161.6 (CO), 162.3 (CO), 165.4 (CO); ESI-MS: m/z = 405 (M+H)+; Anal.
Figure imgf000072_0002
EXAMPLE A13
The process followed in this example is the same as described in example Al .
A13-e intermediate 17: N-(3-Chloro-4-methoxyphenyl)-2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000072_0003
Intermediate 17: purple oil (67%); 100% keto form; 1H NMR (300 MHz, CDC13): δ = 3.79 (s, 3 H, OCH3), 4.17 (s, 1 H, CH), 5.15 (s, 2 H, OCH2), 6.80 (d, 1 H, 3J = 7.2 Hz), 7.20-7.70 (m, 9 H, NH, 8 HAr), 8.23 (m, 2 H, HAr), 8.78 (d, 1 H, H2 », 4J = 1.5 Hz); 13C NMR (75 MHz, CDC13): δ = 55.4 (OCH3), 56.0 (CH), 115.1 (CH), 116.1 (Civ), 120.5 (CH), 120.8 (CH), 126.9 (Civ), 127.1 (CH), 127.6 (CH), 128.1 (CH), 128.2 (Civ), 128.8 (2CH), 129.0 (CH), 129.1 (CH), 129.8 (2CH), 131.3 (Civ), 134.8 (Civ), 148.6 (Civ), 161.3 (CO), 163.3 (CO), 166.4 (CO); ESI-MS: m/z = 451 ((M+H)+ , 100%, 35C1); 453 ((M+H)+, 32%, 37C1); Anal. (C24H19CIN2O5) C, H, N.
EXAMPLE A14
The process followed in this example is the same as described in example Al .
A14-e intermediate 18: N-(4-Fluorobenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000073_0001
Intermediate 18: beige solid (81%); mp 119-121 °C; 100% enol form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.46 (d, 2 H, CH2, 3J = 5.8 Hz), 5.13 (s, 2 H, OCH2), 6.84-7.20 (m, 4 H, HAT), 7.36-7.50 (m, 6 H, HAr), 7.68 (td, 1 H, HAr, 3J = 8.0 Hz, 4J = 1.5 Hz), 8.06 (dd, 1 H, HAr, 3J = 8.0 Hz, 4J = 1.5 Hz), 8.34 (dd, 1 H, HAr, 3J = 8.0 Hz, 4J = 1.5 Hz), 10.65 (t, 1 H, NH, 3J = 5.8 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 42.5 (CH2), 76.7 (OCH2), 83.7 (Civ, C4), 115.0 (d, 2CH, C3 » C5 », 2JC- = 21.4 Hz), 126.2 (Civ), 127.0 (CH), 128.1 (CH), 128.3 (CH), 128.5 (2CH), 130.1 (d, 2 CH, C2 » C6 », 3JC-F = 8.6 Hz), 130.2 (2 CH), 131.1 (CH), 132.1 (CH), 133.8 (Civ), 133.8 (d, Civ, Ci», 4JC- = 3.1 Hz), 135.1 (Civ), 159.1 (CO), 161.2 (d, Civ, C4 » 1JC-F = 245.0 Hz), 161.3 (CO), 165.4 (CO); ESI-MS: m/z = 419 (M+H)+; Anal. (C24Hi9FN204) C, H, N.
EXAMPLE A15
The process followed in this example is the same as described in example Al . A15-e intermediate 19 : N-(4-Methylbenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000074_0001
Intermediate 19: white crystals (85%); mp 149-150 °C; 100% enol form; 1H NMR (300 MHz, DMSO-i¾): δ = 2.28 (s, 3 H, CH3), 4.42 (d, 2 H, 3J = 5.3 Hz), 5.01 (s, 2 H, OCH2), 6.84 (td, 1 H, HAr, 3J = 7.0 Hz, 4J = 1.5 Hz), 7.13 (d, 2 H, 3J = 7.8 Hz), 7.20-7.38 (m, 6 H, HAr), 7.62 (d, 2 H, HAr, 3J = 7.8 Hz), 7.94 (dd, 1 H, HAr, 3J = 8.0 Hz, 4J= 1.5 Hz), 8.38 (dd, 1 H, ¾, 3J = 8.0 Hz, 4J = 1.5 Hz), 10.65 (t, 1 H, NH, 3J = 5.3 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 21.2 (CH3), 42.1 (CH2), 76.6 (OCH2), 86.8 (Civ, C4), 118.5 (Civ), 118.6 (CH), 124.0 (CH), 126.9 (CH), 127.8 (2CH), 128.6 (2 CH), 128.7 (CH), 129.2 (2 CH), 129.3 (2CH), 131.2 (Civ), 131.3 (CH), 136.3 (Civ), 138.3 (Civ), 140.5 (Civ), 159.8 (CO), 161.3 (CO), 169.6 (CO); ESI-MS: m/z = 415 (M+H)+; Anal. (C25H22N204) C, H, N.
EXAMPLE A16
The process followed in this example is the same as described in example Al .
A16-e intermediate 20: N-(2,4-Dimethoxybenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4 tetrahydroisoquinoline-4-carboxamide
Figure imgf000074_0002
Intermediate 20: salmon solid (88%); mp 176-177 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 3.75 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 4.35 (dd, 1 H, C¾ 2J = 11.9 Hz, 3J= 5.1 Hz), 4.38 (dd, 1 H, C¾ 2J = 11.9 Hz, 3J= 5.1 Hz), 4.82 (s, 1 H, CH), 5.01 (d, 1 H, OCH2, 2J= 9.2 Hz), 5.08 (d, 1 H, OCH2, 2J= 9.2 Hz), 6.40 (dd, 1 H, ¾», 3J5-^- = 7.5 Hz, 4J5-.3- = 1.2 Hz), 6.45 (d, 1 H, H3 », 4J3-.5- = 1.2 Hz), 7.05 (t, 1 H, NH, 3J = 5.1 Hz), 7.14 (d, 1 H, He-, 3J --5 " = 7.6 Hz), 7.28-7.39 (m, 5 H, HAr), 7.51-7.70 (m, 3 H, HAr), 8.21 (dd, 1 H, ¾, 3J = 7.6 Hz, 4J = 1.5 Hz); 13C NMR (75 MHz, CDC13): δ = 40.3 (CH2), 55.3 (CH3), 55.4 (CH3), 55.7 (CH), 78.4 (OCH2), 98.6 (CH, C3 »), 103.9 (CH, C5 »), 118.5 (Civ, Ci-), 125.6 (Civ), 126.1 (CH), 128.5 (CH), 128.6 (2CH), 128.7 (CH), 129.0 (CH), 129.9 (2CH), 130.6 (CH), 133.8 (Civ), 133.9 (CH), 135.0 (Civ), 158.5 (CO), 160.8 (CO), 163.9 (CO), 165.0 (CO), 166.6 (CO); ESI-MS: m/z = 461 (M+H)+; Anal. (C26H24N206) C, H, N.
EXAMPLE A17
The process followed in this example is the same as described in example A16.
EXAMPLE A18
The process followed in this example is the same as described in example Al
A18-e intermediate 21 : N-(3,4-Dimethoxybenzyl)-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000075_0001
Intermediate 21: white crystals (48%); mp 186-188 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 3.74 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 4.27 (dd, 1 H, C¾ 2J = 11.9 Hz, 3J= 5.1 Hz), 4.36 (dd, 1 H, C¾ 2J = 11.9 Hz, 3J= 5.1 Hz), 4.73 (s, 1 H, CH), 4.98 (d, 1 H, OCH2, 2J = 9.2 Hz), 5.02 (d, 1 H, OCH2, 2J = 9.2 Hz), 6.50-6.62 (m, 3 H, HAr), 6.96 (t, 1 H, HAr, 3J= 7.6 Hz), 7.20-7.32 (m, 4 H, HAr), 7.40-7.54 (m, 3 H, HAr), 8.13 (dd, 1 H, Hg, 3J = 7.6 Hz, 4J= 1.5 Hz), 9.01 (t, 1 H, NH, 3J = 5.1 Hz); 13C NMR (75 MHz, CDC13): δ = 44.2 (CH2), 55.6 (CH), 55.8 (CH3), 55.9 (CH3), 78.6 (OCH2), 110.8 (CH), 111.1 (CH), 118.5 (Civ), 120.0 (CH), 125.6 (Civ), 128.1 (CH), 128.5 (2CH), 128.8 (CH), 129.1 (CH), 129.2 (CH), 129.9 (2CH), 132.7 (Civ), 134.0 (CH), 134.1 (Civ), 158.8 (CO), 160.8 (CO), 163.9 (CO), 164.5 (CO), 166.6 (CO); ESI-MS: m/z = 461 (M+H)+; Anal. (C26H24N206) C, H, N.
EXAMPLE A19
The process followed in this example is the same as described in example A18 EXAMPLE A20
The process followed in this example is the same as described in example Al
A20-e intermediate 22: N-((Thiophen-2-vnmethylV2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000076_0001
Intermediate 22: beige solid (74%); mp 190 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.56 (m, 2 H, CH2), 5.08 (s, 2 H, OCH2), 5.24 (s, 1 H, CH), 6.75-6.81 (m, 2 H, CH Thioph), 6.90 (d, 1 H, CH Thioph, 3J= 5.0 Hz), 7.00-7.70 (m, 7 H, HAr), 7.78 (t, 1 H, HAr, 3J = 7.2 Hz), 8.16 (d, 1 H, ¾, 3J = 7.7 Hz), 9.48 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-i¾): δ = 37.6 (CH2), 55.4 (CH), 77.2 (OCH2), 125.2 (Civ), 125.4 (CH), 125.7 (CH), 126.7 (2 CH), 128.1 (CH), 128.4 (3 CH), 128.8 (CH), 129.4 (2 CH), 134.1 (CH), 134.4 (2 Civ), 141.2 (Civ), 161.0 (CO), 164.3 (CO), 165.8 (CO); ESI-MS: m/z = 407.1 (M+H)+; Anal. (C22Hi8N204S) C, H, N.
EXAMPLE A21
The process followed in this example is the same as described in example Al
A21-e intermediate 23 : N-r2-(3.4-Dimethoxyphenyl)ethyl1-2-benzyloxy-1.3-dioxo- 1.2.3.4-tetrahydroisoquinoline-4-carboxamide
Figure imgf000076_0002
Intermediate 23: white solid (53%); mp 191-192 °C; 100% keto form; Ή NMR (300 MHz, DMSO-i¾): δ = 2.70 (m, 2 H, CH2), 3.35 (m, 2 H, CH2), 3.71 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 4.95 (d, 1 H, OC¾ 2J= 9.2 Hz), 5.04 (d, 1 H, OC¾ 2J= 9.2 Hz), 5.19 (s, 1 H, CH), 6.20 (d, 1 H, 3J = 7.8 Hz), 6.85-6.92 (m, 2 H, HAr), 7.31 (dd, 1 H, HAr, 3J = 7.8 Hz, 4J = 1.5 Hz), 7.40-7.51 (m, 3 H, HAr), 7.53-7.60 (m, 3 H, HAr), 7.65 (td, 1 H, HAr, 3J = 7.8 Hz, 4J = 1.5 Hz), 8.08 (dd, 1 H, H8, 3J = 7.8 Hz, 4J = 1.5 Hz), 9.06 (t, 1 H, NH, 3J = 5.2 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 34.6 (CH2), 41.3 (CH2), 55.8 (OCH3), 55.9 (OCH3), 55.9 (CH), 77.8 (OCH2), 112.2 (CH), 113.0 (CH), 121.0 (CH), 125.6 (Civ), 127.2 (CH), 128.4 (CH), 128.7 (CH), 128.8 (2CH), 129.3 (CH), 129.8 (2CH), 131.9 (Civ), 134.4 (CH), 134.9 (Civ), 135.2 (Qv), 147.7 (Civ), 149.0 (Civ), 161.5 (CO), 165.0 (CO), 166.4 (CO); ESI-MS: m/z = 475 (M+H)+; Anal. (C27H26N2O6) C, H, N.
EXAMPLE A22
The process followed in this example is the same as described in example A21
EXAMPLE A23
The process followed in this example is the same as described in example Al
A23-e intermediate 24: (2-Benzylox -l -dioxoisoquinolin-4-yl)(piperidin-l-yl)methanone
Figure imgf000077_0001
Intermediate 24: white solid (67%); mp 132 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 1.48-1.62 (m, 6 H, 3 CH2), 3.35 (t, 2 H, N-CH2, 3J= 5.1 Hz), 3.66 (t, 2 H, N-CH2, 3J = 5.1 Hz), 5.00 (s, 2 H, OCH2), 5.93 (s, 1 H, CH), 7.30 (d, 1 H, HAr, 3J = 7.2 Hz), 7.42-7.56 (m, 6 H, HAr), 7.74 (t, 1 H, HAr, 3J= 7.2 Hz), 8.12 (d, 1 H, ¾, 3J= 7.7 Hz); 13C MR (75 MHz, DMSO-i¾): δ = 23.8 (CH3), 25.3 (CH2), 26.1 (CH2), 43.2 (CH2), 47.5 (CH2), 51.0 (CH), 77.5 (OCH2), 125.4 (Civ), 126.9 (CH), 128.1 (CH), 128.3 (CH), 128.4 (2 CH), 128.9 (CH), 129.4 (2 CH), 134.2 (CH), 134.3 (Civ), 135.1 (Civ), 160.9 (CO), 164.4 (CO), 164.6 (CO); ESI-MS: m/z = 379 (M+H)+; Anal. (C22H22N2O4) C, H, N.
EXAMPLE A24
The process followed in this example is the same as described in example Al
A24-e intermediate 25: N,N-Diethyl-2-benzyloxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000077_0002
Intermediate 25: white solid (67%); mp 114 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 1.11 (t, 3 H, CH3, 3J = 6.7 Hz), 1.29 (t, 3 H, CH3, 3J = 6.5 Hz), 3.24-3.43 (m, 2 H, NH-CH2), 3.61-3.76 (m, 2 H, NH-CH2), 5.00 (s, 2 H, OCH2), 5.80 (s, 1 H, CH), 6.50 (s, 1 H, NH), 7.28 (d, 1 H, HAr, 3J = 7.7 Hz), 7.30-7.40 (m, 3 H, HAr), 7.56-7.61 (m, 3 H, HAT), 7.74 (t, 1 H, HAr, 3J = 7.2 Hz), 8.11 (d, 1 H, ¾, 3J = 7.6 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 12.7 (CH3), 14.7 (CH3), 40.5 (CH2), 42.8 (CH2), 51.1 (CH), 77.4 (OCH2), 125.5 (Civ), 126.6 (CH), 128.1 (CH), 128.2 (CH), 128.4 (2 CH), 128.9 (CH), 129.4 (2 CH), 134.3 (CH), 135.3 (2 Civ), 160.9 (CO), 164.5 (CO), 165.7 (CO); ESI-MS: m/z = 367 (M+H)+; Anal. (C2iH22N204) C, H, N.
EXAMPLE A25
The process followed in this example is the same as described in example Al
A25-e intermediate 26: N-Butyl-N-methyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000078_0001
Intermediate 26: white solid (69%); mp 117-120 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 0.83 (t, 3 H, CH3, 3J = 8.4 Hz), 1.20-1.59 (m, 4 H, 2 CH2), 2.88 (s, 3 H, NH-CH3), 3.07 (s, 3 H, NH-CH3), 3.30 (t, 2 H, NH-CH^, 3J = 6.7 Hz), 3.56 (t, 2 H, NH- ¾ 3J= 6.7 Hz), 4.99 (s, 1 H, CH), 5.23 (s, 1 H, CH), 7.06 (m, 1 H, HAr), 7.23-7.25 (m, 3 H, HAT), 7.36-7.47 (m, 4 H, HAr), 8.10 (d, 1 H, ¾, 3J = 7.2 Hz); 13C NMR (75 MHz, CDC13): δ = 13.8 (CH3), 19.9 (CH2), 20.0 (CH2), 29.0 (CH2), 30.9 (CH2), 34.6 (NHCHA 36.5 (NHCHA 48.6 (NHCHZ). 51.0 (NHCHZ). 51.7 (CH), 52.5 (CH), 78.4 (OCH2), 125.9 (Civ), 126.1 (Civ), 126.4 (CH), 128.4 (2 CH), 128.6 (CH), 129.0 (CH), 129.3 (CH), 129.9 (2 CH), 133.9 (Civ), 134.2 (CH), 161.1 (CO), 164.2 (CO), 165.9 (CO); ESI-MS: m/z = 381 (M+H)+; Anal. (C22H24N204) C, H, N.
EXAMPLE A26
The process followed in this example is the same as described in example Al
A26-e intermediate 27: N-Heptyl-2-benzyloxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000079_0001
Intermediate 27: white solid (48%); mp 131-134 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 0.80 (t, 3 H, CH3, 3J = 7.0 Hz), 1.19-1.21 (m, 8 H, 4 CH2), 1.43-1.45 (m, 2 H, CH2), 3.14 (q, 2 H, NH-CH2, 3 J = 7.1 Hz), 4.71 (s, 1 H, CH), 5.05 (m, 2 H, OCH2), 6.40 (m, 1 H, NH), 7.19 (d, 1 H, HAr, 3J = 7.2 Hz), 7.26-7.30 (m, 3 H, HAr), 7.44- 7.56 (m, 4 H, HAr), 8.16 (d, 1 H, ¾, 3J = 8.3 Hz); 13C NMR (75 MHz, CDC13): δ = 14.1 (CH3), 22.6 (CH2), 26.8 (CH2), 28.9 (CH2), 29.3 (CH2), 31.7 (CH2), 40.5 (CH2), 55.7 (CH), 78.5 (OCH2), 125.3 (Civ), 127.8 (CH), 128.5 (3 CH), 129.0 (CH), 129.2 (CH), 129.9 (2 CH), 133.2 (Civ), 133.8 (Civ), 134.0 (CH), 161.2 (CO), 165.0 (CO), 165.1 (CO); ESI-MS: m/z = 409 (M+H)+; Anal. (C24H28N204) C, H, N.
EXAMPLE A27
The process followed in this example is the same as described in example Al
A27-e intermediate 28: N-Octyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000079_0002
Intermediate 28: white solid (49%); mp 137-139 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 0.80 (t, 3 H, CH3, 3J = 7.3 Hz), 1.18-1.22 (m, 10 H, 5 CH2), 1.43-1.45 (m, 2 H, CH2), 3.18 (q, 2 H, ΝΗ-¾, 3J = 7.5 Hz), 4.71 (s, 1 H, CH), 5.07 (m, 2 H, OCH2), 6.37 (m, 1 H, NH), 7.20 (d, 1 H, HAr, 3J = 8.0 Hz), 7.31-7.33 (m, 3 H, HAr), 7.44- 7.59 (m, 4 H, HAr), 8.16 (d, 1 H, H8, 3J = 7.7 Hz); 13C NMR (75 MHz, CDC13): δ = 14.1 (CH3), 22.6 (CH2), 26.8 (CH2), 29.2 (3 CH2), 31.8 (CH2), 40.5 (CH2), 55.7 (CH), 78.5 (OCH2), 125.3 (Civ), 127.8 (CH), 128.5 (3 CH), 128.9 (CH), 129.2 (CH), 129.9 (2 CH), 133.2 (Civ), 133.8 (Civ), 134.0 (CH), 161.1 (CO), 165.0 (CO), 165.1 (CO); ESI-MS: m/z = 423 (M+H)+; Anal. (C25H30N2O4) C, H, N.
EXAMPLE A28
The process followed in this example is the same as described in example Al A28-e intermediate 29: /V-Dodecyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline- 4-carboxamide
Figure imgf000080_0001
Intermediate 29: grey solid (57%); mp 143-145 °C; 100% keto form; 1H MR (300 MHz, CDC13): δ = 0.80 (t, 3 H, CH3, 3J = 6.6 Hz), 1.15-1.29 (m, 20 H, 10 CH2), 3.10 (q, 2 H, H-CH2, 3J= 6.7 Hz), 4.80 (s, 1 H, CH), 5.05 (m, 2 H, OCH2), 6.37 (m, 1 H, H), 7.18 (d, 1 H, HAr, 3J = 7.2 Hz), 7.28-7.33 (m, 4 H, HAr), 7.47 (t, 1 H, HAr, 3J = 8.5 Hz), 7.49-7.52 (m, 1H, HAr), 7.58 (t, 1 H, HAr, 3J = 7.2 Hz), 8.17 (d, 1 H, ¾, 3J = 8.0 Hz); 13C NMR (75 MHz, CDC13): δ = 14.1 (CH3), 22.7 (CH2), 26.9 (CH2), 29.3 (CH2), 29.4 (CH2), 29.7 (5 CH2), 31.9 (CH2), 40.6 (CH2), 55.7 (CH), 78.6 (OCH2), 125.3 (Civ), 128.0 (CH), 128.5 (2 CH), 128.6 (CH), 129.0 (CH), 129.2 (CH), 129.9 (2 CH), 133.1 (Civ), 133.7 (Civ), 134.0 (CH), 161.1 (CO), 164.9 (CO), 165.3 (CO); ESI-MS: m/z = 479 (M+H)+; Anal. (C29H38N204) C, H, N.
EXAMPLE A29
The process followed in this example is the same as described in example Al .
A29-e intermediate 30: /V-Phenyl-2-benzyloxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000080_0002
Intermediate 30: grey solid (60%); mp 143-146 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 5.04 (d, 1 H, CHz, 2J = 9.6 Hz), 5.09 (d, 1 H, ¾, 2J = 9.6 Hz), 5.39 (s, 1 H, CH), 7.13 (t, 1 H, HAr, 3J = 7.3 Hz), 7.36 (t, 1 H, HAr, 3J = 7.7 Hz), 7.42-7.44 (m, 4 H, HAT), 7.59-7.61 (m, 5H, HAr), 7.76 (t, 1 H, HAr, 3J= 7.3 Hz), 8.15 (d, 1 H, HAr, 3J = 7.3 Hz), 10.93 (s, 1 H, NH); 13C NMR (75 MHz, OMSO-d6): δ = 56.5 (CH), 77.4 (OCH2), 119.4 (2 CH), 124.3 (CH), 125.3 (Civ), 126.7 (CH), 128.2 (CH), 128.4 (2 CH), 128.5 (CH), 128.9 (CH), 129.0 (2 CH), 129.4 (2 CH), 134.36 (CH), 134.39 (Civ), 134.5 (Civ), 138.1 (Civ), 161.0 (CO), 164.3 (CO), 164.7 (CO); ESI-MS: m/z = 387 (M+H)+; Anal. (C23Hi8N204) C, H, N.
EXAMPLE A30
The process followed in this example is the same as described in example Al .
A30-e intermediate 31 : N-Methyl-N-phenyl-2-benzyloxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000081_0001
Intermediate 31: white solid (77%); mp 177-180 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 3.31 (s, 3 H, CH3), 3.43 (s, 3 H, CH3), 5.05 (m, 2 H, OCHz), 5.13 (s, 1 H, CH), 7.05-7.07 (m, 1 H, HAr), 7.20 (t, 1 H, HAr, 3J = 7.3 Hz), 7.32-7.42 (m, 8 H, HAr), 7.53-7.55 (m, 3 H, HAr), 8.11 (d, 1 H, HAr, 3J = 7.3 Hz); 13C NMR (75 MHz, CDC13): δ = 38.3 (CH3),52.0 (CH), 78.4 (OCH2), 125.8 (Civ), 126.3 (CH), 128.5 (5 CH), 128.9 (CH), 129.1 (CH), 129.3 (CH), 130.0 (2 CH), 130.4 (2 CH), 134.0 (Civ), 134.1 (CH), 142.8 (Civ), 161.0 (CO), 164.3 (CO), 166.3 (CO); ESI-MS: m/z = 401 (M+H)+; Anal. (C24H20N2O4) C,
H, N.
EXAMPLE A31
The process followed in this example is the same as described in example Al
A31-e intermediate 32: N-(4-Fluorophenyl)-2-benzyloxy-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000081_0002
Intermediate 32: beige solid (78%); mp 177-180 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 5.04 (d, 1 H, CH2, 2J = 9.6 Hz), 5.09 (d, 1 H, CH2, 2J = 9.6 Hz), 5.37 (s,
1 H, CH), 7.20 (t, 2 H, HAr, 3J = 8.8 Hz), 7.41-7.43 (m, 3 H, HAr), 7.53-7.66 (m, 6 H, HAr), 7.76 (t, 1 H, HAr, 3 J = 7.7 Hz), 8.15 (d, 1 H, HAr, 3 J = 7.7 Hz); 13C NMR (75 MHz, CDCI3): δ = 56.5 (CH), 77.4 (OCH2), 115.6 (d, 2 CH, C3 », C5 », 2JC-F = 22.5 Hz), 121.3 (d,
2 CH, C2 », C6 », 3JC-F = 8.2 Hz), 125.3 (Civ), 126.7 (CH), 128.2 (CH), 128.3 (2 CH), 128.5 (CH), 118.4 (d, CH, C6 », 4JC-F = 3.0 Hz), 127.6 (CH), 128.1 (CH), 128.9 (CH), 129.4 (2 CH), 134.3 (CH), 134.4 (2 dv), 134.5 (d, Civ, Ci», 4JC.F = 2.2 Hz), 158.5 (d, Civ, C4-, JC-F = 240.0 Hz), 160.9 (CO), 164.3 (CO), 164.6 (CO); ESI-MS: m/z = 405 (M+H)+; Anal. (C23H17FN204) C, H, N.
EXAMPLE A32
The process followed in this example is the same as described in example Al
A32-e intermediate 33 : N-Benzyl-2-benzyloxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000082_0001
Intermediate 33: white solid (52%); mp 153-155 °C; 100% keto form; 1H NMR (300 MHz, CDCI3): δ = 4.33 (s, 2 H, ¾), 5.01-5.03 (m, 2 H, OCH^), 5.21 (s, 1 H, CH), 7.18- 7.52 (m, 12 H, HAr), 7.73 (t, 1 H, HAr, 3J = 7.0 Hz), 8.10 (d, 1 H, HAr, 3J = 7.7 Hz), 9.33 (s, 1 H, NH); 13C NMR (75 MHz, CDC13): δ = 42.6 (CH2), 55.7 (CH), 77.4 (OCH2), 125.3 (Civ), 126.7 (CH), 127.08 (CH), 127.17 (2 CH), 128.1 (CH), 128.4 (5 CH), 128.9 (CH), 129.4 (2 CH), 134.1 (CH), 134.4 (Civ), 134.6 (Civ), 138.4 (Civ), 161.0 (CO), 164.5 (CO), 166.1 (CO); ESI-MS: m/z = 401 (M+H)+; Anal. (C24H20N2O4) C, H, N.
EXAMPLE A33
The process followed in this example is the same as described in example Al .
A33-e intermediate 34: N-4-Methoxybenzyl-2-benzyloxy-l,3-dioxo-l,2,3,4
tetrahydroisoquinoline-4-carboxamide
Figure imgf000083_0001
Intermediate 34: grey solid (61%); mp 163-167 °C; 100% keto form; 1H MR (300 MHz, CDC13): δ = 3.74 (s, 3 H, OCH3), 4.24 (dd, 1 H, CH2, 2J= 14.7 Hz, 3J= 5.6 Hz), 4.29 (dd, 1 H, CH2, 2J = 14.7 Hz, 3J = 5.6 Hz), 5.00 (d, 1 H, OCH2, 2J = 9.6 Hz), 5.05 (d, 1 H, OCH2, 2J = 9.6 Hz), 5.19 (s, 1 H, CH), 6.91 (d, 2 H, HAr, 3J= 8.5 Hz), 7.19 (d, 2 H, HAr, 3J= 8.5 Hz), 7.40-7.44 (m, 4 H, HAr), 7.56-7.58 (m, 3 H, HAr), 7.74 (t, 1 H, HAr, 3J = 7.4 Hz), 8.10 (d, 1 H, ¾, 3J = 7.6 Hz), 9.25 (t, 1 H, H, 3J = 5.3 Hz); 13C NMR (75 MHz, CDC13): δ = 42.1 (CH2), 55.3 (OCH3), 56.1 (CH), 77.8 (OCH2), 113.8 (2 CH), 125.2 (Civ), 126.6 (CH), 128.0 (CH), 128.30 (CH), 128.37 (2CH), 128.6 (2 CH), 128.8 (CH), 129.3 (2CH), 130.2 (Civ), 134.1 (CH), 134.4 (Civ), 134.7 (Civ), 158.4 (CO), 161.0 (CO), 164.4 (CO), 165.9 (CO); ESI-MS: m/z = 431 (M+H)+; Anal. (C25H22N205) C, H, N.
EXAMPLE A34
The process followed in this example is the same as described in example Al .
A34-e intermediate 35: N-(4-Fluorophenethyl)-2-benzyloxy-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000083_0002
Intermediate 35: white solid (61%); mp 155-165 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 2.73 (t, 2 H, CH2, 3J= 5.0 Hz), 3.36 (q, 2 H, CH2, 3J= 5.0 Hz), 4.97 (d, 1 H, OCH2, 2J = 9.5 Hz), 5.00 (d, 1 H, OCH2, 2J= 9.5 Hz), 5.09 (s, 1 H, CH), 7.12 (t, 2 H, HAr 3J = 8.8 Hz), 7.24-7.28 (m, 4 H, HAr), 7.41-7.43 (m, 3 H, HAr), 7.54-7.58 (m, 3 H, HAT), 7.68 (t, 1 H, HAr 3J = 7.6 Hz), 8.08 (d, 1 H, HAr, 3J = 7.7 Hz), 8.85 (t, 1 H, NH, 3J = 5.0 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 33.8 (CH2), 40.6 (CH2), 54.2 (CH), 77.6 (OCH2), 115.7 (d, 2 CH, C3" C5 », 2JC- = 21.0 Hz), 125.2 (Civ), 126.9 (CH), 127.6 (CH), 128.0 (CH), 129.2 (2CH), 129.6 (2 CH), 130.7 (d, 2 CH, C2 » C6 », JC-F = 8.3 Hz), 133.7 (2 CH), 134.7 (CH), 135.28 (Civ), 135.30 (d, Civ, Ci», 4JC-F = 2.8 HZ), 136.4 (Civ), 162.0 (d, Civ, C4» ^ = 241.5 Hz), 165.2 (CO), 167.5 (CO), 169.2 (CO); ESI-MS: m/z = 433 (M+H)+; Anal. (C25H21FN2O4) C, H, N.
EXAMPLE A35
A35-a intermediate 36: 2-Fluoro- -nitrobenzoic acid
Figure imgf000084_0001
Nitric acid (60% solution, 5.0 mL) was carefully added to a cooled solution of concentrate sulfuric acid (5.0 mL) so that the temperature did not exceed 10 °C. 2-f uorobenzoic acid (2.1 g, 15.0 mmol) was added by small portions while maintaining temperature between 15 and 25 °C. The mixture was stirred for 2 h at room temperature. Ice was added and the precipitate was filtered. After drying at room temperature, intermediate 36 was obtained as a white powder. Yield: 93%; mp 135-137 °C; 1H NMR (300 MHz, OMSO-d6): δ = 7.32 (t, 1 H, H3, 3 J H3_H4 = J H3-F = 9.2 Hz), 8.43 (dt, 1 H, H JH4.H3 = 9.2 Hz, JH4.F = JH4.H6 = 3.5 Hz), 8.89 (dd, 1H, ¾, 4JH6.F = 5.8 Hz, 4JH6.H4 = 3.0 Hz); 13C NMR (75 MHz, DMSO- d6): δ = 118.7 (d, Ci, 2JC-F = 10.9 Hz), 118.7 (d, C3, 2JC-F = 25.0 Hz), 128.9 (d, C6> 3JC-F = 2.2 Hz), 130.6 (d, C4, 3JC- = 10.9 Hz), 143.9 (C5), 165.7 (d, C2, 1JC.F = 272.0 Hz), 166.7 (d, COOH, 3Jc- = 3.8 Hz).
A35-b intermediate 37:Methyl 2-fluoro-5-nitrobenzoate
Figure imgf000084_0002
Intermediate 36 ( 3.7 g, 20.0 mmol) was dissolved at 0 °C in MeOH (100 mL) and thionyl chloride (5.3 mL, 60.0 mmol) was added dropwise. The solution was heated under reflux for 24 h and concentrated in vacuo. The residue was dissolved in EtOAc and washed several times with 1.0 M NaOH. After drying over Na2S04, the solvent was evaporated in vacuo to yield intermediate 37 as a yellow oil, which crystallized upon standing as light yellow needles. Yield: 90%; mp 47-49 °C; 1H NMR (300 MHz, CDC13) δ = 4.01 (s, 3 H, OCH3), 7.35 (t, 1H, H3, 3JH3.H4 = 3JH3.F= 9.2 Hz), 8.44 (dt, 1H, U4 3 JH4-H3 = 9.2 Hz, 4JH4.F = 4JH4-H6 = 3.5 Hz), 8.87 (dd, 1H, ¾, 4JH6-F = 5.9 Hz, 4JH6-H4 = 2.7 Hz); 13C NMR (75 MHz, CDC13): 6 = 47.7 (OCH3), 113.2 (d, C3, 2JC-F = 25.1 Hz), 114.5 (d, Ci, 2JC-F = 12.0 Hz), 122.9 (d, C6> 3JC-F = 3.3 Hz), 124.3 (d, C4> 3JC-F = 10.9 Hz), 138.6 (C5), 157.4 (d, COOCH3, 3JC-F = 3.8 Hz), 159.8 (d, C2, 1JC-F = 269.0 Hz).
A35-c intermediate 38: Methyl 2-{ -dimethoxy-L3-dioxopropan-2-yl|-5-nitrobenzoate
Figure imgf000085_0001
An argon stream was passed on a suspension of sodium hydride (60% dispersion in mineral oil, 1.2 g, 25.1 mmol) in petroleum ether to discard mineral oil. Then sodium hydride was dispersed in THF (30.0 mL) and a solution of methyl malonate (2.9 mL, 25.1 mmol) in THF (20.0 mL) was added dropwise under argon inert atmosphere. After 30 min stirring at room temperature, a solution of intermediate 37 (5.0 g, 25.1 mmol) in THF (20.0 mL) was added dropwise and the solution was heated under reflux for 12 h. The solvent was removed in vacuo. The residue was dissolved in EtOAc and washed several times with water. After column chromatography of the residue (eluent: petroleum ether/EtOAc, 80/20), the product intermediate 38 was obtained as a yellow oil, which crystallized upon standing as light yellow needles. Yield: 67%; mp 63-65 °C; 1H NMR (300 MHz, CDC13) δ = 3.73 (s, 6 H, 2 OCH3), 3.90 (s, 3 H, OCH3), 5.81 (s, 1 H, CH), 7.61 (d, 1H, H3, JH3-H4 = 8.6 Hz), 8.31 (dd, 1H, H4, 3 m-m = 8.6 Hz, 4 m- = 2.2 Hz), 8.80 (dd, 1H, H6, 4JH6-H4 = 2.2 Hz); 13C NMR (75 MHz, CDC13): δ = 52.9 (2 OCH3), 54.7 (OCH3), 59.7 (CH), 125.0 (CH), 126.8 (CH), 131.1 (Civ), 132.5 (CH), 140.3 (Civ), 146.9 (Civ, C5), 165.2 (CO), 167.4 (2 CO).
A35-d intermediate 39:Methyl 2-{ l-r(benzyloxy)amino1-3-methoxy-l -dioxopropan-2- yl I - 5 -nitrob enzoate
Figure imgf000086_0001
A solution of intermediate 38 (0.31 g, 1.0 mmol) and O-benzylhydroxylamine (0.15 g, 1.2 mmol) in toluene (15.0 mL) was refluxed for 8 h using a Dean Stark apparatus. After cooling, the solution was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with 2.0 M HC1 and dried over Na2S04. After concentration in vacuo and column chromatography of the residue (eluent: petroleum ether/EtOAc, 70/30), the product intermediate 39 was obtained as an orange oil. Yield: 50%; 1H NMR (300 MHz, CDC13) δ = 3.65 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.83 (s, 2 H, OCH2), 5.22 (s, 1 H, CH), 7.26 (m, 5 H, HAr), 7.75 (d, 1H, ¾, JH3-H4 = 8.6 Hz), 8.32 (dd, 1H, H4, 3JH4- = 8.6 Hz, 4JH4-H6 = 2.2 Hz), 8.75 (dd, 1H, H6, 4JH6-H4 = 2.2 Hz), 9.62 (s, 1 H, NH); 13C NMR (75 MHz, CDCI3): δ = 52.9 (CH), 53.2 (2 OCH3), 78.8 (OCH2), 125.8 (CH), 126.8 (CH), 128.5 ( 2 CH), 128.7 (CH), 129.3 (2 CH), 130.2 (Civ), 133.7 (CH), 135.0 (Civ), 141.3 (Civ), 147.2 (Civ, C5), 164.1 (CO), 166.2 (CO), 168.4 (CO); ESI-MS: m/z = 403 (M+H)+. A35-e intermediate 40: Methyl 2-(benzyloxy)-3-hvdroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxylate
Figure imgf000086_0002
Intermediate 39 (0.40 g, 1.0 mmol) was dissolved in a solution of methanol (10.0 mL) and 2.0 M KOH (10.0 mL). After 12 h stirring, the solution was acidified with 2.0 M HC1 and extracted three times with dichloromethane (20.0 mL). The combined organic extracts were dried over Na2S04 and concentrated in vacuo. The residue was triturated in ether to afford intermediate 40 as a yellow solid. Yield: 89%; mp 190-196 °C; 100% enol form; 1H NMR (300 MHz, CDC13) δ = 4.17 (s, 3 H, OCH3), 5.31 (s, 2 H, OCH2), 7.45 (m, 3 H, HAr), 7.63 (m, 2 H, HAr), 8.43 (dd, 1H, H6, 3JH6.H5 = 9.4 Hz, 4JH6.H8 = 2.0 Hz), 8.60 (d, 1H, H5> 3JHS-H6 = 9.4 Hz), 9.26 (d, 1H, ¾, 4JH8-H4 = 1.9 Hz); 13C NMR (75 MHz, CDC13): δ = 53.7 (OCH3), 79.4 (OCH2), 84.5 (Qv), 121.2 (Civ), 124.6 (CH), 125.6 (CH), 127.4 (CH), 128.7 (2 CH), 129.6 (CH), 130.1 (2 CH), 133.0 (Crv), 138.0 (Crv), 144.0 (Crv, C7), 157.5 (CO), 164.8 (CO), 173.1 (CO); Anal. (Ci8Hi4N207) C, H, N.
A35-f intermediate 41 : N-(4-Fluorobenzyl)-2-benzyloxy-3-hvdroxy-7-nitro-l-oxo-L2- dihydro- isoquinoline-4-carboxamide
Figure imgf000087_0001
A solution of intermediate 40 (0.37 g, 1.0 mmol) and 4-fluorobenzylamine (0.62 g, 5.0 mmol) in toluene (15.0 mL) was refluxed for 12 h using a Dean Stark apparatus. After cooling, the solution was concentrated in vacuo. The residue was dissolved in EtOAc. The organic layer was washed with 2.0 M HCl and dried over Na2S04. During the washings, an amount of intermediate 41 precipitated and was isolated by filtration. After concentration in vacuo, the residue was triturated with ether and the precipitate was filtered and dried at room temperature. Orange solid. Yield: 75%; mp 183-185 °C; 100% enol form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.48 (d, 2 H, NHCH2, 3J = 5.6 Hz), 5.06 (s, 2 H, OCH2), 7.15 (t, 2 H, UA^JH-H = 3JH-F = 8.8 Hz), 7.40 (m, 5 H, HAr), 7.62 (m, 2 H, HAr), 8.01 (dd, 1 H, ¾, 3JH6.H5 = 9.7 Hz, 4JH6-H8 = 2.3 Hz), 8.78 (d, 1H, ¾, 4JH8-H6 = 2.3 Hz), 9.40 (d, 1H, H5> 3JH5-H6 = 9.7 Hz), 10.35 (t, 1H, NH, 3J = 5.6 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 41.2 (NHCH2), 76.6 (OCH2), 90.2 (C4), 114.9 (d, 2 CH, 2JC-F = 20.7 Hz), 115.8 (Civ), 123.6 (CH), 124.1 (CH), 124.6 (CH), 128.2 (2 CH), 128.5 (CH); 129.21 (2 CH), 129.22 (d, 2 CH, 3JC-F = 7.6 Hz), 135.3 (Crv), 137.0 (d, Crv, 4JC-F = 3.3 Hz), 137.7 (Crv), 144.5 (C7), 159.2 (CO), 161.0 (d, Civ, JC-F = 240.0 Hz), 161.5 (CO), 167.8 (CO); ESI-MS: m/z = 464 (M+H)+; Anal. (C24Hi8FN306) C, H, N.
EXAMPLE A36
The process followed in this example is the same as described in example A35
EXAMPLE A37
A37-a intermediate 42: N-Hexyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
Figure imgf000088_0001
A solution of intermediate 40 (0.37 g, 1.0 mmol) and hexylamine (5.0 mmol) in toluene (15.0 mL) was refluxed for 12 h using a Dean Stark apparatus. The work-up is identical to the one reported for the synthesis of intermediate 41 (A35-f). Orange solid. Yield: 97%; mp 155-156 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6): δ = 0.88 (m, 3 H, CH3), 1.31 (m, 6 H, CH2), 1.49 (m, 2 H, CH2), 3.24 (t, 2 H, CH2, 3JH-H = 6.3 Hz), 5.03 (s, 2 H, OCH2), 7.40-7.42 (m, 2 H, HAr), 7.61-7.63 (m, 3 H, HAr), 7.97 (d, 1 H, ¾, 3JH(6)-H(5) = 10.3 Hz), 8.74 (s, 1H, ¾), 9.32 (d, 1H, H5, 3 JH(S)-H(6) = 10.3 Hz); 13C MR(75 MHz, DMSO-i¾): δ = 14.4 (CH3), 22.6 (CH2), 26.9 (CH2), 29.9 (CH2), 31.5 (CH2), 38.9 (CH2), 77.1 (OCH2), 90.6 (C4), 116.4 (Civ), 124.1 (CHAr), 124.6 (CHAr), 125.1 (CHAr), 128.7 (2 CHAr), 128.9 (CHAr ), 129.7 (2 CHAr ), 135.7 (Civ), 138.3 (Civ), 144.6 (C7), 159.6 (CO), 161.8 (CO), 168.2 (CO) ; ESI-MS: m/z = 440 (M+H)+; Anal. (C23H25N306) C, H, N.
EXAMPLE A38
A38-a intermediate 43 : N-Phenyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-l,2- dihydroisoquinoline-4-carboxamide
Figure imgf000088_0002
A solution of intermediate 40 (0.37 g, 1.0 mmol) and aniline (5.0 mmol) in toluene (15.0 mL) was refluxed for 12 h using a Dean Stark apparatus. The work-up is identical to the one reported for the synthesis of intermediate 41 (A35-f). Yellow solid. Yield: 77%; mp
169-171 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6): δ = 5.10 (s, 2 H, OCH2), 6.98 (t, 1 H, HAr 3JH-H = 7.2 Hz), 7.30 (t, 2 H, HAr 3JH-H = 7.9 Hz), 7.40-7.47 (m, 3 H, HAr), 7.65-7.69 (m, 4 H, HAr), 8.08 (dd, 1 H, H6, 3 JH(6)-H(5) = 9.8 Hz, 4JH(6)-H(8) = 2.5 Hz), 8.79 (d, 1 H, ¾, 4JH(8)-H(6) = 2.5 Hz), 9.42 (d, 1 H, H5, 3 JH(5)-H(6) = 9.8 Hz), 12,41 (s, 1 H, OH); 1JC NMR (75MHz, OMSO-d6): δ = 76.7 (OCH2), 90.1 (C4), 1 16.5 (Cr), Π9.3 (2 CHAr), 121.9 (CHAr), 123.8 (CHAr), 123.9 (CHAr), 124.9 (CHAr), 128.3 (3 CHAr), 128.7 (2 CHAr), 129.3 (2 CHAr), 135.2 (Civ), 138.4 (Civ), 140.2 (Civ), 144.3 (C7), 159.0 (CO), 161.8 (CO), 166.0 (CO); ESI-MS: m/z = 432 (M+H)+; Anal. (C23Hi7N306) C, H, N.
EXAMPLE A39
A39-a intermediate 44: N-(4-Fluorophenyl)-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
Figure imgf000089_0001
A solution of intermediate 40 (0.37 g, 1.0 mmol) and aniline (5.0 mmol) in toluene (15.0 mL) was refluxed for 12 h using a Dean Stark apparatus. The work-up is identical to the one reported for the synthesis of intermediate 41 (A35-f). Beige solid. Yield: 89%; mp 189-190 °C; 100% enol form; 1H NMR (300 MHz, DMSO-i¾): 5 = 5.1 1 (s, 2 H, OCH2), 7.1 1-7.13 (m, 2 H, HAr), 7.31-7.43 (m, 5 H, HAr), 7.65-7.71 (m, 2 H, HAr), 8.09 (d, 1 H, ¾, 3JH(6)-H(5) = 9.8 Hz), 8.80 (s, 1 H, ¾), 9.42 (d, 1 H, H5> 3JH(5)-H(6) = 9.8 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 77.2 (OCH2), 90.3 (C4), 1 15.6 (d, Cy et C5>, 2JC-F = 21.3 Hz), 1 17.0 (Civ), 121.3 (d, C2 > and C6% 3JC-F = 7.6 Hz), 124.2 (CHAr), 124.4 (CHAr), 125.5 (CHAr), 128.8 (2 CHAr), 129.0 (CHAr), 129.8 (2 CHAr), 135.7 (Civ), 137.1 (Civ), 138.9 (Civ), 144.9 (C7), 156.2 (CO), 159.6 (CO), 161.0 (d, C4>, 1JC-F = 252.0 Hz), 166.5 (CO); ESI-MS: m/z = 450 (M+H)+; Anal. (C23Hi6FN306) C, H, N.
EXAMPLE A40
A40-a intermediate 45 : N-Benzyl-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
Figure imgf000089_0002
A solution of intermediate 40 (0.37 g, 1.0 mmol) and benzylamine (5.0 mmol) in toluene (15.0 mL) was refluxed for 12 h using a Dean Stark apparatus. The work-up is identical to the one reported for the synthesis of intermediate 41 (A35-f). Orange solid. Yield: 62%; mp 178-181 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6): δ = 4.49 (s, 2 H, CH2), 5.04 (s, 2 H, OCH2), 7.31- 7.44 (m, 8 H, HAr), 7.61 (d, 2 H, HAr, 3JH-H = 7.3 Hz), 8.00 (dd, 1 H, H6,
Figure imgf000090_0001
9.5 Hz, 4JH(6)-H(8) = 1.8 Hz), 8.76 (d, 1H, ¾, 4JH(8)-H(6) = 1.8 Hz), 9.38 (d, 1 H, H5, 3JH(5)-H(6) = 9.5 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 42.6 (CH2), 77.1 (OCH2), 90.5 (C4), 1 16.5 (Civ), 124.2 (CHAr), 124.5 (CHAr), 125.2 (CHAr), 127.1 (CHAr), 127.8 (3 CHAr), 128.7 (2 CHAr), 128.8 (2 CHAr), 129.8 (2 CHAr), 135.7 (Civ), 138.4 (Civ), 141.0 (Civ), 144.7 (C7), 159.6 (CO), 162.0 (CO), 168.3 (CO); ESI-MS: m/z = 446 (M+H)+; Anal. (C24H19N306) C, H, N.
EXAMPLE A41
A41-a intermediate 46: N-(4-Methoxybenzyl)-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
Figure imgf000090_0002
A solution of intermediate 40 (0.37 g, 1.0 mmol) and 4-methoxybenzylamine (5.0 mmol) in toluene (15.0 mL) was refluxed for 12 h using a Dean Stark apparatus. The work-up is identical to the one reported for the synthesis of intermediate 41 (A35-f). Yellow solid. Yield: 74%; mp 180 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6): δ = 3.74 (s, 3 H, OCH3), 4,41 (s, 2 H, CH2), 5.03 (s, 2 H, OCH2), 6,90 (d, 2 H, HAr 3JH-H = 8.3 Hz), 7.28 (d, 2 H, HAr 3JH-H = 8.3 Hz), 7.40-7.42 (m, 3 H, HAr), 7.59-7.62 (m, 2 H, HAr), 8.00 (dd, 1 H, ¾, 3JH(6)-H(5) = 9.8 Hz, 4JH(6)-H(8) = 2.0 Hz), 8.76 (d, 1 H, ¾, 4JH(8)-H(6) = 2.0 Hz), 9.38 (d, 1 H, ¾, 3JH(5)-H(6) = 9.8 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 42.1 (CH2), 55.5 (OCH3), 77.1 (OCH2), 90.5 (C4), 1 14.2 (C and C5 ), H6.6 (Civ), 124.2 (CHAr), 124.6 (CHAr), 125.2 (CHAT), 128.7 (2 CHAr), 129.0 (CHAr), 129.2 (CY and C6 , 129.7 (2 CHAr), 132.8 (Civ), 135.7 (Civ), 138.4 (Civ), 144.8 (C7), 158.6 (CO), 159.6 (CO), 161.9 (CO), 168.2 (CO); ESI-MS: m/z = 476 (M+H)+; Anal. (C25H2iN307) C, H, N.
EXAMPLE A42 A42-a intermediate 47: N-(4-Fluorophenethyl)-2-benzyloxy-3-hydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
Figure imgf000091_0001
A solution of intermediate 40 (0.37 g, 1.0 mmol) and 4-fluorophenethylamine (5.0 mmol) in toluene (15.0 mL) was refluxed for 12 h using a Dean Stark apparatus. The work-up is identical to the one reported for the synthesis of intermediate 41 (A35-f). Yellow solid. Yield: 81%; mp 171-173 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6): δ = 2.81 (t, 2 H, 3JH-H = 6.8 Hz), 3.48 (t, 2 H, 3JH-H = 6.8 Hz), 5.03 (s, 2 H, OCH2), 7.13 (t, 2 H, H and H5', 3JH-H = 3JH-F = 8.8 Hz); 7.30-7.34 (m, 2 H, HAr), 7.39-7.45 (m, 3 H, HAr), 7.61-7.63 (m, 2 H, HAT), 7.99 (d, 1 H, ¾, 3JH(6)-H(5) = 9.4 Hz), 8.75 (s, 1 H, ¾), 9.32 (d, 1 H, H5> 3JH(5)- H(6) = 9.4 Hz), 9.77 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-i¾): δ = 35.4 (CH2), 40.7 (CH2), 77.1 (OCH2), 90.7 (C4), 115.4 (d, C and C5>, 2JC-F = 20.7 Hz), 116.3 (Civ), 124.1 (CHAr), 124.6 (CHAr), 125.1 (CHAr), 128.7 (2 CHAr), 129.0 (CHAr), 129.8 (2 CHAr), 130.9 (d, C2- and C6% 3JC-F = 7,6 Hz), 135.7 (Civ), 136.6 (d, Cr, 4JC-F = 1.6 Hz), 138.2 (Civ), 144.8 (C7), 159.6 (CO), 161.2 (d, C4>, 1JC-F = 242.7 Hz), 161.8 (CO), 168.2 (CO); ESI-MS: m/z = 478 (M+H)+; Anal. (C25H2oFN306) C, H, N.
EXAMPLE A43
A43-a intermediate 48: Methyl 5-amino-2-{ L3-dimethoxy-L3-dioxopropan-2-yl|benzoate
Figure imgf000091_0002
Intermediate 38 (4.0 g, 12.9 mmol) was dissolved in methanol (100 mL) and hydrogenated for 12 h at room temperature over Pd/C 5% (0.4 g). The catalyst was filtered and the solvent was removed in vacuo. Pink solid. Yield: 95%; mp 89-90 °C; 1H NMR (300 MHz, CDCI3): δ = 3.79 (s, 6 H, 2 OCH3), 3.88 (s, 3 H, OCH3), 5.63 (s, 1 H, CH), 6.84 (d, 1 H, ¾, 3J H(3)-H(4) = 8.3 Hz), 7.21 (dd, 1 H, H4,
Figure imgf000092_0001
8.3 Hz and 4JH(4)-H(6)= 2.2 Hz), 7.32 (d, 1 H, H6, 4JH(6)-H(4) = 2.2 Hz); 13C NMR (75 MHz, CDC13): δ = 52.2 (2 OCH3), 52.7 (OCH3), 54.1 (CH), 116.9 (CHAr), 1 18.7 (CHAr), 123.2 (Civ), 130.1 (Civ), 131.0 (CHAr), 146.6 (C5), 167.5 (CO), 169.6 (2 CO).
A43-b intermediate 49: Methyl 5-acetamido-2-{ l,3-dimethoxy-l,3-dioxopropan-2- yllbenzoate
Figure imgf000092_0002
Acetyl chloride (1.1 mL, 16.0 mmol) was added to a solution of intermediate 48 (3.0 g, 10.7 mmol) in dichloromethane (50 mL). After stirring for 4 h at room temperature, the solution was washed with aqueous 1.0 M HCl. The organic phase was dried over Na2S04.
The solvent was removed under reduced pressure to give an oily residue, which was triturated in ether. After filtration, a white powder was obtained (96%); mp 81-83 °; 1H
NMR (300 MHz, OMSO-d6): δ = 2.06 (s, 3 H, CH3), 3.68 (s, 6 H, 2 OCH3), 3.80 (s, 3 H, OCH3), 5.49 (s, 1 H, CH), 7.26 (d, 1 H, ¾, 3J H(3)-H(4) = 8.5 Hz), 7.80 (dd, 1 H, ¾, 3JH(4)-H(3)
= 8.5 Hz and 4JH(4)-H(6) = 1.9 Hz), 8.20 (d, 1 H, ¾, 4JH(6)-H(4)= 1.9 Hz), 10.24 (s, 1H, NH);
NMR 13C (75 MHz, OMSO-d6): δ = 23.9 (CH3), 52.3 (OCH3), 52.6 (2 OCH3), 54.3 (CH),
120.6 (CHAT), 122.6 (CHAr), 128.0 (Civ), 129.6 (Civ), 130.7 (CHAr), 139.1 (C5), 166.6
(CO), 168.4 (2 CO), 168.7 (CO).
A43-c intermediate 50: Methyl 5-acetamido-2-{ 1 (benzyloxy)amino1-3-methoxy-l,3- dioxopropan-2-yl Ibenzoate
Figure imgf000093_0001
The process followed in this step is the same as described in example A35d. White powder (28%); mp 60-62 °C; 1H NMR (300 MHz, OMSO-d6): δ = 2.06 (s, 3 H, CH3), 3.63 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 4.81 (s, 2 H, OCH2), 5.11 (s, 1 H, CH), 7.36 (s, 6 H, H3 and HAT), 7.73 (dd, 1 H, H4, 3JH(4)-H(3) = 8.5 Hz and 4JH(4)-H(6) = 1.9 Hz), 8.20 (d, 1H, ¾, 4JH(6)- H(4)= 1.9 Hz), 10.20 (s, 1 H, H), 11.46 (s, 1 H, H), NMR 13C (75 MHz, DMSO-d6): δ = 23.9 (CH3), 52.1 (OCH3), 52.24 (OCH3), 52.25 (CH), 76.8 (OCH2), 120.4 (CHAr), 122.5 (CHAT), 128.27 (2 CHAr), 128.32 (CHAr), 128.9 (2 CHAr), 129.0 (Civ), 129.6 (Civ), 129.9 (CHAT), 135.7 (Civ), 138.7 (C5), 164.4 (CO), 166.7 (CO), 168.7 (2 CO); ESI-MS: m/z = 415 (M+H)+.
A43-d intermediate 51 : Methyl 7-acetamido-2-(benzyloxy)-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxylate
Figure imgf000093_0002
The process followed in this step is the same as described in example A35e. Yellow powder (70%); 100% keto form; mp 197-199 °C; 1H NMR (300 MHz, DMSO-i¾): δ = 2009 (s, 3 H, CH3), 3.71 (s, 3 H, OCH3), 5.05 (s, 2 H, OCH2), 5.37 (s, 1 H, H4), 7.36 - 7.42 (m, 4 H, HAT), 7.54-7.57 (m, 2 H, HAr), 7.89 (d, 1 H, H3, ' ½(3)-Η(4) _ 8.6 Hz), 8.40 (d, 1 H, ¾, 4JH(6)-H(4) = 1.9 Hz), 11.34 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-i¾): δ = 24.0 (CH3), 53.5 (OCH3), 54.0 (C4), 77.5 (OCH2), 117.7 (CHAr), 124.7 (CHAr), 125.0 (Civ), 126.3 (Civ), 127.9 (CHAr), 128.4 (2 CHAr), 129.0 (CHAr), 129.5 (2 CHAr), 134.2 (Civ), 139.8 (C5), 160.4 (CO), 163.0 (CO), 167.3 (CO), 168.8 (CO); ESI-MS: m/z = 383 (M+H)+; Anal. (C20Hi8N2O6) C, H, N. A43-e intermediate 52: N-(4-fluorobenzyl)-7-acetamido-2-(benzyloxy)-L3-dioxo-L2,3,4- tetrah droiso uinoline-4-carboxamide
Figure imgf000094_0001
The process followed in this step is the same as described in example A35f. Beige powder (78%); 100% keto form; mp 218-220 °C; 1H NMR (300 MHz, OMSO-d6): δ =
2.10 (s, 3 H, CH3), 4.37 (dd, 1 H, CH2, 2JH-H = 14.6 Hz and 3JH-H = 5.4 Hz), 4.38 (dd, 1 H, CH2, 2JH-H = 14.6 Hz and 3JH-H = 5.4 Hz), 5.02 (s, 2 H, OCH2), 5.18 (s, 1 H, H4), 7.23 (t, 2 H, H3 > and ¾<, 3JH-H = 8.9 Hz and 3JH-F = 8.9 Hz), 7.34 - 7.63 (m, 8 H, HAr), 7.94 (d, 1 H, H , 3JH-H = 8.0 Hz), 8.41 (s, 1 H, HAr), 9.33 (t, 1 H, NH, 3JH-H= 5.4 Hz), 10.36 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-d6): δ = 24.5 (CH3), 42.4 (CH2), 55.7 (C4), 77.8 (OCH2), 1 15.6 (d, Cy and C5 2JC-F = 21.8 Hz), 1 18.1 (CHAr), 125.0 (CHAr), 126.1 (Civ), 127.8 (CHAr), 128.9 (2 CHAr), 129.2 (Civ), 129.4 (CHAr), 129.7 (2 CHAr), 129.8 (d, Cr and C6% 3JC-F = 8.2 Hz), 131.0 (Civ), 135.0 (Civ), 139.8 (Civ), 161.4 (CO), 161.8 (d, C4 >, ^C-F = 240.5 Hz), 165.0 (CO), 166.7 (CO), 169.0 (CO); ESI-MS: m/z = 476 (M+H)+; Anal. (C26H22FN305) C, H, N.
EXAMPLE A44
Figure imgf000094_0002
The process followed in this step is the same as described in example A43b using phenylacetyl chloride (instead of acetyl chloride). White powder (76%); mp 126-128 °C; ¾ NMR (300 MHz, DMSO-i¾): δ = 3.36 (s, 6 H, 2 OCH3), 3.68 (s, 3 H, OCH3), 3.80 (s, 2 H, OCH2), 5.51 (s, 1 H, CH), 7.27 (d, 1 H, H3, 3J H(3)-H(4) = 8.2 Hz), 7.33 (s, 5 H, HAr), 7.82 (dd, 1 H, ¾, 3 JH(4)-H(3) = 8.5 Hz and 4JH(4)-H(6) = 1.9 HZ ), 8.24 (d, 1H, ¾, 4JH(6)-H(4) = 1.9 Hz), 10.49 (s, 1H, H); MR 13C (75 MHz, OMSO-d6): δ = 43.7 (CH2), 52.8 (OCH3), 53.1 (2 OCH3), 54.8 (CH), 121.2 (CHAr), 123.2 (CHAr), 127.1 (CHAr), 128.8 (Civ), 128.8 (2 CHAr), 129.6 (2 CHAr), 130.2 (Civ), 131.2 (CHAr), 136.1 (Civ), 139.5 (C5), 167.1 (CO), 168.9 (2 CO), 170.1 (CO).
A44-b intermediate 54: Methyl 2-{ l-r(benzyloxy)amino1-3-methoxy-1.3-dioxopropan-2- yl|-5-(2-phenylacetamido)benzoate
Figure imgf000095_0001
The process followed in this step is the same as described in example A35d. Light yellow powder (25%); mp 65-70 °C; 1H NMR (300 MHz, OMSO-d6 ): δ = 3.63 (s, 3 H, OCH3), 3.66 (s, 2 H, CH2), 3.79 (s, 3 H, OCH3), 4.81 (s, 2 H, OCH2), 5.13 (s, 1H, CH), 7.33-7.39 (m, 11 H, H3 and HAr), 7.76 (dd, 1 H, H4, 3JH(4)-H(3) = 8.6 Hz and 4JH(4)-H(6) = 2.3 Hz ), 8.23 (d, 1 H, H6, 4JH(6)-H(4) = 2.3 Hz), 10.46 (s, 1 H, NH), 11.47 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-i¾): δ = 43.7 (CH2), 52.71 (CH), 52.73 (2 OCH3), 77.3 (OCH2), 121.0 (CHAr), 123.1 (CHAT), 127.1 (CHAr), 128.7 (2 CHAr), 128.8 (3 CHAr), 129.4 (2 CHAr), 129.6 (2 CHAr), 129.8 (Civ), 130.1 (Civ), 130.5 (CHAr), 136.1 (Civ), 136.2 (Civ), 139.1 (C5), 164.9 (CO), 167.1 (CO), 169.4 (CO), 170.0 (CO); ESI-MS: m/z = 491 (M+H)+.
A44-c intermediate 55: Methyl 2-(benzyloxy)- 7-phenylacetamido -1.3-dioxo-l.2.3.4- tetrahydroisoquinoline-4-carboxylate
Figure imgf000096_0001
The process followed in this step is the same as described in example A35e. White powder (80%); 100% keto form; mp 187-196 °C; 1H NMR (300 MHz, OMSO-d6): δ =
3.70 (s, 3 H, OCH3), 3.99 (s, 2 H, CH2), 5.05 (s, 2 H, OCH2), 5.38 (s, 1 H, H4), 7.26-7.35 (m, 8 H, HAT), 7.54-7.56 (m, 3 H, HAr), 7.92 (d, 1 H, HAr, 3JH-H = 8.2 Hz), 8.42 (s, 1 H, HAr), 10.61 (s, 1 H, H); NMR 13C (75 MHz, DMSO-d6): δ = 43.8 (CH2), 54.0 (OCH3), 54.5 (C4), 77.9 (OCH2), 118.4 (CHAr), 125.3 (CHAr), 125.6 (Civ), 127.1 (CHAr), 128.5 (CHAr), 128.8 (2 CHAr), 128.9 (2 CHAr), 129.6 (3 CHAr), 130.0 (2 CHAr), 134.7 (Civ), 136.1 (Civ), 136.3 (Civ), 140.1 (C5), 160.8 (CO), 163.5 (CO), 167.7 (CO), 170.1 (CO);
ESI-MS: m/z = 459 (M+H)+.
A44-d intermediate 56: N-(4-fluorobenzyl)-2-(benzyloxy)-l,3-dioxo-7-phenylacetamido- 1,2,3, 4-tetrahydroisoquinoline-4-carboxamide
Figure imgf000096_0002
The process followed in this step is the same as described in example A35f. White powder (80%); 100% keto form; mp 225-229 °C; 1H NMR (300 MHz, OMSO-d6): δ =
3.69 (s, 2 H, CH2), 4.31 (dd, 1 H, CH2, 2JH-H = 14.6 Hz and 3JH-H = 5.7 Hz), 4.32 (dd, 1 H, CH2, 2JH-H = 14.6 Hz and 3JH-H = 5.7 Hz), 5.00 (s, 2 H, CH2), 5.13 (s, 1 H, H4), 7.17 (t, 2 H, H4" and ¾», 3JH-F = 3JH-H = 8.6 Hz), 7.26 - 7.37 (m, 8 H, HAr), 7.41 - 7.43 (m, 3 H, HAr), 7.55 -7.58 (m, 2 H, HAr ), 7.92 (d, 1 H, HAr, 3JH-H = 8.3 Hz), 8.36 (s, 1H, ¾), 9.27 (t, 1 H, NH, 3JH-H = 5.7 Hz), 10.55 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-^): δ = 42.4 (CH2), 43.7 (CH2), 55.7 (C4), 77.8 (OCH2), 115.6 (d, C3- and C5», 2JC-F = 21.3 Hz), 118.2 (CHAr), 125.1 (CHAr), 126.1 (Civ), 127.1 (CHAr), 127.8 (CHAr), 128.8 (2 CHAr), 128.9 (2 CHAr), 129.3 (CHAr), 129.5 (Civ), 129.6 (2 CHAr), 129.7 (d, C2- and C6 », 3JC-F = 7.6 Hz), 129.9 (2 CHAr), 134.9 (Civ), 135.2 (d, Ci», 4JC-F = 2.7 Hz), 136.1 (Civ), 139.6 (Civ), 161.3 (CO), 161.8 (d, C4 »,1JC-F = 241.1Hz), 164.9 (CO), 166.6 (CO), 170.0 (CO); ESI-MS: m/z = 552 (M+H)+; Anal. (C32H26FN3O5) C, H, N.
EXAMPLE A45
A45-a intermediate 57: Methyl 5-benzamido-2-{ l -dimethoxy-L3-dioxopropan-2- yllbenzoate
Figure imgf000097_0001
The process followed in this step is the same as described in example A43b using benzoyl chloride (instead of acetyl chloride). White powder (67%); mp 135-137 °C; 1H NMR (300 MHz, DMSO-i¾): δ = 3.71 (s, 6 H, 2 OCH3), 3.87 (s, 3 H, OCH3), 5.60 (s, 1 H, CH), 7.35- 7.37 (m, 1 H, HAr), 7.58-7.61 (m, 3 H, HAr), 8.02-8.06 (m, 3 H, HAr), 8.49 (s, 1 H, HAr), 10.59 (s, 1 H, NH), NMR 13C (75 MHz, OMSO-d6): δ = 52.3 (OCH3), 52.6 (2 OCH3), 54.4 (CH), 122.0 (CHAr), 123.9 (CHAr), 127.7 (2 CHAr), 128.4 (2 CHAr), 128.7 (Civ), 129.6 (Civ), 130.7 (CHAr), 131.9 (CHAr), 134.4 (Civ), 139.1 (C5), 165.8 (CO), 166.7 (CO), 168.5 (2 CO).
A45-b intermediate 58: Methyl 5-benzamido-2-{ l-r(benzyloxy)amino1-3-methoxy-L3- dioxopropan-2-yl Ibenzoate
Figure imgf000098_0001
The process followed in this step is the same as described in example A35d. Light yellow powder (23%); mp 85-94 °C; 1H NMR (300 MHz, DMSO-^ ): δ = 3.66 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 4.84 (s, 2 H, OCH2), 5.17 (s, 1 H, CH), 7.38 (m, 6 H, HAr), 7.56 (m, 3 H, HAT), 7.99 (m, 3 H, HAr), 8.43 (s, 1 H, HAr), 10.52 (s, 1 H, NH), 11.50 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-d6): δ = 52.77 (2 OCH3), 52.78 (CH), 77.3 (OCH2), 122.3 (CHAT), 124.4 (CHAT), 128.2 (2 CHAr), 128.8 (2 CHAr), 128.9 (3 CHAr), 129.5 (2 CHAr), 130.0 (Civ), 130.2 (Civ), 130.4 (CHAr), 132.3 (CHAr), 134.9 (Civ), 136.2 (Civ), 139.2 (C5), 164.9 (CO), 166.2 (CO), 167.2 (CO), 169.4 (CO); ESI-MS: m/z = 491 (M+H)+.
A45-c intermediate 59: Methyl 7-benzamido-2-(benzyloxy)-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline- -carboxylate
Figure imgf000098_0002
The process followed in this step is the same as described in example A35e. Orange powder (83%); 100% keto form; mp 185-187 °C; 1H NMR (300 MHz, OMSO-d6): δ = 3.86 (s, 3 H, OCH3), 5.07 (s, 2 H, OCH2), 5.42 (s, 1 H, H4), 7.29-7.42 (m, 3 H, HAr), 7.57- 7.75 (m, 5 H, HAr), 7.91-8.02 (m, 3 H, HAr), 8.42 (d, 1 H,HAr, 3JH-H = 8.0 Hz), 8.62 (d, 1 H,HAr, 4JH-H = 2.5 Hz), 10.41 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-^): δ =
54.0 (OCH3), 54.5 (C4), 78.0 (OCH2), 119.6 (CHAr), 125.5 (Civ), 126.5 (CHAr), 127.5 (Civ), 128.2 (2 CHAr), 128.4 (CHAr), 128.9 (2 CHAr), 129.0 (2 CHAr), 129.4 (CHAr), 130.0 (2 CHAr), 132.4 (CH), 134.7 (Civ), 134.8 (Civ), 140.2 (C7), 160.9 (CO), 163.5 (CO), 166.3 (CO), 167.8 (CO); ESI-MS: m/z = 445 (M+H)+.
A45-d intermediate 60: N-(4-fluorobenzyl)-7-benzamido-2-(benzyloxy)-L3-dioxo-L2,3,4- tetrah droiso uinoline-4-carboxamide
Figure imgf000099_0001
The process followed in this step is the same as described in example A35f. Beige powder
(54%); 100% keto form; mp 242-244 °C; 1H NMR (300 MHz, OMSO-d6): δ = 4.33 (s, 2 H, CH2), 5.03 (s, 2 H, OCH2), 5.18 (s, 1 H, ¾), 7.20 (t, 2 H, H3- and H5 » , 3JH-H = 3JH-F = 8.7 Hz), 7.31-7.58 (m, 1 1 H, HAr), 8.01-8.04 (m, 2 H, HAr), 8.14 (s, 1 H, HAr), 8.57 (s, 1 H, HAT), 9.30 (s, 1 H, H), 10.62 (s, 1 H, H); NMR 13C (75 MHz, OMSO-d6): δ = 42.5 (CH2), 55.7 (C4), 77.8 (OCH2), 1 15.6 (d, C3 » and C5 » , 2JC-F = 21.3 Hz), 1 19.5 (CHAr), 126.1 (Civ), 126.3 (CHAr), 127.6 (CHAr), 128.2 (2 CHAr), 128.9 (2 CHAr), 129.0 (2 CHAr), 129.3 (CHAr), 129.7 (d, C2" and C6 » 3JC-F = 8.2 Hz), 129.9 (2 CHAr), 132.4 (CHAr), 134.8 (Civ), 134.9 (Civ), 135.1 (Civ), 135.2 (d, Cr>, 4JC-F = 2.7 Hz), 139.7 (C7), 161.4 (CO), 161.8 (d, C4 », 1JC-F = 241.0 Hz), 165.0 (CO), 166.2 (CO), 166.7 (CO); ESI-MS: m/z = 538 (M+H)+; Anal. (C3iH24FN305) C, H, N.
EXAMPLE A46
A46-a intermediate 61 : Methyl 2-{ L3-dimethoxy-L3-dioxopropan-2-yl|-5-
Figure imgf000100_0001
Thionyl chloride (1.1 mL, 15.7 mmol) was added dropwise to a cooled solution of 2- picolinic acid (1.05 g, 8.5 mmol) in a mixture of ethyl acetate (25 mL) and N,N- dimethylformamide (5 mL). After 1 h reflux, the volatiles were removed in vacuo and the crude acid chloride was dissolved in a mixture of ethyl acetate (25 mL) and N,N- dimethylformamide (5 mL). Diisopropylethylamine (3.5 mL, 21.4 mmol) and intermediate 48 (2.0 g, 7.1 mmol) were added. After 12 h stirring at room temperature, the solution was washed several times with 1.0 M NaHC03 and 1.0 M HC1. The organic phase was dried over Na2S04 and concentrated in vacuo. Organic residues were triturated with ether and insoluble materials were filtered. Pink solid (81%); mp 153-155 °C; 1H NMR (300 MHz, CDC13): δ = 3.81 (s, 6 H, 2 OCH3), 3.94 (s, 3 H, OCH3), 5.77 (s, 1 H, CH), 7.47 (d, 1 H, H3, 3J H(3)-H(4) = 8.5 Hz), 7.55 (ddd, 1 H, HAr, 3JH-H = 7.7 Hz, 3JH-H = 4.8 Hz and 4JH-H = 1.2 Hz), 7.97 (td, 1 H, HAr, 3JH-H = 7.7 Hz and 4JH-H = 1,6 Hz), 8.06 (dd, 1 H, H4, 3JH(4)-H(3) = 8.5 Hz and 4JH(4)-H(6) = 2.4 Hz), 8.34 (d, 1 H, H2>, 3JH(2 H(3') = 7.7 Hz), 8,45 (d, 1 H, ¾, 4JH(6)-H(4) = 2.4 Hz), 8.66 (d, 1 H, ¾·, 3JH(5>H(4 <) = 4.7 Hz), 10.22 (s, 1 H, NH); NMR 13C (75 MHz, CDC13): δ = 52.9 (OCH3), 53.2 (2 OCH3), 54.9 (CH), 122.7 (CHAr), 123.1 (CHAT), 124.7 (CHAr), 127.6 (CHAr), 129.5 (Civ), 130.2 (Civ), 131.1 (CHAr), 138.7 (CHAr), 138.8 (Cs), 148.9 (CHAr), 150.0 (Cr), 163.4 (CO), 167.2 (CO), 168.9 (2 CO); ESI-MS: m/z = 387 (M+H)+.
A46-b intermediate 62: Methyl 2-{ l-r(benzyloxy)aminol-3-methoxy-1.3-dioxopropan-2- yll-5-picolinamidobenzoate
Figure imgf000101_0001
The process followed in this step is the same as described in example A35d. White powder (20%); mp 207-208 °C; 1H NMR (300 MHz, CDC13): δ = 3.75 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 4.90 (s, 2 H, OCH2), 5.27 (s, 1 H, CH), 7.33 (s, 5 H, HAr), 7.60 (dd, 1 H, HAr, 3JH-H = 6.1 HZ and 3JH-H = 6.7 Hz), 7.71 (d, 1 H, HAr, 3JH-H = 7.9 Hz), 7.94-8.04 (m, 2 H, HAT), 8.38 (d, 1 H, HAr, 3½-H = 7.9 Hz), 8.55 (s, 1 H, HAr), 8.67 (d, 1 H, HAr, 4JH-H = 4.4 Hz), 9.65 (s, 1 H, NH), 10.33 (s, 1 H, ¾_NMR 13C (75 MHz, CDC13): δ = 52.7 (CH), 52.8 (2 OCH3), 77.3 (OCH2), 122.4 (CHAr), 123.0 (CHAr), 124.7 (CHAr), 127.6 (CHAr), 128.78 (2 CHAr), 128.84 (CHAr), 129.5 (2 CHAr), 130.1 (Civ), 130.3 (CHAr), 130.5 (Civ), 136.2 (Civ), 138.4 (C5), 138.7 (CHAr), 149.0 (CHAr), 150.1 (Cr), 163.4 (CO), 164.9 (CO), 167.2 (CO), 169.4 (CO); ESI-MS: m/z= 478 (M+H)+.
A46-c intermediate 63 : Methyl 2-(benzyloxy)-L3-dioxo-7-picolinamido-L2,3,4- tetrahydroisoquinoline- -carboxylate
Figure imgf000101_0002
The process followed in this step is the same as described in example A35e. Beige powder (51%); 100% keto form; mp 177-180 °C; 1H NMR (300 MHz, DMSO-i¾): δ =
4.13 (s, 3 H, OCH3), 5.30 (s, 2 H, OCH2), 5.31 (s, 1H, H4), 7.42-7.43 (m, 4 H, HAr), 7.56 - 7.65 (m, 3 H, HAr), 7.98 (t, 1 H, HAr, 3J= 7.6 Hz), 8.36 (d, 1 H, HAr, 3JH-H = 7.7 Hz), 8.41 - 8.49 (m, 2 H, HAr), 8.68 (s, 1 H, HAr), 10.32 (s, 1H, NH); NMR 13C (75 MHz, DMSO-i¾): δ = 54.1 (OCH3), 54.5 (C4), 78.0 (OCH2), 119.9 (CHAr), 123.1 (CHAr), 125.5 (Civ), 126.9 (CHAr), 127.7 (CHAr), 127.8 (Civ), 128.3 (CHAr), 130.0 (2 CHAr), 129.4 (CHAr), 130.1 (2 CHAr), 134.7 (Civ), 138.7 (CHAr), 139.5 (Civ), 149.0 (CHAr), 150.0 (Cr), 160.8 (CO), 163.5 (CO), 163.6 (CO), 167.7 (CO); ESI-MS: m/z= 446 (M+H)+; Anal. (C24Hi9N306) C,
H, N.
A46-d intermediate 64: N-(4-fluorobenzyl)- 2-(benzyloxy)-l,3-dioxo-7-picolinamido-
I, 2,3, 4-tetrahydroisoquinoline-4-carboxamide
Figure imgf000102_0001
The process followed in this step is the same as described in example A35f. Beige powder (64%); 100% keto form; mp 240-243 °C; 1H MR (300 MHz, OMSO-d6): δ = 4.33 (dd, 1 H, CH2, 2JH-H = 19.7 Hz and 3JH-H = 5.7 Hz), 4.34 (dd, 1 H, CH2, 2JH-H = 19.7 Hz and 3JH-H = 5.7 Hz), 5.02 (d, 1 H, OCH2, 2JH-H = 15.0 Hz), 5.03 (d, 1 H, OC¾ 2JH-H = 15.0 Hz), 5.17 (s, 1 H, H4), 7.18 (t, 2 H, H3 » and ¾», 3JH-H = 3½-F = 8.9 Hz), 7.31 (dd, 2 H, HAr, 3JH-H = 8.3 Hz and 4JH-F = 5.5 Hz), 7.40-7.44 (m, 4 H, HAr), 7.57-7.59 (m, 2 H, HAr), 7.72 (dd, 1 H, HAr, 3JH-H = 7.1 Hz and 3JH-H = 5.1 Hz), 8.10 (t, 1 H, HAr, 3JH-H = 7.7 Hz), 8.16 - 8.21 (m, 2 H, HAT), 8.77-8.79 (m, 2 H, HAr), 9.30 (t, 1 H, H, 3JH-H = 5.7 Hz), 1 1.06 (s, 1 H, H); MR 13C (75 MHz, DMSO-d6): δ = 42.5 (CH2), 55.7 (C4), 77.8 (OCH2), 1 15,6 (d, C3- and C5 », 2JC-F = 21.3 Hz), 1 19.8 (CHAr), 123.1 (CHAr), 126.1 (Civ), 126.7 (CHAr), 127.6 (CHAr), 127.7 (CHAr), 128.9 (2 CHAr), 129.3 (CHAr), 129.7 (d, C2 » and C6-, 3JC-F = 8.2 Hz), 129.9 (2 CHAr), 130.2 (Civ), 134.9 (Civ), 135.2 (d, Cr >, 4JC-F = 2.7 Hz), 138.7 (CHAr), 138.9 (Civ), 149.0 (CHAr), 150.0 (Cr), 161.3 (CO), 161.8 (d, C4 », 1JC-F = 241.0 Hz), 163.5 (CO), 164.9 (CO), 166.7 (CO); ESI-MS: m/z = 539 (M+H)+; Anal. (C30H23FN4O5) C, H, N.
EXAMPLE A47
A47a intermediate 65 : Methyl 2-{ l,3-dimethoxy-l,3-dioxopropan-2-yl|-5-(2-(thiophen-2- yl)acetamido)benzoate
Figure imgf000103_0001
The process followed in this step is the same as described in example A46a using 2- thienylacetic acid instead of picolinic acid. White powder (33%); mp 135-137 °C; 1H NMR (300 MHz, CDC13): δ = 3.78 (s, 6 H, 2 OCH3), 3.87 (s, 3 H, OCH3), 3.95 (s, 2 H, CH2), 5.68 (s, 1 H, CH), 7.05-7.08 (m, 2 H, Hthiophen), 7.32-7.34 (m, 2 H, Hthiophen and H3), 7.70 (dd, 1 H, H4, 3JH(4)-H(3) = 8.5 Hz and 4J H(4)-H(6) = 1.9 Hz), 8.02 (d, 1 H, H6, 4J H(6)-H(4) = 1.9 Hz), 9.82 (s, 1 H, NH); NMR 13C (75 MHz, CDC13): δ = 38.2 (CH2), 52.5 (OCH3), 53.0 (2 OCH3), 54.5 (CH), 122.2 (CHAr), 123.8 (CHAr), 125.7 (CHAr), 127.4 (CHAr), 127.5 (CHAr), 129.7 (Civ), 129.8 (Civ), 130.7 (CHAr), 135.5 (Civ), 137.8 (C5), 167.0 (CO), 168.5 (CO);, 169.3 (2 CO); ESI-MS: m/z= 406 (M+H)+.
A47-b intermediate 66: Methyl 2-{ l-r(benzyloxy)amino1-3-methoxy-L3-dioxopropan-2- yl|-5-(2-(thiophen-2-yl)acetamido)benzoate
Figure imgf000103_0002
The process followed in this step is the same as described in example A35d. Yellow powder (27%); mp 67-70 °C; 1H NMR (300 MHz, CDC13): δ = 3.68 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.93 (s, 2 H, CH2), 4.88 (s, 2 H, OCH2), 5.12 (s, 1 H, CH), 7.02-7.03 (m, 2 H, HAT), 7.31 (m, 5 H, HAr), 7.41-7.43 (m, 2 H, HAr), 7.93 (s, 1 H, HAr), 8.13 (s, 1 H, HAr), 9.82 (s, 1 H, H), 10.25 (s, 1 H, H);_ MR 13C (75 MHz, CDC13): δ = 38.3 (CH2), 52.6 (CH), 52.7 (OCH3), 52.9 (OCH3), 78.1 (OCH2), 122.0 (CHAr), 123.8 (CHAr), 125.9 (CHAr), 127.5 (CHAr), 127.6 (CHAr), 128.6 (CHAr), 128.7 (CHAr), 129.2 (dv), 129.3 (3 CHAr), 130.1 (Civ), 132.5 (CHAr), 135.0 (Civ), 135.5 (Civ), 137.6 (Civ), 165.5 (CO), 167.8 (CO), 168.3 (CO), 169.5 (CO); ESI-MS: m/z= 497 (M+H)+.
A47-c intermediate 67: Methyl 2-(benzyloxy)-l,3-dioxo-7-(2-(thiophen-2-yl)acetamido)-
I, 2,3, 4-tetrahydroisoquinoline-4-carboxylate
Figure imgf000104_0001
The process followed in this step is the same as described in example A35e. White powder (92%); 100% keto form; mp 179-181 °C; 1H MR (300 MHz, OMSO-d6): δ =
3.71 (s, 3 H, OCH3), 3.93 (s, 2 H, CH2), 5.05 (s, 2 H, OCH2), 5.39 (s, 1 H, H4), 6.99 - 7.01 (m, 2 H, HAT), 7.41 (m, 5 H, HAr), 7.55-7.56 (m, 2 H, HAr), 7.92 (d, 1 H, HAr, 3J = 7.7 Hz), 8.42 (s, 1 H, HAT), 10.63 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-d6): δ = 38.0 (CH2), 54.0 (OCH3), 54.5 (C4), 78.0 (OCH2), 1 18.4 (CHAr), 125.4 (CHAr), 125.6 (Civ), 125.7 (CHAT), 127.0 (CHAr), 127.2 (CHAr), 127.3 (Civ), 128.6 (CHAr), 128.9 (2 CHAr), 129.4 (CHAr), 130.0 (2 CHAr), 134.7 (Civ ), 137.1 (Civ), 140.0 (Civ), 160.8 (CO), 163.4 (CO), 167.7 (CO), 169.1 (CO); ESI-MS: m/z= 465 (M+H)+; Anal. (C24H20N2O6S) C, H, N.
A47-d intermediate 68: N-(4-fluorobenzyl)- 2-(benzyloxy)-l,3-dioxo-7-(2-(thiophen-2- yl)acetamido)-l,2,3,4-tetrahvdroisoquinoline-4-carboxamide
Figure imgf000104_0002
The process followed in this step is the same as described in example A35f. Beige powder (64%); 100% keto form; mp 240-243 °C; 1H NMR (300 MHz, OMSO-d6): δ = 3.92 (s, 2 H, CH2), 4.31 (dd, 1 H, CH2, 2JH-H = 19.5 Hz and 3JH-H = 5.8 Hz), 4.32 (dd, 1 H, CH2, 2JH-H = 19.5 Hz and 3JH-H = 5.8 Hz), 5.00 (d, 1 H, OC¾ 2JH-H = 15.0 Hz), 5.01 (d, 1 H, OC¾ 2JH-H = 15.0 Hz), 5.13 (s, 1 H, H4), 6.98 - 7.01 (m, 2 H, HAr), 7.18 (t, 2 H, H3- and 3JH- H = 3JH-F = 8.9 Hz), 7.30 (dd, 2 H, HAr, 3JH-H = 8.2 Hz and 3JH-F = 5.9 Hz), 7.36-7.43 (m, 5 H, HAT), 7.56-7.59 (m, 2 H, HAr), 7.90 (d, 1 H, HAr, 3JH-H = 8.3 Hz), 8.36 (s, 1 H, HAr), 9.28 (t, 1 H, NH, 3JH-H= 5.8 Hz), 10.59 (s, 1 H, H); NMR 13C (75 MHz, OMSO-d6): δ = 38.0 (CH2), 42.5 (CH2), 55.7 (C4), 77.8 (OCH2), 115.6 (d, C3 » and C5 », 2JC-F = 21.3 Hz), 118.3 (CHAr), 125.2 (CHAr), 125.7 (CHAr), 126.2 (Civ), 127.0 (CHAr), 127.2 (CHAr), 127.8 (CHAr), 128.9 (2 CHAr), 129.3 (CHAr), 129.6 (Crv), 129.7 (d, C2 » and C6 », 3JC-F = 8.2 Hz), 129.9 (2 CHAr), 134.9 (Crv), 135.2 (d, Cr, 4JC-F = 3.3 Hz), 137.2 (Crv), 139.5 (Crv), 161.3 (CO), 161.8 (d, C4 », 1JC-F = 241.1 Hz), 165.0 (CO), 166.7 (CO), 169.0 (CO); ESI-MS: m/z = 558 (M+H)+; Anal. (C30H24FN3O5S) C, H, N.
EXAMPLE A48
A48a intermediate 69: Methyl 5-chloro-2-{ L3-dimethoxy-L3-dioxopropan-2-yl|benzoate
Figure imgf000105_0001
A solution of intermediate 48 (1.0 g, 3.6 mmol) in concentrate hydrochloric acid (8.0 mL) was cooled at 0 -5 °C. A solution of sodium nitrite (0.25 g, 3.6 mmol) in water (3.0 mL) was added dropwise while maintaining temperature below 5 °C. After 10 min stirring, a pink solution of the diazonium salt was obtained. A cold solution of CuCl (0.5 g, 5.1 mmol) in concentrate HCl acid solution was added dropwise to the diazonium mixture while maintaining temperature below 5 °C. After temperature rising and 12 h stirring, water (10.0 mL) was added and the solution was extracted several times with ethyl acetate. Organic layers were dried over Na2S04 and, after removal of the volatiles in vacuo, the crude residue was purified by column chromatography using petroleum ether / ethyl acetate (70/30, % v/v) as eluent. Yellow oil (48%); 1H NMR (300 MHz, CDC13): δ = 3.80 (s, 6 H, 2 OCH3), 3.92 (s, 3 H, OCH3), 5.76 (s, 1 H, CH), 7.40 (d, 1 H, H3, 3JH(3)-H(4) = 8,3 Hz), 7.54 (dd, 1 H, ¾ 3JH(4)-H(3) = 8.3 Hz, 4JH(4)-H(6) = 1.7 Hz), 8.03 (d, 1 H, H6; 4½(6)-Η(4) = 1.7 Hz); NMR 13C (75 MHz, Acetone-^): δ = 53.0 (OCH3), 53.2 (2 OCH3), 54.7 (CH), 130.5 (CH), 131.9 (Civ), 132.8 (2 CH), 133.2 (Civ), 133.5 (Civ), 166.1 (CO), 168.5 (2 CO); MALDI-TOF : m/z = 301 and 303 (M+H)+
A48-b intermediate 70: Methyl 2-{ l-r(benzyloxy)amino1 -3-methoxy-L3-dioxopropan-2- yll-5-chlorobenzoate
Figure imgf000106_0001
The process followed in this step is the same as described in example A35d. White powder (35%); mp 1 12-1 13 °C; 1H NMR (300 MHz, Acetone-^): δ = 3.56 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 4.76 (s, 2 H, OCH2), 5.26 (s, 1 H, CH), 7.22 (m, 5 H, HAr), 7.53 (m, 2 H, H4 and H3), 7.78 (s, 1 H, H6), 10.40 (s, 1 H, NH); NMR 13C (75 MHz, Acetone-^): δ = 52.0 (OCH3), 52.1 (OCH3), 52.2 (CH), 77.4 (OCH2), 128.3 (2 CHAr), 128.4 (CHAr), 129.2 (2 CHAr), 130.0 (CHAr), 131.5 (Civ), 132.0 (CHAr), 132.3 (CHAr), 133.2 (dv), 134.0 (dv), 135.9 (Civ), 164.5 (CO), 166.0 (CO), 168.5 (CO); MALDI-TOF: m/z = 392 and 394 (M+H)+.
A48-c intermediate 71 : Methyl 2-(benzyloxy)-7-chloro-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxylate
Figure imgf000106_0002
The process followed in this step is the same as described in example A35e. White powder (69%); 100% keto form; mp 161-163 °C; 1H NMR (300 MHz, OMSO-d6): δ =
3.72 (s, 3 H, OCH3), 5.05 (s, 2 H, OCH2), 5.48 (s, 1 H, H4), 7.42 (m, 4 H, HAr), 7.58 (m, 2 H, HAr), 8.08 (s, 1 H, HAr), 8.43 (d, 1 H, HAr, 3JH-H = 8.8 Hz); NMR 13C (75 MHz, DMSO- d6): δ = 53.0 (OCH3), 54.2 (C4), 78.0 (OCH2), 126.6 (CHAr), 127.2 (Civ), 128.9 (3 CHAr), 129.5 (CHAr), 130.1 (2 CHAr), 131.8 (Civ), 133.6 (CHAr), 134.7 (Civ), 134.7 (Civ), 161.3 (CO), 163.0 (CO), 167.3 (CO); MALDI-TOF: m/z = 360 and 362 (M+H)+; Anal.
Figure imgf000107_0001
A48-d intermediate 72: N-(4-fluorobenzyl)- 2-(benzyloxy -7-chloro-l,3-dioxo-l,2,3,4- tetrah droiso uinoline-4-carboxamide
Figure imgf000107_0002
The process followed in this step is the same as described in example A35f. White powder (81%); 100% keto form; mp 216-218 °C; 1H MR (300 MHz, DMSO-i¾): δ = 4.31 (dd, 1 H, CH2, 2JH-H = 15.4 Hz and 3JH-H = 5.0 Hz), 4.32 (dd, 1 H, CH2, 2JH-H = 15.4 Hz and 3JH-H = 5.0 Hz), 5.01 (d, 1 H, OCH2, 2JH-H = 14.9 Hz), 5.02 (d, 1 H, OCH2, 2JH-H = 14.9 Hz), 5.20 (s, 1 H, ¾), 7.18 (t, 2 H, ¾' and H5> 3JH-H = 3½-F = 8.3 Hz), 7.30 (t, 2 H, HAr, 3JH-H = 7.6 Hz and 3JH-F = 4.5 Hz), 7.42-7.47 (m, 4 H, HAr), 7.56-7.57 (m, 2 H, HAr), 7.84 (d, 1 H, HAr 3JH- H = 8.2 Hz), 8.05 (s, 1 H, HArj, 9.33 (t, 1 H, NH, 3JH-H = 5.0 Hz); MR 13C (75 MHz, DMSO-i¾): δ = 42.0 (CH2), 55.3 (C4), 77.4 (OCH2), 1 15.2 (d, Cy and C5% 2JC-F = 21.3 Hz), 127.1 (Civ), 127.2 (CHAr), 128.4 (2 CHAr), 128.8 (CHAr), 128.9 (CHAr), 129.2 (d, CY and C6>, 3JC-F = 8.2 Hz), 129.4 (2 CHAr), 133.1 (Qv), 133.5 (dv), 134.0 (CHAr), 134.3 (dv), 134.5 (d, Cr, 4JC-F = 2.7 Hz), 160.0 (CO), 161.3 (d, C4>, ^C-F = 241.6 Hz), 164.1 (CO), 165.7 (CO); MALDI-TOF: m/z = 453 and 455 (M+H)+; Anal. (C24Hi8ClFN204) C, H, N.
EXAMPLE A49
A49a intermediate 73 : Methyl 5-bromo-2-{ l -dimethoxy-L3-dioxopropan-2-yl|benzoate
Figure imgf000108_0001
The process followed in this step is the same as described in example A48a, using hydrobromic acid instead of hydrochloric acid. White solid (61%); 1H NMR (300 MHz, CDC13): δ = 3.80 (s, 6 H, 2 OCH3), 3.92 (s, 3 H, OCH3), 5.74 (s, 1 H, CH), 7.34 (d, 1 H, ¾, 3JH(3)-H(4) = 8.3 Hz), 7.69 (dd, 1 H, H4, 3JH(4)-H(3) = 8.3 Hz, 4JH(4)-H(6) = 1.5 Hz), 8.18 (d, 1 H, H6, 4JH(6)-H(4) = 1 5 Hz); NMR 13C (75 MHz, CDC13): δ = 52.7 (OCH3), 53.0 (2 OCH3), 54.2 (CH), 122.2 (C5), 131.0 (Civ), 131.9 (CHAr), 133.3 (Civ), 133.9 (CHAr), 135.5 (CHAr), 166.1 (CO), 168.5 (2 CO); MALDI-TOF: m/z = 345 and 347 (M+H)+.
A49-b intermediate 74: Methyl 2-{ l-r(benzyloxy)amino1 -3-methoxy-l,3-dioxopropan-2- yl|-5-bromobenzoate
Figure imgf000108_0002
The process followed in this step is the same as described in example A35d. White powder (35%); mp 99-101 °C; 1H NMR (300 MHz, CDC13): δ = 3.64 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 4.81 (s, 2 H, OCH2), 5.12 (s, 1 H, CH), 7.24 (m, 5 H, HAr), 7.45 (d, 1 H, HAr, 3JH-H = 8.6 Hz), 7.62 (d, 1 H, HAr, 3JH-H = 8.6 Hz), 8.02 (m, 1 H, ¾), 9.55 (s, 1 H, NH); NMR 13C (75 MHz, CDCI3): δ = 52.3 (CH), 52.8 (OCH3), 53.0 (OCH3), 78.0 (OCH2), 122.1 (Civ), 128.5 (2 CHAr), 128.7 (CHAr), 129.3 (3 CHAr), 130.39 (Civ), 130.40 (Civ), 133.6 (CHAr), 135.0 (Civ), 135.6 (CHAr), 164.8 (CO), 167.0 (CO), 168.9 (CO); MALDI-TOF: m/z = 436 and 438 (M+H)+.
A49-c intermediate 75: Methyl 2-(benzyloxyV7-bromo-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxylate
Figure imgf000109_0001
The process followed in this step is the same as described in example A35e. White powder (77%); 100% keto form; mp 160-162 °C; 1H NMR (300 MHz, DMSO-i¾): δ = 3.71 (s, 3 H, OCH3), 5.05 (s, 2 H, OCH2), 5.46 (s, 1 H, H4), 7.42-7.59 (m, 5 H, HAr), 7.76 (d, 1 H, HAr, 3JH-H = 8.2 Hz), 7.94 (d, 1 H, HAr, 3½-H = 8.2 Hz), 8.20 (s, 1H, ¾); NMR 13C (75 MHz, DMSO-i¾): δ = 53.1 (OCH3), 54.5 (C4), 78.1 (OCH2), 122.2 (C7), 123.7 (Civ), 126.6 (CHAr), 128.9 (3 CHAr), 129.5 (CHAr), 129.6 (CHAr), 130.0 (CHAr), 133.4 (Civ), 134.6 (Civ), 136.3 (CHAr), 161.4 (CO), 163.0 (CO), 167.2 (CO); MALDI-TOF: m/z = 404 and 406 (M+H)+; Anal. (Ci8Hi4BrN05) C, H, N.
A49-d intermediate 76: N-(4-fluorobenzyl)- 2-(benzyloxy)-7-bromo-L3-dioxo-L2,3,4- tetrah droiso uinoline-4-carboxamide
Figure imgf000109_0002
The process followed in this step is the same as described in example A35f. White powder (77%); 100% keto form; mp 171-177 °C; 1H MR (300 MHz, DMSO-i¾): δ = 4.33 (dd, 1 H, CH2, 2JH-H = 15.4 Hz and 3JH-H = 5.4 Hz), 4.34 (dd, 1 H, CH2, 2JH-H = 15.4 Hz and 3JH-H = 5.4 Hz), 5.02 (d, 1 H, OCH2, 2JH-H = 9.1 Hz), 5.03 (d, 1 H, OCH2, 2JH-H = 9.1 Hz), 5.20 (s, 1 H, H4), 7.18 (t, 2 H, H3 > and ¾< , 3JH-H = 3JH-F = 8.6 Hz), 7.31 (dd, 2 H, H2 > and ¾·, 3JH-H = 8.0 Hz and 4JH-F = 5.7 Hz), 7.39 - 7.43 (m, 4 H, HAr), 7.56 - 7.58 (m, 2 H, HAr), 7.95 (d, 1 H, HAr 3JH-H = 8.0 Hz), 8.18 (s, 1 H, HAr), 9.34 (t, 1 H, NH 3JH-H = 5.4 Hz); NMR 13C (75 MHz, DMSO-d6): δ = 42.5 (CH2), 55.8 (C4), 77.9 (OCH2), 1 15.7 (d, Cy and C5>, 2JC-F = 20.7 Hz), 121.8 (C7), 127.8 (Civ), 128.9 (2 CHAr), 129.4 (CHAr), 129.5 (CHAr), 129.7 (d, C2- and C6% 3JC-F = 8.2 Hz), 129.9 (2 CHAr), 130.6 (CHAr), 134.4 (Civ), 134.8 (Civ), 135.0 (d, Cv, 4JC-F = 3.3 Hz), 137.3 (CHAr), 160.2 (CO), 161.8 (d, C4-, 1JC-F = 241.1 Hz), 164.5 (CO), 166.1 (CO); MALDI-TOF: m/z = 497 and 499 (M+H)+; Anal. (C24Hi8BrFN204) C, H, N.
EXAMPLE A50
A50a intermediate 77: Methyl 5-fluoro-2-{ L3-dimethoxy-L3-dioxopropan-2-yl|benzoate
Figure imgf000110_0001
A solution of intermediate 48 (1.00 g, 3.6 mmol) in aqueous 6.0 M HC1 (5.0 mL) was cooled at 0 -5 °C. A solution of sodium nitrite (0.37 g, 5.4 mmol) in water (3.0 mL) was added dropwise while maintaining temperature below 5 °C. After 10 min stirring, a pink solution of the diazonium salt was obtained. Tetrafluoroboric acid (1.1 mL, 10.8 mmol) was added dropwise and the solution was stirred for 1 h at 5 °C. The formed precipitate was filtered and dried for 2 h at 50 °C in an oven. The residual powder was then heated at 80 °C for several minutes until end of gas evolvement. The residue was dissolved in ethyl acetate and extracted several times with 1.0 M NaHC03. The organic layer was dried over Na2S04 and, after removal of the volatiles in vacuo, the crude residue was purified by column chromatography using petroleum ether / ethyl acetate (70/30, % v/v) as eluent. Yellow oil (42%); 1H NMR (300 MHz, Acetone-^): δ = 3.61 (s, 6 H, 2 OCH3), 3.75 (s, 3 H, OCH3), 5.54 (s, 1 H, CH), 7.30 (td, 1 H, H4, 3 JH(4)-H(3) = 3 JH(4)-F = 8.3 Hz and 4JH(4)-H(6) = 2.5 Hz), 7.36 (dd, 1 H, H3, 3JH(3)-H(4) = 8.3 Hz, 4JH(3)-F = 5.6 Hz), 7.58 (dd, 1 H, H6, 3JH(6)-F = 9.7 Hz and 4JH(6)-H(4) = 2.5 Hz); NMR 13C (75 MHz, Acetone-^): δ = 53.0 (OCH3), 53.1 (2 OCH3), 55.0 (CH), 118.2 (d, CHAr, 2JC-F = 24.0 Hz), 120.2 (CHAr, 2JC-F = 21.3 Hz), 131.5 (Civ), 132.8 (Civ), 133.4 (C3, 3JC-F = 8.2 Hz), 162.6 (C5, ^C-F = 246.0 Hz), 166.9 (CO), 169.3 (2 CO).
A50-b intermediate 78: Methyl 2-{ 1 (benzyloxy)amino1-3-methoxy-L3-dioxopropan-2- yll-5 -fluorob enzoate
Figure imgf000111_0001
The process followed in this step is the same as described in example A35d. White powder (30%); mp 1 18-1 19 °C; 1H NMR (300 MHz, OMSO-d6 ): δ = 3.65 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.81 (s, 2 H, OCH2), 5.15 (s, 1 H, CH), 7.36 (m, 5 H, HAr), 7.49-7.52 (m, 2 H, HAT), 7.64-7.67 (m, 1 H, HAr), 1 1.51 (s, 1 H, NH); NMR 13C (75MHz, OMSO-d6): δ = 52.2 (CH), 52.9 (OCH3), 53.1 (OCH3), 77.3 (OCH2), 1 17.3 (d, CHAr, 2JC-F = 23.5 Hz), 1 19.8 (d, CHAr, 2JC-F = 20.7 Hz), 128.8 (2 CHAr), 128.9 (CHAr), 129.5 (2 CHAr), 131.4 (d, C2, 4JC-F = 3.3 Hz), 131.9 (d, Ci, 3JC-F = 7.1 Hz), 132.3 (d, C3, 3JC-F = 8.2 Hz), 136.1 (Civ), 161.4 (d, C5, .F = 244.4 Hz), 164.6 (CO), 166.3 (d, CO, 4JC-F = 2.7 Hz), 169.1 (CO); MALDI- TOF : m/z = 376 (M+H)+.
A50-C intermediate 79: Methyl 2-(benzyloxy)-7-fruoro-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxylate
Figure imgf000111_0002
The process followed in this step is the same as described in example A35e. Yellow powder (77%); 100% keto form; mp 140-142 °C; 1H NMR (300 MHz, OMSO-d6): δ = 3.72 (s, 3 H, OCH3), 5.05 (s, 2 H, OCH2), 5.18 (s, 1 H, H4), 7.42-7.43 (m, 3 H, HAr), 7.55- 7.67 (m, 4 H, HAr), 7.86 (d, 1 H, HAr, 3J = 8.5 Hz); NMR 13C (75 MHz, OMSO-d6): δ = 54.1 (CH3), 54.3 (C4), 78.0 (OCH2), 1 14.9 (d, CHAr, 2JC-F = 24.0 Hz), 122.3 (d, CHAr, 2JC-F = 22.4 Hz), 127.5 (Civ), 128.9 (2 CHAr), 129.2 (Civ), 129.5 (CHAr), 130.0 (2 CHAr), 130.7 (d, C5, 3JC-F = 8.2 Hz), 134.6 (Civ), 160.1 (CO), 162.3 (d, C7> 1JC-F = 245.7 Hz), 163.2 (CO), 167.5 (CO); MALDI-TOF: m/z = 344 (M+H)+; Anal. (Ci8Hi4FN05) C, H, N.
A50-d intermediate 80: N-(4-fluorobenzyl)- 2-(benzyloxy)-7-fruoro-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000112_0001
The process followed in this step is the same as described in example A35f. White powder (75%); 100% keto form; mp 215-217 °C; 1H NMR (300 MHz, OMSO-d6): δ = 4.32 (d, 1 H, CH2, 2JH-H = 15.6 Hz and 3JH-H = 5.3 Hz), 4.33 (d, 1 H, CH2, 2JH-H = 15.6 Hz and 3JH-H = 5.3 Hz), 5.02 (d, 1 H, OCH2, 2JH-H = 9.5 Hz), 5.03 (d, 1 H, OCH2, 2JH-H = 9.5 Hz), 5.20 (s, 1 H, H4), 7.18 (t, 2 H, H3 > and ¾·, 3JH-H = 3JH-F = 8.5 Hz), 7.30 (dd, 2 H, H2 > and ¾·, 3JH-H = 8.2 Hz and 4JH-F = 5.7 Hz), 7.42 - 7.52 (m, 4 H, HAr), 7.56 - 7.58 (m, 2 H, HAr), 7.64 (t, 1 H, ¾, 3JH-H = 3JH-F = 8.5 Hz), 7.84 (d, 1 H, HAr, 3JH-H = 8.5 Hz), 9.33 (t, 1 H, NH 3JH-H = 5.3 Hz); NMR 13C (75MHz, DMSO-i¾): δ = 42.0 (CH2), 55.1 (C4), 77,4 (OCH2), 1 14.1 (d, CHAr, 2JC-F = 24.0 Hz), 1 15.2 (d, Cy and C5% 2JC-F = 21.3 Hz), 121.6 (d, CHAr, 2JC-F = 22.9 Hz), 127.3 (d, C8a, 3JC-F = 7.6 Hz), 128.4 (2 CHAr), 128.9 (CHAr), 129,2 (d, C5, 3JC-F = 8.2 Hz), 129.3 (d, Cr and C6% 3JC-F = 8.2 Hz), 129.4 (2 CHAr), 130.9 (d, C4a, 4JC-F = 2.7 Hz), 134.3 (Civ), 134.6 (d, Cr, 4JC-F = 2.7 Hz), 160.1 (d, Ci, 4JC-F = 2.7 Hz), 161.3 (d, C7, 1JC-F = 241.1 Hz), 161.5 (C4 1JC-F = 244.9 Hz), 164.2 (CO), 165.9 (CO); MALDI-TOF: m/z = 437 (M+H)+; Anal. (C24Hi8F2N204) C, H, N.
EXAMPLE A51
A51a intermediate 81 : 2-Carboxymethyl-5-nitrobenzoic acid
Figure imgf000112_0002
Fuming nitric acid (20.0 mL) was cooled to 0 °C and 6.25 g of homophthalic acid (35.0 mmol) was carefully added while maintaining temperature below 22 °C. After 2 h, ice (20 g) was added. The precipitate was filtered and washed several times with distilled water. After drying at room temperature, the nitrated compound was obtained as a white powder (90%); mp 235 °C; 1H NMR (300 MHz, OMSO-d6): δ = 4.06 (s, 2 H, CH2), 7.66 (d, 1 H, ¾, 3JH-H = 8.5 Hz), 8.34 (dd, 1 H, H4, 3JH-H = 8.5 Hz, VH = 2.4 Hz), 8.61 (d, 1H, H6, 4J H-H = 2.4 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 39.3 (CH2), 123.6 (CH), 125.5 (CH), 128.6 (CH), 131.0 (Ci), 139.6 (C2), 150.2 (C5), 164.3 (CO), 174.0 (CO).
A51b intermediate 82: 5-Amino-2-carboxymethylbenzoic acid
Figure imgf000113_0001
Intermediate 81 (2.25 g, 10.0 mmol) was solubilized in methanol (10.0 mL) and hydrogenated on 0.2 g Pd/C 5% under normal pressure. Water (50.0 mL) was added and the mixture was refluxed for 5 min. After filtration of the hot solution, intermediate 82 slightly crystallized at room temperature as orange needles, which were washed with cold water and dried at room temperature (80%); mp 218 °C; 1H NMR (300 MHz, OMSO-d6): δ = 3.70 (s, 2 H, CH2), 6.66 (dd, 1 H, ¾, 3JH-H = 8.2 Hz, 4JH-H = 2.4 Hz), 6.92 (d, 1 H, H3, 3JH- H = 8.2 Hz), 7.15 (d, 1 H, H6, 4JH-H = 2.4 Hz); 13C NMR (75 MHz, DMSO-^): δ = 39.5 (CH2), 1 15.1 (CH), 1 17.2 (CH), 123.5 (C2), 128.5 (CH), 131.0 (Ci), 148.4 (C5), 161.3 (CO), 173.8 (CO).
A51c intermediate 83 : 2-Carboxymethyl-5-hvdroxybenzoic acid
Figure imgf000113_0002
Intermediate 82 (1.00 g, 5.1 mmol) was dissolved at 5 °C in an aqueous sulfuric acid solution (3.0 mL of concentrate acid in 4.5 mL of water). A solution of sodium nitrite (0.53 g, 5.1 mmol) in water (3.0 mL) was slowly added while maintaining temperature below 5 °C to obtain a pink solution of the diazonium salt. This diazonium mixture was added dropwise to a boiling aqueous sulfuric solution (1.0 mL concentrate acid in 1.5 mL water) and the solution was kept in an ice bath for 2 h. The precipitate was filtered, washed with distilled water and dried at room temperature. Beige solid (47%); mp 212 °C; 1H NMR
(300 MHz, DMSO-i¾): δ = 3.78 (s, 2 H, CH2), 6.87 (dd, 1 H, H4, 3JH-H = 8.2 Hz, VH = 2.4 Hz), 7.09 (d, 1 H, H3, 3JH-H = 8.2 Hz), 7.30 (d, 1 H, H6, 4JH-H = 2.4 Hz), 9.60 (s, 1 H, OH); 1JC NMR (75 MHz, OMSO-d6): δ = 39.3 (CH2), 115.7 (CH), 126.2 (C2), 129.1 (CH), 131.6 (CO, 154.3 (CO), 156.7 (C5), 172.0 (CO).
A51d intermediate 84: Methyl 5-methoxy-2-(2-methoxy-2-oxoethyl)benzoate
Figure imgf000114_0001
Thionyl chloride (1.5 mL, 20.4 mmol) was added dropwise to a cooled solution of intermediate 83 (1.00 g, 5.1 mmol). After 24 h reflux, the solvent was removed in vacuo. The crude residue was dissolved in dry acetone (50.0 mL) and potassium carbonate (4.20 g, 30.6 mmol) and methyl iodide (1.9 mL, 30.6 mmol) were added. After 12 h reflux, volatiles were removed in vacuo. The residue was taken up in ethyl acetate, washed several times with 1.0 M NaOH and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give an orange solid (43%); mp 212 °C; 1H NMR (300 MHz, DMSO-i¾): δ = 3.48 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.81 (s, 2 H, CH2), 6.98 (dd, 1 H, H4, 3JH-H = 8.4 Hz, VH = 2.7 Hz), 7.15 (d, 1 H, H3, 3JH-H = 8.4 Hz), 7.36 (d, 1 H, H6, H = 2.7 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 39.6 (CH2), 51.8 (OCH3), 52.0 (OCH3), 55.4 (OCH3), 115.8 (CH), 118.3 (CH), 128.0 (Civ), 130.4 (Civ), 133.3 (CH), 158.6 (C5), 167.2 (CO), 172.3 (CO).
A51e intermediate 85: Methyl 2-{ 1 (benzyloxy)amino1 -3-methoxy-L3-dioxopropan-2- yll-5 -methoxyb enzoate
Figure imgf000114_0002
A solution of freshly distilled diisopropylamine (0.77 mL, 5.5 mmol) in 10.0 mL of dry THF under an argon atmosphere was cooled to -78 °C and 3.4 mL of 1.6 M «-butyllithium (5.5 mmol) was added. After 30 min reaction at -78 °C, a solution of intermediate 84 (1.00 g, 4.2 mmol) in 5.0 mL of dry THF was added dropwise. After stirring the solution for 40 min at -78 °C, temperature was risen to 0 °C and the argon inlet was removed. Solid C02 was added portionwise for 1 h. After acidification with 3.0 M HCl, the solution was extracted with ethyl acetate. BOP (2.00 g, 4.6 mmol) and diisopropylethylamine (3.5 mL, 21.0 mmol) were added at -20 °C to the precedent organic solution. After 20 min stirring at -20 °C, a solution of O-benzylhydroxylamine (0.87 g, 5.5 mmol) in ethyl acetate (5.0 mL) was added. After stirring for 1 h at -20 °C and 12 h at room temperature, the mixture was washed with 2.0 M HCl, 1.0 M NaHC03 solutions and brine. The organic layer was dried over Na2S04 and concentrated in vacuo. After column chromatography of the residue (eluent: petroleum ether/AcOEt, 70/30), intermediate 85 was obtained as a yellow oil (40%); 1H NMR (300 MHz, CDC13): δ = 3.65 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.81 (s, 2 H, OCH2), 5.13 (s, 1 H, CH), 7.03 (dd, 1 H, H4, 3JH-H = 8.5 Hz and VH = 2.6 Hz ), 7.23 (s, 5 H, HAr), 7.39 (d, 1 H, H6, 4JH-H = 2.6 Hz), 7.50 (d, 1 H, H3, 3JH-H = 8.5 Hz), 9.49 (s, 1 H, H); NMR 13C (75 MHz, CDC13): δ = 52.1 (CH), 52.5 (OCH3), 52.7 (OCH3), 55.5 (OCH3), 77.9 (OCH2), 115.9 (CHAr), Π8.4 (CHAr), 126.5 (Civ), 128.4 (2 CHAr), 128.6 (CHAr), 129.3 (2 CHAr), 129.9 (Civ), 133.0 (CHAr), 135.2 (Civ), 159.0 (C5), 165.7 (CO), 168.0 (CO), 169.6 (CO); MALDI-TOF: m/z = 388 (M+H)+.
A51-f intermediate 86: Methyl 2-(benzyloxy)-7-methoxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxylate
Figure imgf000115_0001
The process followed in this step is the same as described in example A35e. Yellow powder (61%); 100% keto form; mp 115-117 °C; 1H NMR (300 MHz, DMSO-i¾): δ = 3.70 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 5.05 (s, 2 H, OCH2), 5.38 (s, 1 H, H4), 7.37 - 7.43 (m, 6 H, HAr), 7.55-7.56 (m, 2 H, HAr); NMR 13C (75 MHz, DMSO-i¾): δ = 54.5 (C4), 55.6 (OCH3), 55.8 (OCH3), 78.3 (OCH2), 112.0 (CHAr), 118.1 (CHAr), 126.1 (Civ), 127.1 (2 CHAr), 127.6 (CHAr), 128.9 (2 CHAr), 130.8 (CHAr), 133.2 (Civ), 137.1 (Civ), 159.5 (CO), 161.0 (CO), 164.0 (CO), 169.9 (CO); MALDI-TOF: m/z = 356 (M+H)+; Anal.
Figure imgf000115_0002
A51-g intermediate 87: N-(4-fluorobenzyl)- 2-(benzyloxy)-7-methoxy-l,3-dioxo-l,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000116_0001
The process followed in this step is the same as described in example A35f. White powder (69%); 100% keto form; mp 194-196 °C; 1H NMR (300 MHz, OMSO-d6): δ = 3.86 (s, 3 H, OCH3), 4.31 (s, 2 H, CH2), 5.01 (s, 2 H, OCH2), 5.12 (s, 1 H, H4), 7.19 - 7.56 (m, 12 H, HAT), 9.28 (s, 1 H, H); NMR 13C (75 MHz, DMSO-^): δ = 41.9 (CH2), 54.9 (C4), 55.6 (OCH3), 77.4 (OCH2), 1 1 1.1 (CHAr), 1 15.1 (d, Cy and C5 >, 2JC-F = 20.7 Hz), 121.4 (CHAr), 126.3 (Civ), 126.6 (Civ), 128.1 (CHAr), 128.4 (2 CHAr), 128.9 (CHAr), 129.2 (d, CY and C6% 3JC-F = 8.2 Hz), 129.4 (2 CHAr), 134.4 (Civ), 134.7 (d, Cr, 4JC-F = 2.7 Hz), 159.0 (CO), 160.8 (CO), 161.3 (d, C4-, 1JC-F = 241.1 Hz), 164.5 (CO), 166.3 (CO); MALDI-TOF: m/z = 449 (M+H)+; Anal. (C25H2iFN205) C, H, N.
B FINAL COMPOUNDS EXAMPLE Bl
Compound 1 : N-(3-Chloropropyl)-2-hvdroxy-1.3-dioxo-1.2.3.4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000116_0002
Intermediate 5 (0.387 g, 1.0 mmol) was dissolved in a minimum of CH2C12 and boron tribromide (1.0 M solution in CH2C12, 5.0 mL, 5.0 mmol) was added dropwise at room temperature. The solution was stirred for 1 h and water (20 mL) was slowly added. After 15 min stirring, the precipitate was filtered and the aqueous layer was extracted with ethyl acetate. Organic layers were dried over Na2S04 and concentrated in vacuo. Organic residues and precipitate were gathered and triturated with ether. Insoluble materials were filtered and dried at room temperature giving compound 1. White solid (90%); mp > 180 °C (dec); 94% enol form; 6% keto form; Keto form; 1H NMR (300 MHz, OMSO-d6): δ = 2.22 (m, 2 H, CH2), 4.01 (m, 2 H, CH2), 4.82 (m, 2 H, CH2), 7.41 (td, 1 H, HAr , 3J = 7.6 Hz, 4 J = 1.6 Hz), 7.70 (td, 1 H, HAr, 3 J = 7.6 Hz, 4 J = 1.6 Hz), 8.02 (dd, 1 H, HAr, 3 J = 7.6 Hz, 4J= 1.6 Hz), 8.17 (dd, 1 H, HAr, 5J = 7.6 Hz, 4J= 1.6 Hz), 10.91 (t, 1 H, NH, 3J = 5.5 Hz); Enol form; 1H NMR (300 MHz, OMSO-d6): δ = 2.18 (quin, 2 H, CH2, 3J = 7.0 Hz), 3.59 (t, 2 H, CH2, 3J = 7.0 Hz), 4.64 (m, 2 H, CH2), 7.12 (td, 1 H, HAr , 3J= 8.0 Hz, 4J= 1.2 Hz), 7.49 (td, 1 H, HAr, 3J= 8.0 Hz, ¥J= 1.2 Hz), 8.07 (dd, 1 H, H5, 3J= 8.0 Hz, 4J= 1.2 Hz), 8.22 (dd, 1 H, HAr, 3J= 8.0 Hz, 4J= 1.2 Hz), 12.12 (t, 1 H, NH, 3J = 5.5 Hz); 13C
NMR (75 MHz, OMSO-d6): δ = 20.2 (CH2), 37.8 (CH2), 67.5 (CH2), 84.5 (dv, C4), 119.7 (Civ), 122.0 (CH), 123.7 (CH), 127.8 (CH), 132.7 (CH), 135.0 (Civ), 159.5 (CO), 162.8 (CO), 166.7 (CO); ESI-MS: m/z = 297 ((M+H)+ , 100%, 35C1); 299 ((M+H)+, 32%, 37C1); Anal. (Ci3Hi3ClN204) C, H, N.
EXAMPLE B2
Compound 2j N-Propyl-2-hvdroxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000117_0001
Intermediate 6 (0.265 g, 0.74 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (5 mL) and hydrogenated for 4 h at room temperature over Pd/C 5% (20 mg). The catalyst was filtered and the solvent was removed in vacuo. Trituration of the residue in ether afforded the deprotected compound 2 as a white solid (90%); mp 180 °C;
100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 0.92 (t, 3 H, CH3, 3J= 7.1 Hz), 1.51 (sext, 2 H, NH-CH2-CH2, 3J= 7.0 Hz), 3.11 (dapp, 2 H, NH-CHz, 3J= 5.6 Hz), 5.13 (s, 1 H, CH), 7.46 (d, 1 H, HAr, 3J = 7.7 Hz), 7.60 (t, 1 H, HAr, 3J = 7.2 Hz), 7.76 (t, 1 H, HAr, 3J = 12 Hz), 8.11 (d, 1 H, H8, 3J = 7.7 Hz), 8.82 (m, 1 H, NH), 10.80 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-i¾ ): δ = 11.3 (CH3), 22.1 (CH2), 40.9 (CH2), 55.4 (CH), 125.4 (Civ), 126.6 (CH), 127.9 (CH), 133.8 (CH), 134.7 (Civ), 161.6 (CO), 164.8 (CO), 166.1 (CO); ESI-MS: m/z = 263 (M+H)+; Anal. (Ci3Hi4N204) C, H, N. EXAMPLE B3
Compound 3 : N-Butyl-2-hvdro -L3-dioxo-L2,3,4-tetrahydroisoquinoline-4-carboxamide
Figure imgf000118_0001
Intermediate 7 was hydrogenated over Pd/C 5% giving compound 3. White solid (53%); mp 180 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 0.92 (t, 3 H, CH3, 3J = 7.0 Hz), 1.15-1.36 (m, 4 H, 2 CH2), 3.25 (q, 2 H, H-CH2, 3J = 7.0 Hz), 5.00 (s, 1 H, CH), 7.40 (d, 1 H, HAr, 3 J = 7.7 Hz), 7.69 (t, 1 H, HAr, 3 J = 7.4 Hz), 7.69 (t, 1 H, HAr, 3 J = 7.4 Hz), 8.15 (d, 1 H, ¾, 3J = 8.1 Hz), 8.72 (dapp, 1 H, NH, 3J = 7.0 Hz), 10.45 (s, 1 H, OH); 13C NMR (75 MHz, OMSO-d6 ): δ = 14.0 (CH3), 19.8 (CH2), 31.3 (CH2), 39.2 (CH2), 55.8 (CH), 125.8 (Civ), 127.0 (CH), 128.3 (CH), 128.6 (CH), 135.1 (Civ), 162.0 (CO), 165.2 (CO), 166.4 (CO); ESI-MS: m/z = 277 (M+H)+; Anal. (Ci4Hi6N204) C, H, N.
EXAMPLE B4
Compound 4: N-Pentyl-2-hvdroxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000118_0002
Intermediate 8 was hydrogenated over Pd/C 5% giving compound 4. White solid (52%); mp 130 °C ( dec); 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 0.80 (t, 3 H, CH3, 3J = 6.6 Hz), 1.21-1.22 (m, 4 H, 2 CH2), 1.37-1.39 (m, 2 H, CH2), 3.00 (m, 2 H, NH-CH^), 4.99 (s, 1 H, CH), 7.33 (d, 1 H, HAr, 3J = 7.0 Hz), 7.48 (t, 1 H, HAr, 3J = 7.0 Hz), 7.63 (t, 1 H, HAr, 3J= 7.0 Hz), 8.00 (d, 1 H, ¾, 3J = 7.5 Hz), 8.68 (m, 1 H, NH), 10.51 (s, 1 H, OH); 13C NMR (75 MHz, OMSO-d6 ): δ = 14.3 (CH3), 22.2 (CH2), 28.9 (2 CH2), 39.5 (CH2), 55.8 (CH), 125.2 (Civ), 127.0 (CH), 128.3 (CH), 128.6 (CH), 134.1 (CH), 135.3 (Civ), 162.0 (CO), 165.2 (CO), 166.4 (CO); ESI-MS: m/z = 291 (M+H)+; Anal. (Ci5Hi8N204) C, H, N.
EXAMPLE B5
Compound 5:N-Hexyl-2-hvdroxy-L3-dioxo-L2,3,4-tetrahvdroisoquinoline-4-carboxamide
Figure imgf000119_0001
Intermediate 9 was treated with boron trichloride giving compound 5. Light brown solid (79%); mp 137-138 °C; 90% keto form; 10% enol form; Keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 0.89 (t, 3 H, CH3, 3J = 7.0 Hz), 1.24 (m, 6 H, CH2), 1.40 (quin, 2 H, CH2, 3J = 7.0 Hz), 3.05 (m, 2 H, CH2), 5.05 (s, 1 H, CH), 7.38 (dd, 1 H, H5, 3J = 8.0 Hz, 4J = 1.5 Hz), 7.54 (td, 1 H, HAr, 3J = 8.0 Hz, 4J = 1.5 Hz), 7.69 (td, 1 H, HAr, 3J = 8.0 Hz, 4J = 1.5 Hz), 8.05 (dd, 1 H, ¾, 3J = 8.0 Hz, 4J = 1.5 Hz), 8.75 (t, 1 H, NH, 3J = 6.5 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 13.9 (CH3), 22.0 (CH2), 25.8 (CH2), 28.7 (CH2), 30.8 (CH2), 40.1 (CH2), 55.3 (CH), 125.3 (Civ), 126.4 (CH), 127.8 (CH), 128.1 (CH), 133.7 (CH), 134.6 (Civ), 161.5 (CO), 164.7 (CO), 165.9 (CO); Enol form; only several peaks could be attributed on the 1H NMR spectrum; 1H NMR (300 MHz, OMSO-d6): δ = 0.73 (t, 3 H, CH3, 3J = 7.0 Hz), 3.24 (t, 2 H, CH2, 3J = 7.0 Hz), 7.32 (td, 1 H, HAr, 3J = 7.5 Hz, 4J = 1.2 Hz), 8.15 (dd, 1 H, ¾, 3 J = 8.0 Hz, 4 J = 1.2 Hz); ESI-MS: m/z = 305 (M+H)+; Anal. (C16H20N2O4) C, H, N.
EXAMPLE B6
Compound 6: N-Nonyl-2-hvdroxy-1.3-dioxo-1.2.3.4-tetrahvdroisoquinoline-4- carboxamide
Figure imgf000119_0002
Intermediate 10 was hydrogenated over Pd/C 5% giving compound 6. White solid (54%); mp 164 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 0.70 (t, 3 H, CH3, 3J = 7.0 Hz), 1.10-1.40 (m, 14 H, 7 CH2), 3.05 (m, 2 H, NH-CTL.), 5.00 (s, 1 H, CH), 7.35 (d, 1 H, HAr, 3J = 7.0 Hz), 7.42 (t, 1 H, HAr, 3J = 7.0 Hz), 7.59 (t, 1 H, HAr, 3J = 7.0 Hz), 8.04 (d, 1 H, ¾, 3J = 7.5 Hz), 8.72 (m, 1 H, NH), 10.56 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-i¾ ): δ = 13.9 (CH3), 22.0 (CH2), 26.2 (CH2), 28.6 (CH2), 28.7 (CH2), 28.9 (CH2), 29.5 (CH2), 31.2 (CH2), 39.0 (CH2), 55.3 (CH), 125.3 (Civ), 126.5 (CH), 127.8 (CH), 128.1 (CH), 133.6 (CH), 134.6 (Civ), 161.5 (CO), 164.7 (CO), 165.9 (CO); ESI-MS: /// .- = 347 (M+H)+; Anal. (C19H26N2O4) C, H, N.
EXAMPLE B7
Compound 7: N-Isopropyl-2-hvdroxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000120_0001
Intermediate 11 was treated with boron trichloride giving compound 7. Beige solid (56%); mp 190 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 1.12 (d, 3 H, CH3, 3J = 6.5 Hz), 1.19 (d, 3 H, CH3, 3J = 6.5 Hz), 3.80 (sext, 1 H, CH, 3J = 6.5 Hz), 5.07 (s, 1 H, CH), 7.45 (d, 1 H, HAr, 3J = 7.7 Hz), 7.60 (t, 1 H, HAr, 3J = 7.7 Hz), 7.77 (t, 1 H, HAr, 3J = 7.3 Hz), 8.12 (d, 1 H, ¾, 3 J = 7.5 Hz), 8.75 (dapp, 1 H, H, 3J = 7.3 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 22.1 (2 CH3), 41.3 (CH), 55.3 (CH), 125.4 (Civ), 126.4 (CH), 127.9 (CH), 128.2 (CH), 133.8 (CH), 134.7 (Civ), 161.6 (CO), 164.8 (CO), 165.1 (CO); ESI-MS: m/z = 263 (M+H)+; Anal. (Ci3Hi4N204) C, H, N.
EXAMPLE B8
Compound 8 : N-7ert-butyl-2-hydrox - 1 ,3-dioxoisoquinoline-4-carboxamide
Figure imgf000120_0002
Intermediate 12 was treated with boron trichloride giving compound 8. White solid (49%); mp 174 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 1.25 (s, 9 H, 3 CH3), 5.09 (s, 1 H, CH), 7.42 (d, 1 H, HAr, 3J = 7.3 Hz), 7.53 (t, 1 H, HAr, 3J = 7.7 Hz), 7.70 (t, 1 H, HAr, 3J = 7.7 Hz), 8.05 (d, 1 H, ¾, 3J = 7.7 Hz), 8.47 (s, 1 H, NH); 13C NMR (75 MHz, DMSO-i¾): δ = 28.1 (3 CH3), 50.9 (Civ), 55.7 (CH), 125.3 (Civ), 126.3 (CH), 127.8 (CH), 128.0 (CH), 133.7 (CH), 134.9 (Civ), 161.6 (CO), 164.9 (CO), 165.3 (CO); ESI-MS: m/z = 277 (M+H)+; Anal. (Ci4Hi6N204) C, H, N.
EXAMPLE B9
Compound 9: N-Cvclopentyl-2-hvdroxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000121_0001
Intermediate 13 was hydrogenated over Pd/C 5% giving compound 9. Brown solid (64%); mp 160 °C; 100% keto form; 1H MR (300 MHz, DMSO-i¾): δ = 1.40-1.80 (m, 8 H, 4 CH2), 3.97 (m, 1 H, CH), 5.09 (s, 1 H, CH), 7.42 (d, 1 H, HAr, 3J = 7.0 Hz), 7.57 (t, 1 H, HAr, 3J = 7.2 Hz), 7.72 (t, 1 H, HAr, 3J = 7.3 Hz), 8.10 (d, 1 H, ¾, 3J = 7.6 Hz), 8.81 (dapp, 1 H, H, 3J = 6.1 Hz), 10.63 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-^): δ = 23.41 (CH2), 23.45 (CH2), 32.1 (CH2), 32.2 (CH2), 50.9 (CH), 55.1 (CH), 125.3 (Civ), 126.3 (CH), 127.8 (CH), 128.1 (CH), 133.7 (CH), 134.7 (Civ), 161.5 (CO), 164.7 (CO), 165.4 (CO); ESI-MS: m/z = 289 (M+H)+; Anal. (Ci5Hi6N204) C, H, N.
EXAMPLE B10
Compound 10 : N- Allyl-2-hydroxy- 1 ,3 -dioxo- 1,2,3 ,4-tetrahydroi soquinoline-4- carboxamide
Figure imgf000121_0002
Intermediate 14 was treated with boron trichloride giving compound 10. Brown solid
(53%); mp 178 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 3.73 (m, 2 H, CH2-CH=CH2), 5.02-5.20 (m, 3 H, C4H, CH2-CH=CH2), 5.80 (m, 1 H, CH2-CH=CH2), 7.43 (d, 1 H, HAr, 3J = 7.5 Hz), 7.55 (t, 1 H, HAr, 3J = 7.2 Hz), 7.71 (t, 1 H, HAr, 3J = 7.2 Hz), 8.07 (d, 1 H, Hg, 3J = 7.5 Hz), 9.00 (m, 1 H, NH); 13C NMR (75 MHz, OMSO-d6): δ = 41.7 (CH2-CH=CH2), 55.7 (CH), 1 15.9 (CH2-CH=CH2), 125.8 (Civ), 127.1 (CH), 128.3 (CH), 128.7 (CH), 134.2 (CH), 134.8 (CH), 135.0 (Civ), 162.0 (CO), 165.2 (CO), 166.5 (CO); ESI-MS: m/z = 261.1 (M+H)+; Anal. (C13H12N2O4) C, H, N.
EXAMPLE Bll
Compound 11 : Ethyl 2-r(2-hvdroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- vDformamidolacetate
Figure imgf000122_0001
Intermediate 15 was treated with boron trichloride giving compound 11. Beige solid (88%); mp 97-98 °C; 100% keto form; 1H MR (300 MHz, CDC13): δ = 1.20 (t, 3 H, CH3, 3J = 7.0 Hz), 4.01-4.12 (m, 4 H, CH2), 5.12 (s, 1 H, CH), 7.48-7.70 (m, 4 H, H, 3 HAr), 8.01 (dd, 1 H, ¾, 3J = 8.0 Hz, 4J = 1.5 Hz); 13C MR (75 MHz, CDC13): δ = 14.2 (CH3), 42.1 (CH2), 55.3 (CH), 61.0 (OCH2), 127.3 (Civ), 128.1 (CH), 129.0 (CH), 129.1 (CH), 132.8 (Civ), 134.1 (CH), 161.1 (CO), 163.8 (CO), 164.8 (CO), 169.4 (CO); ESI-MS: m/z = 307 (M+H)+; Anal. (C14H14N2O6) C, H, N.
EXAMPLE B12
Compound 12: N-(3-Fluorophenyl)-2-hvdroxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000122_0002
Intermediate 16 was treated with boron trichloride giving compound 12. Black solid (68%); mp 170-172 °C; 100% keto form; 1H NMR (300 MHz, CDC13): δ = 4.27 (s, 1 H, CH), 6.82-6.95 (m, 2 H, HAr), 7.00-7.49 (m, 5 H, NH, 4 HAr), 7.75 (d, 1 H, HAr, 3J = 7.5 Hz), 8.23 (dd, 1 H, ¾, 3J = 8.0 Hz, 4J = 1.5 Hz); 13C NMR (75 MHz, CDC13): δ = 55.9 (CH), 108.9 (d, CH, Cr, 2JC-F = 28.0 Hz), 111.2 (d, CH, C4>, 2JC-F = 28.1 Hz), 118.4 (d, CH, Ce, 4JC-F = 3.2 Hz), 126.8 (Civ), 127.3 (CH), 128.4 (CH), 128.5 (d, CH, C5>, 3JC- F = 8.4 Hz), 129.1 (CH), 130.3 (CH), 131.4 (Civ), 136.1 (d, Civ, Cr, 3JC-F = 10.0 Hz), 161.1 (d, Civ, Cy, JJC-F = 255.6 Hz), 161.4 (CO), 161.8 (CO), 166.2 (CO); ESI-MS: m/z = 315 (M+H)+; Anal. (C16H11FN2O4) C, H, N.
EXAMPLE B13
Compound 13 : N-(3 -Chloro-4-methoxyphenyl)-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000123_0001
Intermediate 17 was treated with boron trichloride giving compound 13. Purple solid (79%); 33% keto form; 67% enol form; Keto form; 1H NMR (300 MHz, Acetone-^): δ = 3.93 (s, 3 H, OCH3), 5.27 (s, 1 H, CH), 7.04 (d, 1 H, ¾>, 3J = 7.5 Hz), 7.35 (dd, 1 H, HAr, 3J = 7.5 Hz, 4J = 1.4 Hz), 7.51-7.62 (m, 2 H, HAr), 7.70 (td, 1 H, HAr, 3J = 7.5 Hz, 4J = 1.4 Hz), 7.78 (d, 1 H, H , 4J = 1.4 Hz), 8.11 (dd, 1 H, ¾, 3J = 7.5 Hz, 4J = 1.4 Hz), 9.82 (s, 1 H, NH); 13C NMR (75 MHz, Acetone-^): δ = 55.5 (OCH3), 56.2 (CH), 115.1 (CH), 116.2 (Civ), 120.5 (CH), 120.7 (CH), 127.0 (Civ), 127.1 (CH), 127.8 (CH), 128.2 (CH), 128.3 (Civ), 129.1 (CH), 131.5 (Civ), 148.5 (CO), 161.3 (CO), 161.5 (CO), 164.4 (CO); Enol form; 1H NMR (300 MHz, Acetone-^): δ = 3.95 (s, 3 H, OCH3), 7.15 (d, 1 H, ¾<, 3J = 7.5 Hz), 7.51-7.62 (m, 3 H, HAr), 7.71 (td, 1 H, HAr, 3J = 7.6 Hz, 4J = 1.5 Hz), 7.80 (d, 1 H, H2>, 4J = 1.5 Hz), 8.18 (dd, 1 H, ¾, 3 J = 7.6 Hz, 4 = 1.5 Hz), 10.03 (s, 1 H, NH); 13C NMR (75 MHz, Acetone-^): δ = 56.1 (OCH3), 84.3 (Civ, C4), 117.8 (CH), 118.5 (Civ), 119.2 (CH), 119.5 (CH), 127.6 (CH), 128.4 (CH), 129.2 (Civ), 130.1 (Civ), 131.1 (CH), 132.4 (CH), 133.5 (Civ), 148.6 (CO), 160.1 (CO), 160.5 (CO), 162.4 (CO); ESI-MS: m/z = 361 ((M+H)+ , 100%, 35C1); 363 ((M+H)+, 32%, 37C1); Anal. (Ci7Hi3ClN205) C, H, N.
EXAMPLE B14
Compound 14: N-(4-Fluorobenzyl)-2-hvdroxy-l,3-dioxo- 1,2,3, 4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000123_0002
Intermediate 18 was treated with boron trichloride giving compound 14. Compound 14: light yellow solid (81%); mp > 155 °C (dec); 100% keto form; 1H NMR (300 MHz, Acetone-^): δ = 4.43 (m, 2 H, CH2), 5.18 (s, 1 H, CH), 7.08 (t, 2 H, ¾<, H5',3JH-H = 3 H-F = 7.7 Hz), 7.34 (m, 2 H, HAr), 7.46-7.60 (m, 2 H, HAr), 7.71 (td, 1 H, HAr, 5J = 7.5 Hz, 4J = 1.5 Hz), 8.15 (dd, 1 H, ¾, 3J = 7.5 Hz, 4J = 1.5 Hz), 8.51 (t, 1 H, H, 3J = 5.0 Hz); 13C NMR (75 MHz, Acetone-^): δ = 42.5 (CH2), 55.8 (CH), 1 15.0 (d, 2 CH, Cy, C5 2JC-F = 21 A Hz), 125.2 (Civ), 127.0 (CH), 128.1 (CH), 128.3 (CH), 129.3 (d, 2CH, C2 > CE, 3JC-F = 8.6 Hz), 133.7 (CH), 133.8 (Civ), 134.2 (d, Civ, Cr, 4JC-F = 3.1 Hz), 161.3 (d, Civ, C4', 'JC-F = 241.2 Hz), 162.1 (CO), 163.0 (CO), 166.4 (CO); ESI-MS: m/z = 329 (M+H)+; Anal.
Figure imgf000124_0001
EXAMPLE B15
Compound 15 : N-(4-Methylbenzyl)-2-hvdroxy-L3-dioxo- 1,2,3, 4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000124_0002
Intermediate 19 was treated with boron trichloride giving compound 15. Beige solid (88%); mp 171 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 2.32 (s, 3 H, CH3), 4.38 (d, 2 H, 3J = 5.3 Hz), 5.27 (s, 1 H, CH), 7.27 (m, 4 H, HAr), 7.52 (dd, 1 H, H5, 3 J = 7.9 Hz, 4J = 1.2 Hz), 7.67 (td, 1 H, HAr, 3J = 7.9 Hz, 4J = 1.2 Hz), 7.82 (td, 1 H, HAr, 3J = 7.9 Hz, 4J = 1.2 Hz), 8.19 (dd, 1 H, ¾, 3J = 7.9 Hz, 4J = 1.2 Hz), 9.37 (t, 1 H, NH, 3J = 5.3 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 21.2 (CH3), 42.9 (CH2), 55.8 (CH), 125.9 (Civ), 127.1 (CH), 127.7 (2CH), 128.4 (CH), 128.7 (CH), 129.4 (2CH), 134.3 (CH), 135.0 (Civ), 135.9 (Civ), 136.6 (Civ), 162.1 (CO), 165.2 (CO), 166.6 (CO); ESI-MS: m/z = 325 (M+H)+; Anal. (Ci8H16N204) C, H, N.
EXAMPLE B16
Compound 16 : N-( 2.4-DimethoxybenzvO-2-hvdroxy- 1.3 -dioxo- 1.2.3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000125_0001
Intermediate 20 was treated with boron trichloride giving compound 16. Salmon solid (93%); mp 125-127 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 3.75 (s, 3
H, OCH3), 3.79 (s, 3 H, OCH3), 4.15 (dd, 1 H, CH2, 2J = 11.9 Hz, 3J = 5.1 Hz), 4.19 (dd, 1 H, CH2, 2J = 1 1.9 Hz, 3J = 5.1 Hz), 5.17 (s, 1 H, CH), 6.48 (dd, 1 H, ¾<, 3J= 7.6 Hz, 4J=
I .2 Hz), 6.57 (d, 1 H, ¾<, 4J= 1.2 Hz), 7.11 (d, 1 H, H6>, 3J= 7.6 Hz), 7.40 (dd, 1 H, HAr, 3J= 7.5 Hz, 4J= 1.5 Hz), 7.54 (td, 1 H, HAr, 3J = 7.5 Hz, 4J= 1.5 Hz), 7.69 (td, 1 H, HAr, 3 = 7.5 Hz, 4J = 1.5 Hz), 8.05 (dd, 1 H, ¾, 3J = 7.5 Hz, 4J = 1.5 Hz), 9.00 (t, 1 H, NH, 3J = 5.1 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 38.2 (CH2), 55.6 (OCH3), 55.7 (OCH3), 55.9 (CH), 98.8 (CH, C3 , 104.7 (CH, C5 ), H8.3 (Civ, Cr), 125.8 (Civ), 127.1 (CH), 128.3 (CH), 128.6 (CH), 129.7 (CH), 134.2 (CH), 135.0 (Civ), 158.3 (CO), 160.5 (CO), 162.1 (CO), 165.3 (CO), 166.4 (CO); ESI-MS: m/z = 371 (M+H)+; Anal. (Ci9Hi8N206) C, H, N.
EXAMPLE B17
Compound 17 : N-(2,4-Dihvdroxybenzyl)-2-hvdroxy- 1 ,3 -dioxo- 1 ,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000125_0002
Intermediate 20 was treated with boron tribromide giving compound 17. Pink solid (66%); mp > 111 °C (dec); 55% keto form; 45% enol form; Keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.10 (dd, 1 H, C¾ 2J = 11.9 Hz, 3J= 5.1 Hz), 4.12 (dd, 1 H, C¾ 2J = 11.9 Hz, 3J = 5.1 Hz), 5.17 (s, 1 H, CH), 6.28 (dd, 1 H, ¾·, 3J= 7.6 Hz, 4J= 1.2 Hz), 6.31 (d, 1 H, H3>, 4J= 1.2 Hz), 6.88 (d, 1 H, H6>, 3J= 7.6 Hz), 7.43 (dd, 1 H, ¾, 3J = 7.5 Hz, 4J = 1.5 Hz), 7.52 (td, 1 H, HAr, 5J = 7.5 Hz, 4J = 1.5 Hz), 7.69 (td, 1 H, HAr, 3J = 7.5 Hz, 4J = 1.5 Hz), 8.05 (dd, 1 H, H8, 3J = 7.5 Hz, 4J = 1.5 Hz), 8.90 (t, 1 H, NH, 3J = 5.1 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 38.2 (CH2), 56.0 (CH), 106.3 (CH), 108.3 (Civ), 108.6 (CH), 125.9 (Civ), 126.1 (CH), 128.3 (CH), 128.6 (CH), 129.7 (CH), 134.2 (CH), 135.0 (Civ), 153.2 (CO), 159.3 (CO), 162.1 (CO), 163.3 (CO), 165.7 (CO); Enol form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.29 (dd, 1 H, CH2, 2J = 11.9 Hz, 3J = 5.1 Hz), 4.31 (dd, 1 H, CH2, 2J= 11.9 Hz, 3J = 5.1 Hz), 6.15 (dd, 1 H, ¾<, 3J= 7.6 Hz, 4J= 1.2 Hz), 6.26 (d, 1 H, Hr, 4J= 1.2 Hz), 7.01 (d, 1 H, H6>, 3J= 7.6 Hz), 7.19 (td, 1 H, HAr, 3J = 7.5 Hz, 4J= 1.5 Hz), 7.51 (td, 1 H, HAr, 3J = 7.5 Hz, 4J = 1.5 Hz), 8.05 (dd, 1 H, H5, 3J = 7.5 Hz, 4J = 1.5 Hz), 8.27 (t, 1 H, NH, 3J = 5.1 Hz), 8.89 (dd, 1 H, ¾, 3J = 7.5 Hz, 4J = 1.5 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 39.2 (CH2), 84.3 (Civ, C4), 106.1 (Civ), 106.3 (CH), 108.3 (CH), 126.8 (Civ), 127.9 (CH), 128.3 (CH), 129.2 (CH), 129.7 (CH), 131.2 (CH), 134.5 (Civ), 149.2 (CO), 156.5 (CO), 159.5 (CO), 161.3 (CO), 166.5 (CO); ESI-MS: m/z = 343 (M+H)+; Anal. (Ci7Hi4N206) C, H, N.
EXAMPLE B18
Compound 18 : N-(3 ,4-Dimethoxybenzyl)-2-hvdroxy- 1 ,3 -dioxo- 1 ,2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000126_0001
Intermediate 21 was treated with boron trichloride giving compound 18. Salmon solid (67%); mp 126-127 °C; 66% keto form; 34% enol form; Keto form; 1H NMR (300 MHz, Acetone-^): δ = 3.79 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.38 (m, 2 H, CH2), 4.72 (s, 1 H, CH), 6.76-6.90 (m, 3 H, HAr), 7.36 (td, 1 H, HAr, 3J= 7.5 Hz, 4J= 1.5 Hz), 7.56 (td, 1 H, HAr, 3J= 7.5 Hz, 4J= 1.5 Hz), 7.69 (dd, 1 H, HAr, 3J = 7.5 Hz, 4J = 1.5 Hz), 8.15 (dd, 1 H, ¾, 3J = 7.5 Hz, 4J = 1.5 Hz), 9.82 (t, 1 H, NH, lJ = 5.2 Hz); 13C NMR (75 MHz, Acetone- d6): δ = 46.1 (CH2), 55.2 (OCH3), 55.3 (OCH3), 55.6 (CH), 111.0 (CH), 111.5 (CH), 114.4 (CH), 114.8 (CH), 118.6 (CH), 120.0 (CH), 128.6 (Civ), 128.7 (CH), 131.9 (Civ), 133.1 (Civ), 149.9 (CO), 152.1 (CO), 160.5 (CO), 161.3 (CO), 164.2 (CO); Enol form; 1H NMR (300 MHz, Acetone-^): δ = 3.82 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.34 (m, 2 H, CH2), 6.76-6.90 (m, 3 H, HAr), 7.40 (td, 1 H, HAr, 3J= 7.5 Hz, 4J= 1.5 Hz), 7.59 (td, 1 H, HAr, 3 J = 7.5 Hz, 4J= 1.5 Hz), 7.71 (dd, 1 H, HAr, 3J= 7.5 Hz, 4J = 1.5 Hz), 8.17 (dd, 1 H, ¾, 3J = 7.5 Hz, 4J = 1.5 Hz), 10.35 (t, 1 H, NH, 3J = 5.2 Hz); 13C NMR (75 MHz, Acetone-^): δ = 42.8 (CH2), 55.1 (OCH3), 55.2 (OCH3), 84.2 (Civ, C4), 111.1 (CH), 111.7 (CH), 119.4 (CH), 125.8 (Civ), 127.0 (CH), 128.1 (CH), 128.2 (CH), 128.9 (Civ), 131.8 (Civ), 133.6 (CH), 149.9 (CO), 151.0 (CO), 157.3 (CO), 161.3 (CO), 162.4 (CO); ESI-MS: m/z = 371 (M+H)+; Anal. (Ci9Hi8N206) C, H, N.
EXAMPLE B19
Compound 19: N-(3,4-Dihvdroxybenzyl)-2-hydroxy-l,3-dioxoisoquinoline-4- carboxamide
Figure imgf000127_0001
Intermediate 21 was treated with boron tribromide giving compound 19. Salmon solid (95%); mp > 150 °C (dec); 100% keto form; 1H NMR (300 MHz, Acetone-^): δ = 4.15 (dd, 2 H, CH2, 2J= 11.9 Hz, V= 5.0 Hz), 4.17 (dd, 2 H, CH2, 2J= 11.9 Hz, 3J = 5.0 Hz), 5.12 (s, 1 H, CH), 6.52 (d, 1 H, ¾>, 3J = 7.6 Hz), 6.64-6.73 (m, 2 H, HAr), 7.39 (dd, 1 H, H5, 3J= 7.6 Hz, 4J= 1.5 Hz, ), 7.54 (td, 1 H, HAr, 3J= 7.6 Hz, 4J= 1.5 Hz), 7.69 (td, 1 H, HAr, 3J = 7.6 Hz, 4J = 1.5 Hz), 8.06 (dd, 1 H, H8, 3J = 7.6 Hz, 4J = 1.5 Hz), 9.12 (t, 1 H, H, 3 J = 5.2 Hz); 13C NMR (75 MHz, Acetone-^): δ = 42.6 (CH2), 55.9 (CH), 114.8 (CH), 118.6 (CH), 122.8 (CH), 123.8 (Civ), 127.2 (CH), 128.7 (CH), 129.3 (CH), 131.9 (Civ), 132.4 (CH), 134.9 (Civ), 146.2 (Civ), 151.0 (Civ), 161.5 (CO), 165.0 (CO), 166.4 (CO); ESI-MS: m/z = 343 (M+H)+; Anal. (Ci7Hi4N206) C, H, N.
EXAMPLE B20
Compound 20 : N-((TMophen-2-yl¼iethvn-2-hvdroxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000127_0002
Intermediate 22 was hydrogenated on Pd/C 5% giving compound 20. Brown solid (66%); mp > 110 °C (dec); 100% enol form; 1H NMR (300 MHz, OMSO-d6): δ = 4.44 (m, 2 H, CH2), 6.75-6.81 (m, 2 H, CH Thioph), 6.90 (d, 1 H, CH Thioph, 3J= 5.0 Hz), 7.41 (d, 1 H, HAr, 3J = 7.2 Hz), 7.69 (t, 1 H, HAr, 3J = 7.2 Hz), 7.78 (t, 1 H, HAr, 3J = 7.2 Hz), 8.11 (d, 1 H, Hg, 3 J = 7.7 Hz), 9.19 (s, 1 H, NH), 10.8 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-i¾): δ = 38.0 (CH2), 78.4 (Civ), 125.1 (Civ), 125.5 (CH), 125.8 (CH), 125.85 (CH),
127.0 (CH), 127.9 (CH), 129.7 (CH), 134.3 (CH), 139.5 (Civ), 142.1 (Civ), 161.8 (CO),
168.1 (CO), 168.3 (CO); ESI-MS: m/z = 317 (M+H)+; Anal. (C15H12N2O4S) C, H, N.
EXAMPLE B21
Compound 21 : N-\2-(3A- Dimethoxyphenv0ethyl1-2-hvdroxy-1.3-dioxo-1.2.3.4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000128_0001
Intermediate 23 was treated with boron trichloride giving compound 21. Orange solid (95%); mp 112-114 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 2.70 (m, 2 H, CH2), 3.35 (m, 2 H, CH2), 3.74 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 4.72 (s, 1 H, CH), 6.80-6.90 (m, 3 H, HAr), 7.42 (dd, 1 H, H5, 3J= 7.9 Hz, 4J= 1.5 Hz), 7.67 (td, 1 H, HAr, 3J= 7.9 Hz, 4J= 1.5 Hz), 7.75 (td, 1 H, HAr, 3J = 7.9 Hz, 4J = 1.5 Hz), 8.17 (dd, 1 H, ¾, 3J = 7.9 Hz, 4J = 1.5 Hz), 8.76 (t, 1 H, H, 3J = 5.2 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 34.5 (CH2), 41.2 (CH2), 55.1 (OCH3), 55.2 (OCH3), 55.8 (CH), 111.9 (CH), 112.7 (CH), 121.7 (CH), 125.6 (Civ), 127.0 (CH), 128.0 (CH), 128.2 (CH), 131.9 (Civ), 133.6 (CH), 134.5 (Civ), 149.8 (CO), 152.1 (CO), 161.5 (CO), 162.1 (CO), 164.7 (CO); ESI-MS: m/z = 385 (M+H)+; Anal. (C2oH2oN206) C, H, N.
EXAMPLE B22
Compound 22: N-r2-(3.4-Dihvdroxyphenyl)ethyl1-2-hvdroxy-1.3-dioxoisoquinoline-4- carboxamide
Figure imgf000128_0002
Intermediate 23 was treated with boron tribromide giving compound 22. Orange solid (95%); mp 148-150 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 2.34 (m, 2 H, CH2), 3.47 (m, 2 H, CH2), 5.07 (s, 1 H, CH), 6.75-6.90 (m, 3 H, HAr), 7.40-7.55 (m, 2
H, HAT), 7.67 (dd, 1 H, HAr, 3J= 7.9 Hz, 4J= 1.5 Hz), 8.12 (dd, 1 H, ¾, 3J = 7.9 Hz, 4J =
I .5 Hz), 8.56 (t, 1 H, NH, 3J = 5.2 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 35.0 (CH2), 41.7 (CH2), 55.9 (CH), 115.0 (CH), 116.1 (CH), 123.5 (CH), 127.7 (CH), 127.8 (Civ), 128.0 (CH), 129.4 (CH), 129.7 (CH), 129.8 (Civ), 131.3 (Civ), 142.8 (CO), 144.0 (CO), 160.5 (CO), 161.4 (CO), 162.7 (CO); ESI-MS: m/z = 357 (M+H)+; Anal. (Ci8Hi6N206) C, H, N.
EXAMPLE B23
Compound 23 : (2-hvdroxy-L3-dioxoisoquinolin-4-yl)(piperidin-l-yl)methanone
Figure imgf000129_0001
Intermediate 24 was hydrogenated on Pd/C 5% giving compound 23. Black solid (64%); mp > 128 °C (dec); 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 1.49-1.64 (m, 6 H, 3 CH2), 3.35 (t, 2 H, N-CHz, 3J = 5.1 Hz), 3.66 (t, 2 H, N-CHz, V = 5.1 Hz), 5.97 (s, 1 H, CH), 7.30 (d, 1 H, HAr, 3J = 7.7 Hz), 7.61 (t, 1 H, HAr, 3J = 7.7 Hz), 7.76 (t, 1 H, HAr, 3 = 7.7 Hz), 8.12 (d, 1 H, H8, 3J = 7.7 Hz), 10.8 (s, 1 H, OH); 13C NMR (75 MHz, DMSO- d6): δ = 23.7 (CH3), 25.1 (CH2), 26.0 (CH2), 43.0 (CH2), 47.4 (CH2), 50.3 (CH), 125.3 (Civ), 126.7 (CH), 127.7 (CH), 127.9 (CH), 133.7 (CH), 135.0 (Civ), 161.3 (CO), 164.6 (CO), 164.7 (CO); ESI-MS: m/z = 289 (M+H)+; Anal. (Ci5Hi6N204) C, H, N.
EXAMPLE B24
Compound 24: N.N-Diethyl-2-hvdroxy-1.3-dioxo-1.2.3.4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000129_0002
Intermediate 25 was hydrogenated on Pd/C 5% giving compound 24. White solid (52%); mp 178 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 1.21 (t, 3 H, CH3, 3J = 6.4 Hz), 1.28 (t, 3 H, CH3, 3J = 6.6 Hz), 3.21-3.41 (m, 2 H, NH-CH2), 3.60-3.73 (m, 2 H, NH-CEb), 5.77 (s, 1 H, CH), 7.22 (d, 1 H, HAr, 3J= 7.7 Hz), 7.55 (t, 1 H, HAr, 3J= 7.6 Hz), 7.70 (t, 1 H, HAr, 3J= 7.5 Hz), 8.08 (d, 1 H, H8, 3J= 7.7 Hz), 10.50 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-i¾): δ = 12.7 (CH3), 14.8 (CH3), 40.4 (CH2), 42.8 (CH2), 50.6 (CH), 125.5 (Civ), 126.5 (CH), 127.9 (CH), 128.0 (CH), 133.9 (CH), 135.3 (Civ), 161.5 (CO), 164.8 (CO), 166.0 (CO); ESI-MS: m/z = 277 (M+H)+; Anal. (Ci4Hi6N204) C, H, N.
EXAMPLE B25
Compound 25: N-Butyl-N-methyl-2-hydroxy-l ,3-dioxo- 1,2,3, 4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000130_0001
Intermediate 26 was hydrogenated on Pd/C 5% giving compound 25. Brown solid (62%); mp 120-124 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 0.92 (t, 3 H, CH3, 3J = 8.4 Hz), 1.27-1.70 (m, 4 H, 2 CH2), 2.95 (s, 3 H, NH-CH^), 3.34 (m, 2 H, NH- CUg), 5.90 (s, 1 H, CH), 7.32 (d, 1 H, HAr, 3J = 7.5 Hz), 7.61 (t, 1 H, HAr, 3J = 7.5 Hz), 7.76 (d, 1 H, HAr, 3 J = 7.5 Hz), 8.12 (d, 1 H, ¾, 3 J = 7.2 Hz); 13C NMR (75 MHz, CDC13): 5 = 14.2 (CH3), 19.8 (CH2), 29.0 (CH2), 31.0 (CH2), 34.2 (NHCHA 36.7 (NHCH^), 47.7 (NHCHA 50.7 (NHCHA 51.0 (CH), 51.5 (CH), 126.0 (Civ), 127.3 (CH), 128.3 (CH), 128.6 (CH), 134.3 (CH), 135.6 (Civ), 161.9 (CO), 165.2 (CO), 167.3 (CO); ESI-MS: m/z = 291 (M+H)+; Anal. (Ci5Hi8N204) C, H, N.
EXAMPLE B26
Compound 26: N-Heptyl-2-hvdroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000130_0002
Intermediate 27 was hydrogenated on Pd/C 5% giving compound 26. Grey solid (74%); mp 120-130 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 0.90 (t, 3 H, CH3, 3J= 7.0 Hz), 1.23-1.25 (m, 8 H, 4 CH2), 1.40-1.42 (m, 2 H, CH2), 3.07 (q, 2 H, NH-CH2, 3 J = 7.1 Hz), 5.08 (s, 1 H, CH), 7.40 (d, 1 H, HAr, J = 7.2 Hz), ), 7.55 (t, 1 H, HAr, J = 7.5 Hz), 7.70 (t, 1 H, HAr, 3J = 7.5 Hz), 8.11 (d, 1 H, H8, 3J = 7.5 Hz), 8.82 (s, 1 H, H); 13C NMR (75 MHz, OMSO-d6): δ = 13.9 (CH3), 22.0 (CH2), 26.1 (CH2), 28.3 (CH2), 28.8 (CH2), 31.2 (CH2), 38.7 (CH2), 55.3 (CH), 125.3 (Civ), 126.4 (CH), 127.8 (CH), 128.1 (CH), 133.6 (CH), 134.6 (Civ), 161.5 (CO), 164.7 (CO), 165.9 (CO); ESI-MS: m/z = 319 (M+H)+; Anal. (Ci7H22N204) C, H, N.
EXAMPLE B27
Compound 27: N-Octyl-2-hvdroxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000131_0001
Intermediate 28 was hydrogenated on Pd/C 5% giving compound 27. Beige solid (67%); mp 92-96 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 0.92 (t, 3 H, CH3, 3J = 7.3 Hz), 1.29-1.31 (m, 10 H, 5 CH2), 1.47-1.49 (m, 2 H, CH2), 5.11 (s, 1 H, CH), 7.44 (d, 1 H, HAr, 3J= 7.3 Hz), 7.60 (t, 1 H, HAr, 3J = 7.0 Hz), 7.75 (t, 1 H, HAr, 3J = 7.0 Hz), 8.1 1 (d, 1 H, He, 3J = 7.3 Hz), 8.80 (s, 1 H, NH), 10.63 (s, 1 H, OH); 13C NMR (75 MHz, DMSO- d6 ): = 13.9 (CH3), 22.0 (CH2), 26.2 (CH2), 28.6 (2 CH2), 28.7 (CH2), 31.1 (CH2), 39.0 (CH2), 55.3 (CH), 125.3 (Civ), 126.5 (CH), 127.8 (CH), 128.1 (CH), 133.6 (CH), 134.6 (Civ), 161.5 (CO), 164.7 (CO), 165.9 (CO); ESI-MS: m/z = 333 (M+H)+; Anal.
Figure imgf000131_0002
EXAMPLE B28
Compound 28: N-Dodecyl-2-hvdroxy-1.3-dioxo-1.2.3.4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000131_0003
Intermediate 29 was hydrogenated on Pd/C 5% giving compound 28. Grey solid (52%); mp 132-144 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 0.86 (t, 3 H, CH3, 3J = 6.6 Hz), 1.20-1.26 (m, 18 H, 9 CH2), 1.39-1.41 (m, 2 H, CH2), 3.06 (m, 2 H, CH^), 5.08 (s, 1 H, CH), 7.39 (d, 1 H, HAr, 3J = 7.2 Hz), 7.54 (t, 1 H, HAr, 3J = 8.0 Hz), 7.68 (t, 1 H, HAr, 3J = 8.0 Hz), 8.05 (d, 1 H, ¾, 3J = 8.0 Hz), 8.75 (s, 1 H, H), 10.57 (s, 1 H, OH); 13C NMR (75 MHz, OMSO-d6): δ = 14.4 (CH3), 22.6 (CH2), 26.7 (CH2), 29.1 (CH2), 29.2 (2 CH2), 29.5 (4 CH2), 31.8 (CH2), 39.5 (CH2), 55.8 (CH), 125.8 (Civ), 127.0 (CH), 128.3 (CH), 128.6 (CH), 134.1 (CH), 135.2 (Civ), 162.0 (CO), 165.2 (CO), 166.4 (CO); ESI-MS: m/z = 389 (M+H)+; Anal. (C22H32N204) C, H, N.
EXAMPLE B29
Compound 29: N-Phenyl-2-hvdroxy-L3-dioxo-L2,3,4-tetrahydroisoquinoline-4- carboxamide
Figure imgf000132_0001
Intermediate 30 was treated with boron trichloride giving compound 29. Grey solid (73%); mp 170-175 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 5.33 (s, 1 H, CH), 7.11 (t, 1 H, HAr, 3J = 7.0 Hz), 7.34 (t, 2 H, HAr, 3J = 7.5 Hz), 7.52 (t, 1 H, HAr, 3 J = 7.2 Hz), 7.57-7.61 (m, 3 H, HAr), 7.69 (t, 1 H, HAr, 3J = 7.0 Hz), 8.10 (d, 1 H, HAr, 3J = 7.7 Hz), 10.94 (s, 1 H, NH); 13C NMR (75 MHz, OMSO-d6): δ = 56.1 (CH), 119.4 (2 CH), 124.2 (CH), 125.4 (Civ), 126.7 (CH), 128.0 (CH), 128.4 (CH), 128.9 (2 CH), 133.9 (CH), 134.3 (Civ), 138.2 (Civ), 161.5 (CO), 164.6 (CO), 164.8 (CO); ESI-MS: m/z = 297 (M+H)+; Anal. (Ci6H12N204) C, H, N.
EXAMPLE B30
Compound 30 : N-Methyl-N-phenyl-2-hvdroxy- 1 , 3 -dioxo- 1,2,3 ,4-tetrahydroi soquinoline-4- carboxamide
Figure imgf000133_0001
Intermediate 31 was hydrogenated on Pd/C 5% giving compound 30. Brown solid (40%); mp 130-135 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 3.25 (s, 3 H, CH3), 5.23 (s, 1 H, CH), 7.16 (d, 1 H, HAr, 3J = 5.7 Hz), 7.22 (d, 1 H, HAr, 3J = 7.7 Hz), 7.43 (t, 1 H, HAr, 3J = 7.3 Hz), 7.48-7.55 (m, 4 H, HAr), 7.67 (t, 1 H, HAr, 3J = 7.3 Hz), 8.00 (d, 1 H, HAr, 3J = 7.3 Hz); 13C NMR (75 MHz, DMSO-i¾): δ = 38.1 (CH3), 51.8 (CH), 125.8 (Civ), 125.9 (CH), 126.8 (CH), 128.4 (2 CH), 128.6 (CH), 128.9 (CH), 130.5 (2 CH), 134.3 (2 CH), 135.1 (Civ), 143.3 (Civ), 161.6 (CO), 165.0 (CO), 166.8 (CO); ESI- MS: m/z = 311 (M+H)+; Anal. (C17H14N2O4) C, H, N.
EXAMPLE B31
Compound 31 : N-(4-Fluorophenyl)-2-hvdroxy-1.3-dioxo-1.2.3.4-tetrahvdroisoquinoline-4- carboxamide
Figure imgf000133_0002
Intermediate 32 was treated with boron trichloride giving compound 31. Beige solid (76%); mp 172-180 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 5.29 (s, 1 H, CH), 7.19 (t, 2 H, HAr, 3J = 8.6 Hz), 7.48 (d, 1 H, HAr, 3J = 7.5 Hz), 7.54-7.63 (m, 4 H, HAr), 7.71 (t, 1 H, HAr, 3J = 7.0 Hz), 8.1 1 (d, 1 H, HAr, 3J = 7.7 Hz), 10.94 (s, 1 H, NH); 13C NMR (75 MHz, OMSO-d6): δ = 56.3 (CH), 1 16.0 (d, 2 CH, C3 », C5 », 2JC-F = 22.5 Hz), 121.8 (d, 2 CH, C2 », C6 », 3JC-F = 9.0 Hz), 125.9 (Civ), 127.1 (CH), 128.5 (CH), 128.9 (CH), 134.4 (CH), 134.7 (Civ), 135.1 (Civ), 158.9 (d, Civ, C4 », JC-F = 239.2 Hz), 161.9 (CO), 165.0 (CO), 165.3 (CO); ESI-MS: m/z = 3 15 (M+H)+; Anal. (C16H11FN2O4) C, H, N.
EXAMPLE B32
Compound 32: N-Benzyl-2-hvdroxy-l,3-dioxo-l,2,3,4-tetrahvdroisoquinoline-4- carboxamide
Figure imgf000134_0001
Intermediate 33 was hydrogenated on Pd/C 5% giving compound 32. Beige solid (69%); mp 152- 155 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.32 (s, 2 H, CH2), 5. 17 (s, 1 H, CH), 7.28-7.33 (m, 5 H, HAr), 7.42 (m, 1 H, HAr), 7.55 (m, 1 H, HAr), 7.70 (m, 1 H, HAT), 8.07 (d, 1 H, HAr, 3J = 7.7 Hz), 9.3 1 (s, 1 H, H), 10.62 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-i¾): δ = 42.6 (CH2), 55.2 (CH), 125.3 (Civ), 126.6 (CH), 127.0 (CH), 127.2 (2 CH), 128.0 (CH), 128.2 (CH), 128.4 (2 CH), 133.7 (CH), 134.4 (Civ), 138.5 (Civ), 161.5 (CO), 164.7 (CO), 166.2 (CO); ESI-MS: m/z = 3 1 1 (M+H)+; Anal. (C17H14N2O4) C, H, N.
EXAMPLE B33
Compound 33 : N-(4-Methoxybenzyl)-2-hvdroxy- L3-dioxo- L2,3,4-tetrahydroisoquinoline- 4-carboxamide
Figure imgf000134_0002
Intermediate 34 was treated with boron trichloride giving compound 33. Brown solid
(45%); mp > 170 °C (dec); 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 3.74 (s,
3 H, OCH3), 4.24 (dd, 1 H, CH2, 2J = 14.7 Hz, 3J = 5.6 Hz), 4.29 (dd, 1 H, CH2, 2J = 14.7 Hz, J = 5.6 Hz), 5.14 (s, 1 H, CH), 6.90 (d, 2 H, HAr, J= 8.2 Hz), 7.19 (d, 2 H, HAr, J= 8.2 Hz), 7.39 (d, 1 H, HAr, 3J= 7.5 Hz), 7.55 (t, 1 H, HAr, 3J = 7.3 Hz), 7.70 (t, 1 H, HAr, 3 J = 6.9 Hz), 8.06 (d, 1 H, ¾, 3J = 7.6 Hz), 9.21 (t, 1 H, H, 3J = 5.3 Hz), 10.59 (s, 1 H, OH); 13C NMR (75 MHz, OMSO-d6): δ = 42.1 (CH2), 55.0 (OCH3), 55.2 (CH), 113.7 (2 CH), 125.3 (Civ), 126.6 (CH), 127.9 (CH), 128.2 (CH), 128.6 (2 CH), 130.3 (Civ), 133.7 (CH), 134.5 (Civ), 158.4 (CO), 161.5 (CO), 164.7 (CO), 166.0 (CO); ESI-MS: m/z = 341 (M+H)+; Anal. (Ci8Hi6N205) C, H, N.
EXAMPLE B34
Compound 34: N-(4-Fluorophenethyl)-2-hydroxy-L3-dioxo-L2,3,4- tetrahydroisoquinoline-4-carboxamide
Figure imgf000135_0001
Intermediate 35 was hydrogenated on Pd/C 5% giving compound 34. Grey solid (60%); mp 100-110 °C; 100% keto form; 1H NMR (300 MHz, OMSO-d6): δ = 2.73 (t, 2 H, CH2, 3J = 5.0 Hz), 3.37 (m, 2 H, CH2), 5.03 (s, 1 H, CH), 7.12-7.24 (m, 5 H, HAr), 7.53 (t, 1 H, HAT, 3J = 7.3 Hz), 7.63 (t, 1 H, HAr 3J = 6.8 Hz), 8.04 (d, 1 H, HAr, 3J = 8.1 Hz), 8.83 (m, 1 H, NH), 10.58 (s, 1 H, OH); 13C NMR (75 MHz, OMSO-d6): δ = 33.8 (CH2), 40.7 (CH2), 55.2 (CH), 114.9 (d, 2 CH, C3 » , C5", 2JC-F = 20.9 Hz), 125.3 (Civ), 126.6 (CH), 127.8 (CH), 128.1 (CH), 130.6 (d, 2 CH, C2 », C6", 3JC-F = 8.2 Hz), 133.6 (CH), 134.4 (Civ), 135.2 (Civ), 160.9 (d, Civ, C4 » 'JC-F = 241.5 Hz), 161.5 (CO), 164.7 (CO), 166.0 (CO); ESI-MS: m/z = 343 (M+H)+; Anal. (Ci8Hi5FN204) C, H, N.
EXAMPLE B35
Compound 35: N-(4-Fluorobenzyl)-2,3-dihvdroxy-7-nitro-l-oxo-L2-dihydroisoquinoline-
4-carboxamide
Figure imgf000136_0001
Intermediate 41 (0.46 g, 1.0 mmol) was dissolved in a minimum of CH2CI2 at -78 °C and boron trichloride (1.0 M solution in CH2C12, 5.0 mL, 5.0 mmol) was added dropwise. The solution was stirred for 1 h at -78 °C and the reaction mixture was allowed to reach 0 °C. Then water (5.0 mL) was added. The first precipitate (impure fraction) was filtered and the filtrate was kept several hours at room temperature. The second precipitate was filtrated and triturated with ether. Orange solid (15%); mp 159-162 °C; 100% enol form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.46 (d, 2 H, NHCH2, 3J = 5.0 Hz), 7.14 (t, 2 H, UAr 3JH.H= 3JH. F = 8.6 Hz), 7.36 (dd, 2 H, YiAr 3JH.H = 8.8 Hz, 4JH.F= 5.7 Hz), 7.98 (dd, 1 H, ¾, 3J= 9.6 Hz, 4J= 2.6 Hz), 8.75 (d, 1H,
Figure imgf000136_0002
9.7 Hz), 10.07 (s, 1 H, OH), 10.28 (t, 1H, NH, 3J = 5.0 Hz); 13C NMR (75 MHz, OMSO-d6): δ = 41.4 (NHCH2), 89.7 (C4), 115.0 (d, 2 CH, 2JC-F = 21.3 Hz), 116.0 (Civ), 123.7 (CH), 123.8 (CH), 124.2 (CH), 129.2 (d, 2 CH, 3JC-F = 8.2 Hz), 136.7 (Civ), 138.3 (Civ), 143.0 (C7), 157.5 (CO), 159.5 (CO), 161.1 (d, Civ, 'JC-F = 241.0 Hz), 167.6 (CO); ESI-MS: m/z = 374 (M+H)+; Anal. (C17H12FN306) C, H, N.
EXAMPLE B36
Compound 36 : N-(4-Fluorobenzyl)-7-amino-2-hvdroxy- 1 , 3 -dioxo- 1,2,3 ,4-tetrahydro- isoquinoline-4-carboxamide
Figure imgf000136_0003
Intermediate 41 (0.46 g, 1.0 mmol) was dissolved in a mixture of ethyl acetate (10 mL) and methanol (5 mL) and hydrogenated for 4 h at room temperature over Pd/C 5% (50.0 mg). The catalyst was filtered and the solvent was removed in vacuo. Trituration of the residue in ether afforded the deprotected compound as a green solid. Yield: 70%; mp 212- 216 °C; 100% keto form; 1H NMR (300 MHz, DMSO-i¾): δ = 4.25 (dd, 1 H, NHCH^, 2J = 15.3 Hz, 3J= 5.5 Hz), 4.32 (dd, 1 H, NHCiL., 2J= 15.3 Hz, 3J= 5.5 Hz), 4.90 (s, 1 H, CH), 5.60 (s, 2 H, H2), 6.85 (dd, 1 H, ¾, 3J = 8.2 Hz, 4J= 2.0 Hz), 7.02 (d, 1 H,
Figure imgf000137_0001
8.2 Hz), 7.17 (t, 2 H, 3JH-H = 3JH-F = 8.6 Hz), 7.25 (d, 1H, ¾, 4J= 2.0 Hz), 7.30 (dd, 2 H, 3JH.H = 8.4 Hz, 3JH_F = 5.7 Hz), 9.15 (t, 1H, NH 3J= 5.1 Hz), 10.46 (s, 1 H, OH); 13C NMR (75 MHz, DMSO-i¾): δ = 42.9 (NHCH2), 55.4 (CH), 112.3 (CH), 116.1 (d, 2 CH, 2JC-F = 21.3 Hz), 120.6 (CH), 121.7 (Civ), 126.7 (Civ), 128.2 (CH), 130.2 (d, 2 CH, 3JC-F = 8.2 Hz), 135.9 (d, 2 CH, 4JC-F = 2.7 Hz), 149.7 (C7), 162.3 (d, Civ, 'JC-F = 241.0 Hz), 163.0 (CO), 166.2 (CO), 168.0 (CO); ESI-MS: m/z = 344 (M+H)+; Anal. (Ci7Hi4FN304) C, H, N.
EXAMPLE B37
Compound 37 : N-Hexyl-2, 3 -dihydroxy-7-nitro- 1 -oxo- 1 ,2-dihydroi soquinoline-4- carboxamide
Figure imgf000137_0002
Intermediate 42 was treated with boron trichloride according to example B35. Yellow powder (20%); mp 114-116 °C; 100% enol form; 1H NMR (300 MHz, DMSO-i¾ ): δ = 0.87 (m, 3 H, CH3), 1.30 (m, 6 H, CH2), 1.48 (m, 2 H, CH2), 3.24 (t, 2 H, C¾ 3J= 5.1 Hz), 7.99 (d, 1 H,
Figure imgf000137_0003
9.5 Hz); NMR 13C (75 MHz, DMSO-i¾): δ = 14.4 (CH3), 22.6 (CH2), 26.8 (CH2), 29.8 (CH2), 31.5 (CH2), 38.8 (CH2), 90.3 (C4), 116.4 (Civ), 124.1 (CHAr), 124.3 (CHAr), 124.6 (CHAr), 138.7 (Civ), 143.2 (Civ), 157.9 (CO), 161.0 (CO), 167.9 (CO); MALDI-TOF: m/z = 350 (M+H)+; Anal.
Figure imgf000137_0004
EXAMPLE B38
Compound 38 : N-Phenyl-2,3 -dihydroxy-7-nitro- 1 -oxo- 1 ,2-dihydroisoquinoline-4- carboxamide
Figure imgf000137_0005
Intermediate 43 was treated with boron trichloride according to example B35. Yellow powder (32%); mp 162-165 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6 ): δ = 6.98 (t, 1 H, 3J = 7.4 Hz), 7.29 (t, 2 H, H and 3J = 7.6 Hz), 7.65 (d, 2 H, H2> and H6% 5J = 7.8 Hz), 8.07 (d, 1 H, H6, 3J= 9.8 Hz), 8.79 (s, 1 H, ¾), 9.40 (d, 1H, H5> 3J= 9,8 Hz), 12.43 (s, 1H, OH); NMR 13C (75 MHz, OMSO-d6): δ = 90.3 (C4), 116.9 (Cr), 119.6 (2 CHAr), 119.6 (CHAr), 124.2 (2 CHAr), 125.0 (CHAr), 129.2 (2 CHAr), 139.1 (Civ), 140.7 (Civ), 143.6 (C7), 158.3 (CO), 161.6 (CO), 166.3 (CO); MALDI-TOF: m/z = 342 (M+H)+; Anal. (CieHnNsOe) C, H, N.
EXAMPLE B39
Compound 39 : N-(4-Fluorophenyl)-2,3 -dihydroxy-7-nitro- 1 -oxo- 1 ,2-dihydroi soquinoline- 4-carboxamide
Figure imgf000138_0001
Intermediate 43 was treated with boron trichloride according to example B35. Brown powder (40%); mp 178-180 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6 ): δ = 7.13 (t, 2 H, ¾' and ¾<, 3JH-H = 3JH-F = 8.3 Hz), 7.66 (dd, 2 H, H2> and ¾>, 3JH-H = 8.3 Hz and 4JH-F = 5.3 Hz), 8.06 (d, 1 H, H6 3J= 9.8 Hz), 8.78 (s, 1 H, ¾), 9.40 (d, 1 H, H5, 3J = 9.8 Hz), 12.46 (s, 1 H, OH); NMR 13C (75 MHz, DMSO-i¾): δ = 90.1 (C4), 115.7 (d, Cy and C5>, 2JC-F = 21.8 Hz), 116.9 (Civ), 121.2 (d, C2> and C6% 3JC-F = 6.5 Hz), 124.2 (2 CHAr), 125.0 (CHAT), 137.1 (Civ), 139.0 (Civ), 143.6 (C7), 156.2 (CO), 159.3 (CO), 160.1 (d, C4>, ^C-F = 259.0 Hz), 166.3 (CO); MALDI-TOF: m/z = 360 (M+H)+; Anal. (Ci6Hi0FN3O6) C,
H, N.
EXAMPLE B40
Compound 40 : N-Benzyl-2, 3 -dihydroxy-7-nitro- 1 -oxo- 1 ,2-dihydroi soquinoline-4- carboxamide
Figure imgf000139_0001
Intermediate 45 was treated with boron trichloride according to example B35. Yellow powder (25%); mp 164-166 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6 ): δ = 4.49 (s, 2 H, CH2), 7.25-7.34 (m, 5 H, HAr), 8.02 (d, 1H,
Figure imgf000139_0002
9.1 Hz), 8.76 (s, 1 H, ¾), 9.24 (d, 1 H, H5, 3J = 9.1 Hz); NMR 13C (75 MHz, OMSO-d6): δ = 42.6 (CH2), 90.2 (C4), 116.5 (Civ), 124.1 (CHAr), 124.2 (CHAr), 124.7 (CHAr), 127.0 (CHAr), 127.7 (2 CHAr), 128.8 (2 CHAr), 138.7 (Civ), 140.9 (Civ), 143.4 (C7), 158.0 (CO), 161.1 (CO), 167.9 (CO); MALDI-TOF: m/z = 356 (M+H)+; Anal. (C17Hi3N306) C, H, N.
EXAMPLE B41
Compound 41 : N-(4-Methoxybenzyl)-2,3-dihvdroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
Figure imgf000139_0003
Intermediate 46 was treated with boron trichloride according to example B35. Orange powder (40%); mp 137 °C; 100% enol form; 1H NMR (300 MHz, OMSO-d6 ): δ = 3.73 (s, 3 H, OCH3), 4.40 (s, 2 H, CH2), 6.89 (d, 2 H, HAr 3J= 8.1 Hz), 7.26 (d, 2 H, HAr 3J= 8.1 Hz), 8.00 (d, 1 H, H6, 3J= 9.2 Hz), 8.75 (s, 1 H, ¾), 9.28 (d, 1 H, H5, 3J= 9.2 Hz), NMR 13C (75 MHz, DMSO-i¾): δ = 42.1 (CH2), 55.5 (OCH3), 90.2 (C4), 114.2 (C and C5 ), 116.6 (Civ), 124.1 (CHAr), 124.2 (CHAr), 124.7 (CHAr), 129.1 (C2> and C6'), 132.6 (Civ), 138.8 (Civ), 143.2 (Civ), 158.0 (CO), 158.5 (CO), 160.9 (CO), 167.8 (CO); MALDI-TOF: m/z = 386 (M+H)+; Anal. (Ci8Hi5N307) C, H, N.
EXAMPLE B42
Compound 42: N-(4-Fluorophenethyl)-2,3-dihydroxy-7-nitro-l-oxo-L2- dihydroisoquinoline-4-carboxamide
Figure imgf000140_0001
Intermediate 47 was treated with boron trichloride according to example B35. Yellow powder (18%); mp 153 °C; 100% enol form; Ή NMR (300 MHz, OMSO-d6 ): δ = 2.79 (t, 2 H, CH2, 3J= 7.3 Hz), 3.48 (t, 2 H, CH2, 3J= 7.3 Hz), 7.1 1 (t, 2 H, Hy and Η5·, 3JH-H= 3JH- F= 7.5 Hz), 7.30 (dd, 2 H, Η2· and H6-, 3JH.„= 7.3 Hz and 4JH.F= 6.0 Hz), 7.97 (d, 1 H, H6, J= 9.8 Hz), 8.73 (s, 1 H, H8), 9.35 (d, 1 H, Hs. 3J= 9.8 Hz); NMR 13C (75 MHz, DMSO- d6): δ = 34.9 (CH2), 40.7 (CH2), 89.9 (C4), 1 15.2 (d, C3- and C5-, 2JC-F = 20.7 Hz), 1 16.3 (Civ), 124.0 (CHAT), 124.6 (CHAT), 128.2 (CHAr), 130.4 (d, C2- and C6-, 3JC.F = 7.6 Hz), 136.2 (CIV), 136.5 (C,v), 142.8 (C7), 157.9 (CO), 160.4 (CO), 160.9 (d, C4-, 'JC.F = 242.7 Hz), 167.7 (CO); MALDI-TOF: m/z = 388 (M+H)+; Anal. (C,8H,4FN306) C, H, N.
EXAMPLE B43
Compound 43 : N-(4-Fluorobenzyl)-7-acetamido-2-hvdroxy- 1 ,3-dioxo- 1.2.3 ,4- tetrahvdroisoquinoline-4-carboxamide
Figure imgf000140_0002
Intermediate 52 (1.0 mmol) was dissolved in a minimum of CH2C12 and boron trichloride (1.0 M solution in CH2C12, 6.0 mL, 6.0 mmol) was added dropwise at -78 °C. The solution was stirred for 1 h at -78 °C and water (20 mL) was slowly added. After 15 min stirring, the precipitate was filtered and triturated with ether. Beige solid (43%); 100% keto form; mp 227-230 °C; Ή NMR (300 MHz, DMSO-rfi ): δ = 2.08 (s, 3 H, CH3), 4.29 (dd, 1 H, CH2, J = 15.5 Hz and 3J= 5.6 Hz), 4.30 (dd, 1 H, CH2, 2J = 15.5 Hz and 3J = 5.6 Hz), 5.08 (s, 1 H, H4), 7.17 (t, 2 H, Η3· and Η5·, 3JH-H = F = 8.9 Hz), 7.28-7.32 (m, 3 H, H5, Η2· and H6 ), 7.84 (dd, 1 H, H6, 3J= 8.5 Hz and 4J = 2.2 Hz), 8.32 (d, 1 H, H8, 4J= 2.2 Hz), 9.27 (t, 1 H, NH, 3J= 5.6 Hz), 10.27 (s, 1 H, NH); NMR l3C (75 MHz, DMSO-c¾: δ = 24.5 (CH3),
139
RECTIFIED SHEET (RULE 91)
ISA/EP 42.4 (CH2), 55.2 (C4), 1 15.6 (d, C3- and C5-, 2JC-F = 21.3 Hz), 1 17.9 (CHAr), 124.7 (CHAT), 126.2 (C,v), 127.6 (CHAT), 129.1 (Qv), 129.7 (d, C2- and C6-, 3JC-F = 8.7 Hz), 135.2 (d, C,-, 4JCF = 2.2 Hz), 139.7 (C7), 161.7 (Cr, 'JC-F = 241.6 Hz), 161.9 (CO), 165.2 (CO), 166.8 (CO), 169.3 (CO); MALDI-TOF: m/z = 386 (M+H)+; Anal. (C19H16FN3O5) C, H, N.
EXAMPLE B44
Compound 44: N-(4-Fluorobenzyl)-2-hvdroxy-l .3-dioxo-7-phenylacetamido-l,2,3.4- tetrahvdroisoquinoline-4-carboxamide
Figure imgf000141_0001
Intermediate 56 (0.10 g) was dissolved in a mixture of N,N-dimethylforrnamide (10 mL) and methanol (10 mL) and hydrogenated for 3 h at room temperature over Pd/C 5% (10 mg). The catalyst was filtered and the solvent was removed in vacuo. Trituration of the residue in ether afforded the deprotected compound 44 as a grey solid (83%); mp 203-204
°C; 100% keto form; Ή NMR (300 MHz, DMSO-ck): δ = 3.67 (s, 2 H, CH2), 4.29 (d, 2 H, CH2, 3J= 5.8 Hz), 5.08 (s, 1 H, H4), 7.17 (t, 2 H, H3- and ¾··, 3JH-H = 3JH-F= 8.8 Hz), 7.25- 7.35 (m, 8 H, HM, Hs, H2» and H6-), 7.87 (dd, 1 H, H6, JJ= 8.4 Hz and 4J = 2.2 Hz), 8.33 (d, 1 H, Hg, V= 2.2 Hz), 9.25 (t, 1 H, NH, V= 5.8 Hz), 10.51 (s, 1 H, NH), 10.61 (s, 1 H, NOH); NMR 13C (75 MHz, DMSO-d6): δ = 42.4 (CH2), 43.7 (CH2), 55.2 (C4), 1 15.6 (d, C3" and C5 », 2JC-F = 20.7 Hz), 1 18.1 (CHAX), 124.8 (CHAT), 126.2 (C,v), 127.1 (CH^), 127.7 (CHAT), 128.8 (2 CHAT), 129.3 (C,v), 129.6 (2 CHA,), 129.7 (d, C2- and C6 », 3JC-F = 8.2 Hz), 135.2 (d, C , 4JC.F= 2.7 Hz), 136.1 (dv), 139.6 (C1V), 161.7 (d, C4-, 'JC.F= 241.1 Hz), 161.8 (CO), 165.2 (CO), 166.8 (CO), 170,0 (CO); MALDI-TOF: m z = 462 (M+H)+; Anal. (C25H2oFN305) C, H, N.
EXAMPLE B45
Compound 45: N-(4-Fluorobenzvn-7-benzamido-2-hvdroxy-L3-dioxo- 1.2.3,4- tetrahvdroisoquinoline-4-carboxamide
1 40
RECTIFIED SHEET (RULE 91 )
ISA7EP
Figure imgf000142_0001
Intermediate 60 was hydrogenated over Pd/C 5% according to example B44. Grey powder (89%); mp 196-198 °C; 100% keto form; Ή NMR (300 MHz, DMSO-< tf ): δ = 4.32 (d, 1 H, CH2, 2J=15.2 Hz and 3J = 5.7 Hz), 4.33 (d, 1 H, CH2, 2J=15.2 Hz and 3J= 5.7 Hz), 5.12 (s, 1 H, H4), 7.18 (t, 2 H, H3- and Hs », 3JH-H = -F= 8.9 Hz), 7.32 (dd, 2 H, ¾·· and ¾■·, 3JH-H = 8.9 Hz and 4JH.F = 5.6 Hz), 7.37 (d, 1 H, H5, 3J= 8.5 Hz), 7.56-7.62 (m, 3 H, HAT), 7.99-8.01 (m, 2 H, HAr), 8.1 1 (dd, 1H, H6, J= 8.5 Hz and 4J= 2.2 Hz), 8.53 (d, 1 H,
Figure imgf000142_0002
5.7 Hz), 10.56 (s, 1 H, NH), 10.63 (s, 1 H, NOH); NMR 13C (75 MHz, DMSO-ck): δ = 42.4 (CH2), 55.3 (C4), 1 15.6 (d, C3- and C5-, 2JC-F = 21.3 Hz), 119.4 (CHAT), 126.0 (CHAT), 126.2 (CIV), 127.5 (CHAT), 128.2 (2 CHAT), 129.0 (2 CHAT), 129.7 (d, C2- and C6 » 3JC-F= 8.2 Hz), 132.4 (CHAT), 134.1 (Crv), 134.8 (CIV), 135.2 (C,v), 139.6 (C7), 161.8 (C4-, 'JC-F = 241.0 Hz), 161.9 (CO), 165.3 (CO), 166.2 (CO), 166.8 (CO); MALDI-TOF: m/z = 448 (M+H)+; Anal. (C24H18FN3O5) C, H, N.
EXAMPLE B46
Compound 46: -V-(4-Fluorobenzyl')-2-hvdroxy-1.3-dioxo-7-picolinamido-l.2.3.4- tetrahvdroisoquinoline-4-carboxamide
Figure imgf000142_0003
Intermediate 64 was treated with boron trichloride according to example B43. Yellow powder (33%); mp 21 -212 °C; 100% keto form; Ή NMR (300 MHz, OUSQ-d6 ): 6 = 4.31 (dd, 1 H, CH2, = 15.6 Hz and JJ= 5.6 Hz), 4.32 (dd, 1 H, CH2, 2 J = 15.6 Hz and 3 J = 5.6 Hz), 5.14 (s, 1 H, C4), 7.18 (t, 2 H, C3 - and C5". W-W= 3JH-F= 8.6 Hz), 7.31 (dd, 2 H, Η2·. and ¾··, 3JH-H = 8.6 Hz and 4JH.F ~ 5.7 Hz), 7.38 (d, 1 H, 5J = 8.3 Hz, HAT), 7.69-7.73 (m, 1 H, HAT), 8.07-8.20 (m, 3 H, HAT), 8.74-8.78 (m, 2 Η, HAT), 9.32 (t, 1 Η, NH, 3J = 5.6 Hz), 1 1.02 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-i rt): δ = 42.4 (CH2), 55.3 (C4), 115.6 (d, C3- and C5-, 2JC-F = 21.3 Hz), 1 19.6 (CHAT), 123.1 (CHAT), 126.2 (C,v), 126.4 (CHAT),
141
RECTIFIED SHEET (RULE 91 )
ISA/EP 127.5 (CHAR), 127.6 (CHAR), 129.7 (d, C2 · and C6-, 3JC-F = 85 Hz), 130.1 (C,v), 135.3 (d, C,-, <Jc.F= 3.3 Hz), 138.7 (CHAT), 138.8 (C7), 149.0 (CHAR), 150.0 (C, ), 161.7 (d, C4-, 'JC- F= 241.0 Hz), 161.9 (CO), 163.4 (CO), 165.2 (CO), 166.8 (CO); MALDI-TOF: m/z = 449 (M+H)+; Anal. (C23H,7FN405) C, H, N.
EXAMPLE B47
Compound 47: N-(4-Fluorobenzyl)-2-hvdroxy-l .3-dioxo-7-(2-(thiophen-2-vDacetamido)- 1.23.4-tetrahvdroisoquinoline-4-carboxamide
Figure imgf000143_0001
Intermediate 68 was treated with boron trichloride according to example B43. Green powder (61%); mp 183-186 °C; 100% keto form; Ή NMR (300 MHz, DMSO-rftf ): δ =
3.91 (s, 2 H, CH2), 4.30 (dd, 1 H, CH2> 2J = 15.6 Hz and 3J= 5.7 Hz), 4,31 (dd, 1 H, CH2, 2J = 15.6 Hz and 3J= 5.7 Hz), 5.09 (s, 1 H, C4), 6.99-7.00 (m, 2 H, HAT), 7.17 (t, 2 H, ¾·· and Hy, 3JH.H = 3JH-F = 8.8 Hz), 7.31 (dd, 2 H, H2- and ¾··, 3JH-H = 8.6 Hz and 4JH.F = 5.1 Hz), 7.41-7.42 (m, 2 H, HAT), 7.86 (d, 1 H, HA,, 3J= 8.6 Hz), 8.34 (s, 1 H, H8), 9.27 (t, 1 H, NH, JJ= 5.7 Hz), 10.56 (s, 1 H, NH); NMR 13C (75 MHz, DMSO-^): δ = 38.0 (CH2), 42.4 (CH2), 55.2 (C4), 1 15.5 (d, C3- and Cy, 2Jc-F = 21.3 Hz), 1 18.1 (CHAT), 124.9 (CHAT), 125.7 (CHAR), 126.2 (C,v), 127.0 (CHAT), 127.2 (CHAT), 128.9 (CHAR), 129.5 (C,v), 129.7 (d, C2" and C6-, 3JC-F = 8.2 Hz), 135.2 (d, C , 4JC-F = 2.7 Hz), 137.2 (C,v), 139.4 (C,v), 1613.7 (d, C4 ., 'JC.F = 240.5 Hz), 161.8 (CO), 165.2 (CO), 166.8 (CO), 168.9 (CO); MALDI-TOF: m/z = 468 (M+H)+; Anal. (C23H18FN305S) C, H, N.
EXAMPLE B48
Compound 48 : N-(4-Fluorobenzyl)-7-chloro-2-hydroxy- 1.3 -dioxo- 1.2.3.4- tetrahvdroisoQuinoline-4-carboxamide
Figure imgf000143_0002
RECTIFIED SHEET (RULE 91 )
ISA/EP Intermediate 72 was treated with boron trichloride according to example B43. Beige powder (69%); mp 168-169 °C; 100% keto form; Ή NMR (300 MHz, OMSO-d6 ): δ = 4.28 (dd, 1 H, CH2, 2J = 15.5 Hz and 3J = 6.2 Hz), 4.29 (dd, 1 H, CH2, 2J= 15.5 Hz and 3 J = 6.2 Hz), 5.16 (s, 1 H, H4), 7.18 (t, 2 H, Η3· and Y, 3JH.H = 3JH.F= 9.0 Hz), 7.30 (dd, 2 H, Η2· and Η6·, 3JH.H = 9.0 Hz and 3JH-F= 5.6 Hz), 7.41 (d, 1 H, HAT. 3J= 8.2 Hz), 7.79 (d, 1 H, HAT, 3J = 8.2 Hz), 8.02 (s, 1H, H8), 9.34 (t, 1 H, NH, 3 J = 6.2 Hz); NMR L3C (75 MHz, DMSO-4 : δ = 42.5 (CH2), 55.3 (C4), 1 15.6 (d, C3- and C5., 2JC.F= 21.3 Hz), 127.5 (CHAT), 127.7 (C,v), 129.2 (CHAT), 129.7 (d, Cr and C6-, 3JC-F= 8.2 Hz), 133.5 (Qv), 133.8 (C,V), 134.1 (CHAT), 135.1 (C,v), 161.0 (CO), 161.8 (d, C4-, 'JC-F= 240.6 Hz), 164.9 (CO), 166.4 (CO); MALDI-TOF: m/z = 363 and 365 (M+H)+; Anal. (C,7H I2C1FN204) C, H, N.
EXAMPLE B49
Compound 49: N-(4-Fluorobenzyl)-7-bromo-2-hvdroxy- 1.3-dioxo- 1 ,2.3,4- tetrahvdroisoquinoline-4-carboxamide
Figure imgf000144_0001
Intermediate 76 was treated with boron trichloride according to example B43. Pink powder (45%); mp 170-171 °C; 100% keto form; Ή NMR (300 MHz, DMSO-ek): δ = 4.28 (dd, 1 H, CH2, 2JH-H = 15.3 Hz and 3JH-F = 5.1 Hz), 4.29 (dd, 1 H, CH2, 2JH-H = 1 .3 Hz and 3JH-F = 5.1 Hz), 5.14 (s, 1 H, H4), 7.18 (t, 2 H, ¾· and Η5·,
Figure imgf000144_0002
8.6 Hz), 7.28-7.36 (m, 3 H, HAr), 8.06 (d, 1 H, HAT, JJ= 8.2 Hz), 8.14 (s, 1 H, Hg), 9.33 (t, 1 H, NH, = 5.1 Hz); NMR l3C (75 MHz, DMSO-¾: δ = 42.5 (CH2), 55.4 (C4), 1 15.6 (d, C3- and C5., Jc.F= 21.3 Hz), 121.6 (C7), 127.9 (CIV), 129.4 (CHAT), 129.7 (d, C2- and C6; 3JC-F = 8.2 Hz), 130.5 (CHAT), 134.2 (CIV), 135.1 (d, Cr, 4JC-F = 22 HZ), 136.9 (CHAT), 160.9 (CO), 161.8 (d, C4., lJC-F= 240.6 Hz), 164.9 (CO), 166.3 (CO); MALDI-TOF: m/z = 407 and 409(M+H)+; Anal. (C17H12BrFN20 ) C, H, N.
EXAMPLE B50
Compound 50: N-(4-Fluorobenzv0-7-fluoro-2-hvdroxy-1.3-dioxo-1.2,3.4- tetrahvdroisoquinoline-4-carboxamide
143
RECTIFIED SHEET (RULE 91 )
ISA/EP
Figure imgf000145_0001
Intermediate 80 was treated with boron trichloride according to example B43. Pink powder (55%); mp 179-180 °C; 100% keto form; Ή NMR (300 MHz, DMSO-d6): δ = 4.30 (dd, 1 H, CH2, 2J = 15.6 Hz and 3J = 5.3 Hz), 4.31 (dd, 1 H, CH2, 2J = 15.6 Hz and 3 J = 5.3 Hz), 5.15 (s, 1 H, H ), 7.17 (t, 2 H, H3- and HyT 3JH.H = 3JH-F = 8.6 Hz), 7.30 (dd, 2 H, Hr and Η6·, 3JH.H = 8.6 Hz and .F= 5.7 Hz), 7.44 (dd, 1 H, H5, 3JH-H = 8.0 Hz and 4J„.F = 5.1 Hz), 7.60 (td, 1 H, H6, 3JH-H = 3JH-F = 8.0 Hz and 4JH-H = 1.9 Hz), 7.79 (dd, 1 H, H8, 3JH- r= 9.1 Hz and 4JH-H = 1.9 Hz), 9.33 (t, 1 H, NH 3J= 5.3 Hz); NMR l3C (75 MHz, DMSO- d6): δ = 42.4 (CH2), 55.2 (C4), 1 14.3 (d, CHAT, 2JC-F = 23.5 Hz), 1 15.6 (d, C3- and C5-, JC-F = 21.3 Hz), 121.7 (d, CHAT, ≥ C-F = 22 A Hz), 127.9 (d, C8A, 3JC-F = 8.2 Hz), 129.6 (d, 1H, C5, 3JC.F = 8.2 Hz), 129.7 (d, C2- and C6-, 3JC-F = 8.2 Hz), 131.2 (d, C4A, 4JC.F = 3.3 Hz), 135.1 (d, Cr, 4JC-F = 3.3 Hz), 161.1 (d, C,, 4JC-F = 2.2 Hz), 161.7 (d, C7, 'JCF = 241.1 Hz), 162.0 (C4., JC-F = 244.4 Hz), 165.0 (CO), 166.5 (CO); MALDI-TOF: m/z = 347 (M+H)+; Anal. (C,7H12F2N204) C, H, N.
EXAMPLE B51
Compound 51 : N-(4-Fluorobenzyl)-2-hvdroxy-7-methoxy- 1.3 -dioxo- 1.2.3.4- tetrahvdroisoquinoline-4-carboxamide
Figure imgf000145_0002
Intermediate 87 was hydrogenated over Pd/C 5% according to example B44. White powder (86%); mp 174-177 °C; 100% keto form; Ή NMR (300 MHz, DMSO-ck ): δ =
3.85 (s, 3 H, OCH3), 4.29 (dd, 1 H, CH2, V=14.6 Hz, 3J= 5.0 Hz), 4.30 (dd, 1 H, CH2, 2J =14.6 Hz, 3J= 5.0 Hz), 5.06 (s, 1 H, H4), 7.17 (t, 2 H, H3- and Η5-, 3JH-H = 3JH-F = 8.9 Hz), 7.26-7.32 (m, 4 H, HAT), 7.52 (d, 1 H, H8, = 2.3 Hz), 9.25 (t, 1 H, NH. = 5.1Hz), 10.61 (s, 1 H, NOH); NMR , 3C (75 MHz, DMSO--¾: δ = 41.9 (CH2), 54.5 (C4), 55.5 (OCH3), 1 10.9 (CHAT), Π5.1 (d, C3- and Cy, 2JC.F = 2\ Hz), 121.0 (CHAT), 126.4 (C,V), 126.5
144
RECTIFIED SHEET (RULE 91 )
ISA/EP (Civ), 128.0 (CHAr), 129.1 (d, CY and C6% 3JC-F = 8.2 Hz), 134.7 (d, Cr, 4JC.F = 2.7 Hz), 158.9 (CO), 161.2 (d, C4>, 'JC-F = 240.6 Hz), 161.4 (CO), 164.8 (CO), 166.4 (CO); MALDI-TOF: m/z = 359 (M+H)+; Anal. (Ci8Hi5FN205) C, H, N. C BIOLOGICAL EXAMPLES
EXAMPLE CI: Integrase assays.
The enzymatic integration reactions were carried out with minor modifications as described previously (Christ et al., Debyser et al.). To determine the susceptibility of the HIV-1 IN enzyme to different compounds, we used an enzyme-linked immunosorbent assay (ELISA) (adapted from Hwang et al.). The overall integration assay uses an oligonucleotide substrate for which one oligonucleotide (5'- ACTGCTAGAGATTTTCCACACTGACTAAAAGGGTC-3' (SEQ ID NO 1)) is labeled with biotin at the 3' end and the other oligonucleotide (5'- GACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGT-3' (SEQ ID NO 2)) is labeled with digoxigenin at the 5' end. For the strand transfer assay, a precleaved oligonucleotide substrate (the second oligonucleotide lacks GT [underlined] at the 3' end) was used. The IN enzyme was diluted in 750 mM NaCl, 10 mM Tris (pH 7.6), 10% glycerol, and 1 mM β- mercaptoethanol. To perform the reaction, 4 μΐ of diluted IN (corresponding to a concentration of 1.6 μΜ) and 4 μΐ of annealed oligonucleotides (7 nM) were added in a final reaction volume of 40 μΐ containing 10 mM MgCl2, 5 mM dithiothreitol, 20 mM HEPES (pH 7.5), 5% polyethylene glycol, and 15% dimethyl sulfoxide. As such, the final concentration of IN in this assay was 160 nM. The reaction was carried out for 1 h at 37°C. Reaction products were denatured with 30 mM NaOH and detected by ELISA on avi din- coated plates. For determining the effect of compounds on the 3 'processing activity a classical cleavage assay with detection of products by denaturating gel electrophoresis was performed as described previously (Christ et al. Debyser et al.). Briefly, 0.2 pmol of the radioactive labeled oligonucleotide substrate (INT1, 32P-5' TGTGGAAAATCTCTAGCAGT 3' (SEQ ID NO 3); INT2, 5'ACTGCTAGAGATTTTCCACA 3' (SEQ ID NO 4)) and 10 nmol IN in a final volume of 10 μΐ was incubated for 1 h at 37°C. The final reaction mixture contained 20 mM HEPES pH 7.5), 5 mM dithiothreitol (DTT), 10 mM MgCl2, 0.5% (v/v) polyethylene glycol 8000, 15% DMSO,. IN was diluted previously in 750 mM NaCl, 10 mM Tris (pH 7.6), 10% glycerol and 1 mM β-mercaptoethanol. The reactions were stopped by the addition of formamide loading buffer (95% formamide, 0.1% xylene cyanol, 0.1% xylene cyanol, 0.1% bromophenol blue and 0.1% sodium dodecyl sulfate). Samples were loaded on a 15%) denaturating polyacrylamide/ureum gel. The extent of 3 '-processing or DNA strand transfer was based on measuring the respective amounts of -2 bands or strand transfer products relative to the intensity of the total radioactivity present in the lane. These data were determined using the OptiQuant Acquisition and Analysis software (Perkin Elmer Corporate, Fremont, C A). The results are shown in table 1.
EXAMPLE C2: Drug susceptibility assay.
The inhibitory effect of antiviral drugs on the HIV-induced cytopathic effect (CPE) in MT- 4 cell culture was determined by the MTT-assay (Pauwels et al.). This assay is based on the reduction of the yellow colored 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) by mitochondrial dehydrogenase of metabolically active cells to a blue formazan derivative, which can be measured spectrophotometrically. The 50% cell culture infective dose of the HIV strains was determined by titration of the virus stock using MT-4 cells. For the drug susceptibility assays, MT-4 cells were infected with 100 to 300 50% cell culture infective doses of the HIV strains in the presence of fivefold serial dilutions of the antiviral drugs. The concentration of the compound achieving 50% protection against the CPE of HIV, which is defined as the 50% effective concentration (IC50), was determined. The concentration of the compound destroying 50% of the MT-4 cells, which is defined as the 50% cytotoxic concentration (CC50), was determined as well. The results are shown in table 1.
References
Hwang, Y., D. Rhodes, and F. Bushman. 2000. Rapid microtiter assays for poxvirus topoisomerase, mammalian type IB topoisomerase and HIV-1 integrase: application to inhibitor isolation. Nucleic Acids Res. 28:4884-4892.
Pauwels, R., J. Balzarini, M. Baba, R. Snoeck, D. Schols, P. Herdewijn, J. Desmyter, and E. De Clercq. 1988. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 20:309-21. Debyser, Z., et al., Assays for the evaluation of HIV-1 integrase inhibitors., in Methods in Molecular Biology., C.H. Schein, Editor. 2001, Humana Press Inc.: Totowa, NJ. p. 139- 155.
Christ, F., Busschots, K., Hendrix, J., Engelborghs, Y., Debyser, Z., Assays for the evaluation of HIV-1 integrase enzymatic activity, DNA-binding and co-factor interaction. In Integrase Ed. N. Neamati To be published 2009.
TABLE 1
Figure imgf000148_0001
ComIntegrase enzymatic activity Activity in MT-4 cells pound
number
Overall Strand transfer 3' processing HIV-1 Cytotoxicity enzymatic enzymatic activity EC50 in μΜ CC50 in μΜ activity activity IC5o in μΜ
IC50 in μΜ IC50 in μΜ
18 0.235±0.007 0.307±0.072 - >125 125
19 0.205±0.035 0.258±0.184 - >11 11
20 4.5±0.02 3.49±2.57 - >175 175
21 0.495±0.078 0.126±0.008 - 70.77±9.34 >125
22 0.673±0.538 0.296±0.196 - >63 63
23 8.12±1.61 9.1±1.85 - >120 120
24 123±58 206±17 - >28 28
25 8.66±1.27 8.7±0.49 - >63.76 63.76
26 0.86±0.03 1.05±0.13 - 32.53±13.91 109.5±1.5
27 9.05±0.28 9.13 - 27.96 98.5±6.5
28 17.46±0.66 20.73±5.08 - >18.55 18.55
29 0.31±0.13 0.73±0.33 - 4.95 105.5±5.5
30 5.21±0.51 5.6±0.19 - >107.2 107.2
31 0.8±0.3 1.12±0.78 - 1.75 114.5±2.5
32 0.08±0.01 0.03±0.01 - 3.12 130±10
33 1.19±0.47 1.03±0.4 - 17.63 118.5±8.5
34 0.16±0.13 0.37±0.18 - 9.39±4.75 134±22
35 0.0106±0.0013 0.0145±0.0000 0.103±0.027 121.5±3.5
2
36 0.3±0.014 0.382±0.282 - 23.29±3.58 217
37
0.9±0.12 1.64±0.01 4.21±0.69 >250
VS47
38
0.02±0.01 0.03±0.01 0.17 115.5±18.5
VS52 ComIntegrase enzymatic activity Activity in MT-4 cells pound
number
Overall Strand transfer 3' processing HIV-1 Cytotoxicity enzymatic enzymatic activity EC50 in μΜ CC50 in μΜ activity activity IC5o in μΜ
IC50 in μΜ IC50 in μΜ
39
0.03±0 0.01±0 0.19 186.5±7.5
VS49
40 0.003±0
0.01±0 0.21 118.5±8.5
VS53
41
0.04±0.01 0.01±0 2.97 >250
VS51
42
0.06±0.01 0.03±0 0.95 >250
VS50
43
0.1±0.02 0.06±0 29.28±4.46 149±149
VS41
44
0.43±0.28 0.27±0.18 >31.86 31
VS43
45
0.31±0.15 0.21±0.04 >21.06 21
VS42
46
0.16±0 0.77±0.01 >1.17 1
VS44
47
0.26±0.16 0.27±0.0 >41.09 41
VS46
48
0.51±0.18 0.26±0.01 1.19 105.5±4.5
VS55
49
0.43±0.06 0.21±0.05 2.99 99.5±7.5
VS54
50
0.73±0.03 0.5±0.01 0.72 116.5±2.5
VS56 ComIntegrase enzymatic activity Activity in MT-4 cells pound
number
Overall Strand transfer 3' processing HIV-1 Cytotoxicity enzymatic enzymatic activity EC50 in μΜ CC50 in μΜ activity activity IC50 in μΜ
IC50 in μΜ IC50 in μΜ
51
0.35±0.03 0.62±0.02 6.5±1.45 21±0
VS45

Claims

1. A compound of formula (I),
Figure imgf000152_0001
or a tautomer (Γ) thereof, or a pharmaceutically acceptable salt or solvate or prodrug of said compound or tautomer thereof, wherein
R1 and R2 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; C(=0)R9; C(=S)R9;
C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3;
C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents selected from halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NR7R8,
-OCF3, C(=0)R9, C(=S)R9, and Ar3;
Ar1;
Het1; or R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)5- (a-3); R3, R4, R5 and R6 are each independently selected from: hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; C1-6alkyl optionally substituted with halo, C1-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3; -NHC(=0)Ar2; or -NHC(=0)Het2; each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or
Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or Het4;
each R10, R11, and R12 ;is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4; each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents independently selected from halo, Ci-6alkyl, OH,
Ci-6alkyloxy, N02, -OCF3, and CF3; each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3.
provided that the following compounds are excluded:
Figure imgf000154_0001
2-Hydroxy- 1 ,3-dioxo- 1 ,2,3,4-tetrahydro-isoquinoline-4-carboxamide,
Figure imgf000154_0002
2-Hydroxy-6,7-dimethyl-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4-carboxamide.
2. The compound as claimed in claim 1 wherein
R1 is hydrogen;
Figure imgf000154_0003
or C2-i2 lkenyl, which are each optionally substituted with one or more substituents selected from halo, C(=0)R9, Ar3, and Het3; C3-iocycloalkyl; or Ar1;
R2 is hydrogen or Ci-6alkyl; or
R1 and R2 together form the bivalent radical of formula (a-3);
R3, R4, R5 and R6 are each, independently, hydrogen, N02, - R7R8, Ci-6 alkoxy, optionally substituted with -C(=0)OCi-6alkyl or Ar3, - HC(=0)Ar2, or - HC(=0)Het2;
R7 and R8 are each, independently, hydrogen or Ci-6alkyl;
R9 is Ci-6 alkoxy; and
Ar1 and Ar3 are each optionally substituted with 1 or 2 substituents independently selected from halo, Ci-6alkyl, OH, and Ci-6alkyloxy;
Het2 is pyridinyl; and
Het3 is thienyl.
3. The compound as claimed in any one of claims 1 or 2 wherein R1 is hydrogen; Ci-i2alkyl or C2-i2 lkenyl, which are each optionally substituted with one or more substituents selected from halo, -C(=0)OC2H5, phenyl, and thienyl;
C5cycloalkyl; or phenyl;
R2 is hydrogen, methyl, or ethyl; or
R1 and R2 together form the bivalent radical of formula (a-3);
R3, R4, R5 and R6 are each, independently, hydrogen, N02, or H2, methyloxy,
- HCOCH3, - HCOCH2phenyl, - HCOphenyl, - HCOpyridinyl, or
- HCOCH2thienyl; and
each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy.
4. The compound as claimed in any one of claims 1 to 3, wherein
R1 is hydrogen, Ci-i2alkyl, phenylmethyl, phenylethyl, or phenyl;
R2 is hydrogen; and
R5 is hydrogen, methyloxy, - HCOCH2phenyl, -NHCOphenyl, -NHCOpyridinyl, or -NHCOCH2thienyl; and
each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, methyl, OH, and methyloxy.
5. The compound as claimed in any one of claims 1 to 4 wherein the compound is
N-(3-Chloropropyl)-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-Hexyl-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4-carboxamide,
N-(3-Fluorophenyl)-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(3-Chloro-4-methoxyphenyl)-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(2,4-Dimethoxybenzyl)-2 -hydroxy- 1,3-dioxo-l, 2,3,4-tetrahydroisoquinoline-4- carboxamide, N-(2,4-Dihydroxybenzyl)-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4- carboxamide,
N-(3,4-Dihydroxybenzyl)-2-hydroxy-l,3-dioxoisoquinoline-4-carboxamide,
N-Dodecyl-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4-carboxamide, N-Benzyl-2-hydroxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydroisoquinoline-4-carboxamide,
N-(4-Fluorobenzyl)-2,3-dihydroxy -7-nitro- l-oxo-l,2-dihydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-7-amino-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4- carboxamide,
N-Phenyl-2,3-dihydroxy -7-nitro -l-oxo-l,2-dihydroisoquinoline-4-carboxamide, N-(4-Fluorophenyl)-2,3 -dihydroxy -7-nitro - 1 -oxo- 1 ,2-dihydroisoquinoline-4- carboxamide,
N-Benzyl-2,3-dihydroxy -7-nitro -l-oxo-l,2-dihydroisoquinoline-4-carboxamide, N-(4-Methoxybenzyl)-2,3-dihydroxy -7-nitro -l-oxo-l,2-dihydroisoquinoline-4- carboxamide,
N-(4-Fluorophenethyl)-2,3-dihydroxy -7-nitro -l-oxo-l,2-dihydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-7-acetamido-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide,
N-(4-Fluorobenzyl)-2-hydroxy-l,3-dioxo-7-phenylacetamido-l,2,3,4- tetrahydroisoquinoline-4-carboxamide,
N-(4-Fluorobenzyl)- 7-benzamido-2-hydroxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-
4-carboxamide,
N-(4-Fluorobenzyl)- 2-hydroxy- 1 ,3 -dioxo-7-picolinamido- 1 ,2,3,4- tetrahydroisoquinoline-4-carboxamide,
N-(4-Fluorobenzyl)- 2-hydroxy- 1 ,3 -dioxo-7-(2-(thiophen-2-yl)acetamido- 1 ,2,3,4- tetrahydroisoquinoline-4-carboxamide, or
N-(4-Fluorobenzyl)-2-hydroxy-7-methoxy-l,3-dioxo-l,2,3,4-tetrahydroisoquinoline-4- carboxamide.
6. The compound as claimed in any one of claims 1 to 5 for use as a medicine.
7. A pharmaceutical composition comprising an effective amount of a compound as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition as claimed in claim 7, further comprising a therapeutically effective amount of an HIV/AIDS treatment agent selected from the group consisting of: an HIV/AIDS antiviral agent; an anti-infective agent; and an immunomodulator.
9. The compound as claimed in any one of claim 1 to 5, or the pharmaceutical composition as claimed in claims 7 or 8 for use as a treatment of infection by HIV, or for treating AIDS.
10. A compound of formula (I),
Figure imgf000157_0001
or a tautomer (Γ) thereof, or a pharmaceutically acceptable salt or solvate of said compound or tautomer thereof, wherein
R1 and R2 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; - R7R8; -OCF3; C(=0)R9; C(=S)R9;
Ci-i2alkyl, C2-i2alkenyl, or C2-i2alkynyl, which are each optionally substituted with one or more substituents selected from halo, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, and Het3; C3-iocycloalkyl or C3-iocycloalkenyl, which are each optionally substituted with one or more substituents selected from halo, C1-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, and Ar3;
Ar1;
Het1; or
R1 and R2 together form a bivalent radical of formula
-(CH2)3- (a-1),
-(CH2)4- (a-2), or
-(CH2)s- (a-3);
R3, R4, R5 and R6 are each independently selected from:
hydrogen; halo; -OH; -SH; -CN; -N02; -NR7R8; -OCF3; CF3; C(=0)R9; C(=S)R9; C1-6alkyl optionally substituted with halo, C1-6alkyl, -OH, -SH, -CN, -N02, -NR7R8, -OCF3, C(=0)R9, C(=S)R9, Ar3, or Het3;
Ci-6alkyloxy; Ci-6alkylthio; Ar2; Ar2oxy; Ar2thio; Het2; Het2oxy; Het2thio; C3-6Cycloalkyl;
-NHC(=0)Ci-6alkyl optionally substituted with halogen, -C(=0)OCi-6alkyl, or Ar3; -NHC(=0)Ar2; or -NHC(=0)Het2; each R7 and R8 is independently selected from hydrogen; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; or C(=0)R12;
each R9 is hydrogen; OH; Ci-6alkyl optionally substituted with halo, -OH, -SH, -CN, -N02, -NR10RU, -OCF3, C(=0)R12, C(=S)R12, Ar3, or Het3; Ci-6 alkoxy; -NR10RU; Ar4; or Het4;
each R10, R11, and R12 is independently selected from hydrogen; OH; Ci-6alkyl optionally substituted with halo, Ci-6alkyl, -OH, -SH, -CN, -N02, -NH2, -OCF3, C(=0)H, C(=S)H, Ar3, or Het3; Ci-6 alkoxy; Ar4; or Het4; each of Ar1, Ar2, Ar3 ; and Ar4, is independently phenyl or naphthyl, and is optionally substituted with 1 to 5 substituents independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and CF3; each of Het1, Het2, Het3, and Het4, is independently a mono- or bicyclic heterocyclic ring system containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S, and said heterocyclic ring system is optionally substituted with 1 to 4 substituents independently selected from halo, Ci-6alkyl, OH, Ci-6alkyloxy, N02, -OCF3, and -CF3; for use as an antiviral agent or for treating AIDS.
11. . A process for making a compound as claimed in any one of claims 1 to 5 wherein a) the intermediate of formula (II) is reacted with a boron halide or is deprotected by catalytic dehydrogenation with the formation of a compound of formula (I)
Figure imgf000159_0001
(Π) (I)
12. The process for making a compound according to claim 11 wherein
a) the intermediate of formula (II) is obtained by reacting intermediate of formula (III) with a suitable amine
Figure imgf000160_0001
(III) (II)
13. An intermediate of formula (II) or (IF) wherein the substituents R1, R2, R3, R4, R5 and R6, are as defined in any one of claims 1 to 5
Figure imgf000160_0002
provided that the following compounds are excluded:
Figure imgf000160_0003
2-Benzyloxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4-carboxamide,
Figure imgf000161_0001
2-Benzyloxy-l,3-dioxo-l,2,3,4-tetrahydro-isoquinoline-4-(l,l-dimethyl-but-2-ynyl)- carboxamide,
Figure imgf000161_0002
2-Benzyloxy-7-chloro- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydro-isoquinoline-4-carboxamide,
Figure imgf000161_0003
2-Benzyloxy-6,7-dimethoxy- 1 ,3 -dioxo- 1 ,2,3 ,4-tetrahydro-isoquinoline-4-( 1 , 1 -dimethyl- but-2-ynyl)-carboxamide.
14. An intermediate as claimed in claim 13 for use as medicine.
15. An intermediate as claimed in claim 14 for use as an antiviral agent.
16. A process for preparing a pharmaceutical composition as claimed in claim 7 or 8 wherein a therapeutically effective amount of a compound as claimed in any one of claims 1 to 5 is intimately mixed with a pharmaceutically acceptable carrier.
17. The process for preparing a pharmaceutical composition as claimed in claim 9 wherein a therapeutically effective amount of a compound as claimed in any one of claims 1 to 5 and a therapeutically effective amount of an HIV/ AIDS treatment agent as claimed in claim 8 are intimately mixed with a pharmaceutically acceptable carrier.
18. The use of a compound of formula (I) as defined in claim 10 for the manufacture of a medicament for the prevention or treatment of viral infections in mammals.
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