WO2006066414A1 - Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase - Google Patents

Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase Download PDF

Info

Publication number
WO2006066414A1
WO2006066414A1 PCT/CA2005/001964 CA2005001964W WO2006066414A1 WO 2006066414 A1 WO2006066414 A1 WO 2006066414A1 CA 2005001964 W CA2005001964 W CA 2005001964W WO 2006066414 A1 WO2006066414 A1 WO 2006066414A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydroxy
optionally substituted
benzyl
fluoro
Prior art date
Application number
PCT/CA2005/001964
Other languages
French (fr)
Inventor
Laval Chan Chun Kong
Bingcan Liu
Nghe Nguyen-Ba
Caroline Cadilhac
Nathalie Turcotte
Original Assignee
Virochem Pharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Virochem Pharma Inc. filed Critical Virochem Pharma Inc.
Priority to CA002634499A priority Critical patent/CA2634499A1/en
Priority to EP05849193A priority patent/EP1973906A1/en
Publication of WO2006066414A1 publication Critical patent/WO2006066414A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to novel compounds and method for the treatment or prevention of HIV infection/ AIDS .
  • Nair V Rev. Med. Virol . 2002 , ⁇ 2 , 179-193) . It is a protein of M r 32000 encoded at the 3 ' -end of pol gene .
  • This viral enzyme catalyses the integration of viral DNA into host cell chromosomal DNA to form a provirus .
  • This essential step in the viral life cycle proceeds by integrase recognizing and binding to attachment sites located at the ends of linear viral DNA, followed by the cleavage of highly conserved CA dinucleotides from the 5' and 3' long-terminal repeats .
  • This reaction known as 3' -processing, occurs in the cytoplasm and exposes the 3 ' -0H group from the CA unit .
  • This OH group subsequently acts as a nucleophile by attacking the host DNA in a transesterification reaction .
  • strand transfer or integration occurs in the nucleus .
  • HIV integrase is further attractive as a target for the development of anti-HIV drugs because there is apparently no functional equivalent of this enzyme in human cells . It has also been reported that integrase inhibitors in combination with either reverse transcriptase or protease inhibitors are potently synergistic against both wild-type HIV and reverse transcriptase inhibitor resistant viruses (Robinson WE Jr et al Antiviral Res . 1998 , 39, .101-111 ; Beale K et al Antiviral Res 2000 , 46, 223-232 ) .
  • integrase inhibitors A number of integrase inhibitors have been reported, including nucleotide-based inhibitors, DNA binders, catechols , hydrazides, etc (Neamati N : Expert Opin Ther Patents 2002 , 12 , 709-724 ) . Most of these compounds inhibit integrase function in extracellular oligonucleotide assays but often lack inhibitory potency when assayed using fully assembled preintegration complexes or fail to show antiviral effects against HIV-infected cells .
  • a class of diketo- containing int'egrase inhibitors has been found to inhibit viral replication by blocking the strand transfer step of integrase reactions ( Pais GCG & Burke TR Jr : Drugs of the Future, 2002 , 27 , 1101-1111 ) .
  • An inhibitor of this class has been in clinical trials for the treatment of HIV infection (Billich A: Curr . Opin . Investig . Drugs 2003 , 4 , 206-209 ) .
  • diketo- containing compounds are electrophilic and they bind covalently to human cellular proteins leading to potential cytotoxicity.
  • A is a single or double bond, and when A is a double bond R. 2 or R' 2 and R 3 or R' 3 are absent ; '
  • Ri is H, OH, optionally substituted C 6 -io aryl , optionally substituted 5-10 member heteroaryl , optionally substituted 4-10 member heterocycle, or Ci-10 alkyl optionally substituted , with one or more substituents selected from optionally substituted C 3 - 10 cycloalkyl, optionally substituted C 6 _io aryl , optionally substituted 5-1O 1 member heteroaryl, or optionally substituted 4-10 member heterocycle ( e . g . , R 1 can be optionally substituted (CH 2 ) 1 -4 phenyl ) ;
  • R 2 or R' 2 can also be taken together with R 3 or R' 3 , and the atoms to which they are attached, to form an optionally substituted C 3 - 10 cycloalkyl, an optionally substituted 4-10 member heterocycle, an optionally substituted C 6 _io aryl or an optionally substituted 5-10 member heteroaryl;
  • R 2 and R' 2 or R 3 and R' 3 can also be j oined together, with the atoms to which they are attached, to form an optionally substituted C 3 - 10 cycloalkyl or an optionally substituted 5-10 member heterocycle;
  • n 0 , 1 , or 2 ;
  • R 4 and R 5 can also be taken together, with the atoms to which they are attached, to form an optionally substituted C 5 - 10 cycloalkyl, optionally substituted 5- 10 member heterocycle, optionally substituted 5-10 member heteroaryl, or optionally substituted C 6 -io aryl ;
  • Re, R 7 , R' 7 are each independently hydrogen, optionally substituted Ci-io alkyl, optionally substituted C 6 - 10 aryl, or optionally substituted C 7 _i 2 aralkyl;
  • R 6 can also be taken together with R 7 or R' 7 , with the atoms to which they are attached, to form a 5-10 member heterocycle;
  • R 7 and R' 7 can be taken together, with the atom to which they are attached, to form a 4-10 member heterocycle .
  • the compound of formula I can also be in the form of a pharmaceutically acceptable solvate or a solvate of a pharmaceutically acceptable salt thereof
  • a method of preventing or treating HIV infection in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention .
  • a method of preventing, delaying or treating AIDS in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention .
  • a method of inhibiting HIV integrase in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention .
  • a method of preventing integration of HIV DNA into host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention .
  • a method of preventing HIV DNA strand transfer to the host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition
  • the invention provides the use of a compound or combination of the present invention for the manufacture of a medicament for preventing or treating HIV infection or preventing, delaying or treating AIDS .
  • the invention provides the use of a compound or combination of the present invention for the manufacture of a medicament for preventing any one of HIV replication, integration of HIV DNA into host cell DNA, 3' -end processing of HIV DNA or HIV DNA strand transfer to the host cell DNA.
  • the present invention provides a combination comprising a therapeutically effective amount of compound of the present invention, and a therapeutically effective amount of at least one antiviral agent .
  • a further aspect of the invention is therefore presented as a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or combination of the present invention together with at least one pharmaceutically acceptable carrier or excipient thereof .
  • compounds of the present invention comprise those wherein the following embodiments are present, either independently or in combination.
  • A is a single or double bond, and when A is a double bond R 2 or R ' 2 and R 3 or R' 3 are absent ;
  • Ri is H, OH, optionally substituted C 6 - I0 aryl , optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member heterocycle, or Ci_i 0 alkyl optionally substituted with one or more substituents selected from optionally substituted C 3 - I0 cycloalkyl, optionally substituted C 6 - I0 . aryl, optionally substituted 5-10 member heteroaryl, or optionally substituted 4-10 member heterocycle (e . g . , Ri can be optionally substituted (CH 2 ) 1 - 4 phenyl ) ;
  • R 2 or R' 2 can also be taken together with R 3 or R' 3 , and the atoms to which they are ' attached, to form an optionally substituted C 3 - I0 cycloalkyl, an optionally substituted 4-10 member heterocycle, an optionally substituted C 6 - I0 aryl or an optionally substituted 5-10 member heteroaryl ;
  • R 2 and R' 2 or R 3 and R' 3 can also be j oined together, with the atoms to which they are attached, to form an optionally .substituted ,C 3 _io cycloalkyl or an optionally substituted 5-10 member heterocycle ;
  • n 0 , 1 , or 2 ;
  • R 4 and R 5 can also be taken together, with the atoms to which they are attached, to form a optionally substituted C5-.1 0 cycloalkyl, optionally substituted 5- 10 member heterocycle, optionally substituted 5-10 member heteroaryl, or optionally substituted C ⁇ -io aryl ;
  • R 6 , R 7 , R' 7 are each independently hydrogen, optionally substituted C ⁇ _io alkyl, optionally substituted C ⁇ -io aryl, or optionally substituted C 7 _ ⁇ 2 aralkyl; R 6 can also be taken together with R 7 or R' 7 , with the atoms to which they are attached, to form a 5-10 member heterocycle; and
  • R 7 and R' 7 can be taken together, with the atom to which they are attached, to form a 4-10 member heterocycle .
  • the compound of formula I can also be in the form of a pharmaceutically acceptable solvate or a solvate of a pharmaceutically acceptable salt thereof
  • A is a single bond .
  • Ri can be H, OH, optionally substituted C ⁇ -io aryl, optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member heterocycle, optionally substituted cycloalkylalkyl wherein the cycloalkyl portion has 3 to 10 carbon atoms and the alkyl portion has 1 to 10 carbon atoms, optionally substituted aralkyl wherein the aryl portion has 6 to carbon atoms and the alkyl portion has 1 to 10 carbon atoms, optionally substituted heteroaralkyl wherein the heteroaryl portion is a 5-10 member heteroaryl and the alkyl portion has 1 to 10 carbon atoms , or optionally substituted hetefocycle-alkyl wherein the heterocyclic portion is a 4-10 member heterocycle and the alkyl portion has 1 to 10 carbon atoms .
  • R 1 is hydrogen . In one embodiment of the invention, Ri is hydroxy.
  • Ri is C1-4 alkyl substituted by an optionally substituted aryl group .
  • Ri is (CH 2 ) i- 4 phenyl where phenyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro, nitroso, urea,
  • Ci-ioalkyl C 7 - I0 aralkyl
  • Ri is (CH 2 ) i_ 4 phenyl where phenyl is unsubstituted or substituted with one or more substituents " independently selected from: halogen, amino, amido, cyano, hydroxyl, urea, OCi-io alkyl,
  • R b and Rb ' are each independently H, Ci-io alkyl,' C 7 - I2 aralkyl or 3-10 member heterocycle, or
  • R b and R b ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
  • Ci_io alkyl, C 7 - I2 aralkyl or 3-10 member heterocycle, or R b and R b ' are taken together with the atoms to which
  • Ri is (CH2) i- 4 phenyl where phenyl is substituted with one or more substituents independently selected from: fluoro, bromo, chloro,
  • Ri is CH 2 - ( 4-fluorophenyl) .
  • Ri is CH 2 - ( 3 , 4 dichlorophenyl ) . In another embodiment Ri is CH 2 - ( 3-chloro-4- fluorophenyl) .
  • Ri is CH 2 - (2-N-methylamido-4- fluorophenyl) .
  • R 2 and R' 2 are each independently chosen from:
  • R 2 and R' 2 are each independently chosen from: H;
  • R 2 and R' 2 are each independently chosen from: H,
  • Phenyl , Ci_ 6 alkyl, COOCi-ealkyl, CONR 7 R' ⁇ , and CR 6 NOR' 6 .
  • R 3 and R' 3 are each independently chosen from:
  • R 3 and R' 3 are each independently chosen from:
  • R 3 and R' 3 are each independently chosen from:
  • R 4 is : H, halogen, amino, amidino, amido, azido, cyano, guanidino, nitro, nitroso, urea, S(0)o- 2 R a (wherein R a is H, Ci-I 0 alkyl, C 6 - I0 aryl or 3-10 member heterocycle) ,
  • Rb is H, Ci_io alkyl, C 6 -I 0 aryl, C 7 -I 2 aralkyl—or 3-10 member heterocycle
  • Ci-io alkyl, C 6 - I0 aryl, C 7 - I2 aralkyl or 3-10 member heterocycle, or R b and R b ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , NR b SO 2 NR b 'Rc (wherein R b , R b ' and R c are each independently H, Ci- I0 alkyl, C 6 - I0 aryl, C 7 - I2 aralkyl or 3-10 member heterocycle, or R b and R c are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
  • CR b N OR b ' (wherein R b and R b ' are each independently H, Ci-io alkyl, C 6 _ 10 aryl, C 7 _i2 aralkyl or 3-10 member heterocycle ) ,
  • NR b COOR b ' wherein R b and R b ' are each independently H or Ci-io alkyl, C 6 -io aryl, C 7 -I 2 aralkyl or 3-10 member heterocycle, or NR b COCONR b ' R c (wherein R b , R b ' and R c are each independently H or Ci_i 0 alkyl, C ⁇ -io aryl, C 7 -i 2 aralkyl or 3-10 member heterocycle, or Rb ' and R c are taken together with the atoms to which they are attached to form a 4-10 member heterocycle) .
  • R 4 is halogen, amino, amido, cyano, urea
  • R b and R b ' are each independently H, Ci-io alkyl, C ⁇ -io aryl, C 7 - I2 aralkyl or 3-10 member heterocycle, or R b and R b ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
  • NRbSO 2 Rb ' (wherein R b and Rb ' are each independently H, C 1 -IO alkyl , C 6 -I 0 aryl , C 7 -I 2 aralkyl or 3-10 member heterocycle, or R b and R b ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
  • R C (wherein R b , R b ' and R c are each independently H, Ci_io alkyl, C 6 _io aryl, C 7 - I2 aralkyl or 3-10 member heterocycle, or R b ' and R c are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
  • R b and R b ' are each independently H, Ci-io alkyl, C 6 -Io aryl, C 7 - I2 aralkyl or 3-10 member heterocycle, or
  • R b , R b ' and R c are each independently H, Ci-I 0 alkyl, C 6 -io aryl, C 7 - I2 aralkyl or 3-10 member heterocycle, or R b f and R c are taken together with the atoms to which they are attached to form a 4-10 member he'terocycle) .
  • R 4 is halogen, NR b SO 2 R b ' (wherein R b and R b ' are each independently H,
  • Ci- 10 alkyl , C 6 - I0 aryl, C 7 - I2 aralkyl or 3-10 member heterocycle, or R b and R b ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle ) , NR b SO 2 NR b ' R c (wherein R b , R b ' and R c are each independently H, Ci- 10 alkyl , C 6 - I0 aryl , C 7 - I2 aralkyl or 3-10 member heterocycle, or R b ' and R c are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
  • R b and R b ' are each independently H, Ci-io alkyl, C ⁇ -io aryl, C 7 -i2 aralkyl or 3-l ⁇ member ' heterocycle, or R b and R b ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , or
  • R b , Rb 1 and R c are each independently H, Ci_io alkyl, C ⁇ -io aryl, C 7 _i 2 aralkyl or 3-10 member heterocycle, or R b ' and R c are taken together with the atoms to 'which they are attached to form a 4-10 member heterocycle) .
  • R 4 is Br, NHCOCON ( CHS ) 2 ,
  • R 4 is optionally substituted Ci- io alkoxy (e . g . , Ci-ealkoxy) , optionally substituted C ⁇ -io aryloxy, or optionally s ⁇ bstituted C 6 aryl-Ci_i 0 alkyloxy.
  • R 4 is optionally substituted Ci- io alkoxy (e . g . , Ci- ⁇ alkoxy) .
  • R 4 is optionally substituted C & - io aryloxy (e . g . , phenoxy, 4-fluorophenoxy) . In another embodiment, R 4 is optionally substituted C 6 aryl-Ci_ 10 alkyloxy .
  • R4 is optionally halogenated Ci- 10 alkoxy (e . g . , Ci_ 6 alkoxy) .
  • R 4 is optionally halogenated CQ- 10 aryloxy.
  • R 4 is optionally halogenated C ⁇ aryl-Ci-ioalkyloxy .
  • R 4 is an optionally substituted 5-10 member heterocycle, or optionally substituted 5-10 member heteroaryl .
  • Suitable heterocycle and heteroaryl for R 4 include : piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, and pyrazinyl .
  • R 4 is an amino group selected from NH2, monoalkylamino in which the alkyl group has 1 to 6, preferably 1 to 4 , carbon atoms , and dialkylamino in which each alkyl group has , independently, 1 to 6, preferably 1 to 4 , carbon atoms , and -N (Ci- 4 -alkyl) -aryl wherein the aryl j is optionally substituted (e . g . , phenylamino wherein the phenyl group is substituted by halogen such as F) .
  • R 4 is an optionally substituted -O-heterocycle wherein the heterocycle group has 5-10 members , or optionally substituted -O-heteroaryl wherein the heteroaryl group has 5-10 members .
  • Suitable heterocycle and heteroaryl for R 4 include : piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl)
  • R 4 is , an optionally substituted -0-Ci_ 4 -alkyl-heterocycle wherein the heterocycle group has 5-10 members , or optionally substituted -0-Ci- 4 -alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • morpholinylethoxy tetrahydropyranylmethoxy, 1 , 3- dioxanylmethoxy, dimethyl-1, 3-dioxanylmethoxy, 1 , 3- dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo-tetrahydrofuranylmethoxy) .
  • R 5 is
  • R 4 and R 5 are j oined to form a 5-
  • the compounds are selected from subformulas Ia-Ij j , which correspond, respectively, to Formula I , but which exhibit the following groups :
  • Ia A is a single bond
  • R 4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, or N (Ci-4-alkyl) 2 ⁇ phenoxy optionally substituted by F, Cl, Br, Ci_ 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1 -
  • CONHCi- 4 -alkyl or CON (Ci- 4 -alkyl) 2 , or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci-4-alkyl, NH 2 , NHCi_ 4 -alkyl,
  • Ib A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H; and R 4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl , CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, or
  • N (Ci-4-alkyl) 2 phenoxy optionally substituted by F, Cl, Br, Ci_ 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-C 1 - 4 - alkyl , NH 2 , NHCi- 4 -alkyl, N (Ci_ 4 -alkyl) 2 , CONH 2 , CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2 , or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi- 4 -alkyl, N(Ci_ 4 -alkyl) 2 , CONH 2 , CONHCi_ 4 -alkyl,
  • A is a single bond
  • R 2 , R' 2 , R 3 , and R' 3 are each H;
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl, Br, Cx- ⁇ -alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1- 4 - alkyl, NH 2 , NHCi_ 4 -alkyl, N (d- 4 -alkyl) 2 , CONH 2 ,
  • R 4 is Ci- 10 alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 -.
  • Ci- 10 alkoxy e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy
  • CONHCi- 4 -alkyl or CON (Ci_ 4 -alkyl ) 2 , or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl , CO-Ci_ 4 -alkyl , NH 2 , NHCi_ 4 -alkyl,
  • A is a single bond;
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H ;
  • R 1 is benzyl optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci_ 4 -alkyl , NH 2 , NHCi_ 4 -alkyl ,
  • R 4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, or N (Ci- 4 -alkyl) 2 , phenoxy optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-C
  • A is a single bond;
  • R 2 , R' 2 , R 3 , and R' 3 are each H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, C 1 -. 4 - alkyl, hydroxyalkyl having 1 to 4 carbon atoms, C 2 - 4 -alkenyl, COOH, COO-Ci-4-alkyl, NH 2 ,
  • R 4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl, CO-Ci-4-alkyl, NH 2 , NHCi-4-alkyl, or
  • N (Ci- 4 -alkyl ) 2 phenoxy optionally substituted by F, Cl, Br, Ci_ 4 -alkyl, cyano, ⁇ hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1 - 4 - alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci_ 4 -alkyl ).
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, C 1 - 4 - alkyl, hydroxyalkyl having 1 to 4 carbon atoms , C 2 -4-alkenyl , COOH, C00-Ci- 4 -alkyl, NH 2 , NHCi- 4 -alkyl, or N (Ci_ 4 -alkyl ) 2 ;
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl , Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-C 1 - 4 - ⁇ . alkyl, NH 2 , NHCi-4-alkyl, N (Ci_ 4 -alkyl) 2 , CONH 2 , CONHCi-4-alkyl, or CON (Ci_ 4 -alkyl ) 2 ; and R 4 is Ci-io alkoxy (e . g .
  • methoxy, ethoxy, propoxy isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyaho, hydroxy, carboxy, COO-Ci_ 4 - alkyl, CO-Ci_ 4 -alkyl , NH 2 , NHCi- 4 -alkyl, or
  • N (Ci_ 4 -alkyl) 2 phenoxy optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1 - 4 - alkyl, NH 2 , NHCi-4-alkyl, N (C ⁇ _ 4 -alkyl) 2 , CONH 2 , CONHCi- 4 -alkyl, or CON (Ci- 4 -alkyl ) 2 , or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- • Ci- 4 -alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi-4-alkyl , N (Ci- 4 -alkyl) 2 , CONH 2 , CON
  • Ig A is a single bond
  • R 2 , R' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen
  • R 4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, ' difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi- 4 -alkyl, or N (Ci_4-alkyl ) 2 A phenoxy optionally substituted by F, Cl, Br, Ci_ 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C
  • CONHCi- 4 -alkyl or CON (Ci_ 4 -alkyl) 2 , or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl ,
  • Ih A is a single bond
  • R 2 , R' 2 , R 3 , and R' 3 are each H; R 5 is hydrogen;
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, In 1 each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl , cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1 - 4 - alkyl, NH 2 , NHCi- 4 -alkyl, N (Ci-4-alkyl ) 2 , CONH 2 , CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2 ; and
  • R 4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexyimethoxy) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl , CO-Ci-4-alkyl, NH 2 , NHCi_ 4 -alkyl, or N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl , ' Br, Ci_ 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen
  • R 1 is benzyl optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi- 4 -alkyl , N (Ci- 4 -alkyl) 2 , CONH 2 , CONHCi-4-alkyl, or
  • R 4 is Ci- 10 alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, or
  • N (Ci- 4 -alkyl ) 2 phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl , CO-C 1 - 4 - alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci-4-alkyl ) 2 , CONH 2 , CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2 , or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl , cyano, hydroxy, carboxy, COO- Ci_ 4 -alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi- 4 -alkyl, N (Ci_ 4 -alkyl) 2 , CONH 2 , CONHCi-4-alkyl, or
  • R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-Ci- 4-alkyl, NH 2 , NHCi_ 4 -alkyl, or N (Ci_ 4 -alkyl ) 2 , phenoxy optionally substituted by F, Cl , Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, N (C ⁇ 4 - alkyl) 2 , CONH 2 ,
  • Ik A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 4 is an a 5-10 member heterocycle , or 5-10 member heteroaryl ( e . g . piperidinyl , morpholinyl, pyrrolidinyl , pyridinyl , tetrahydrofuranyl , and pyrazinyl ) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano , hydroxy, carboxy, COO-Ci- 4 -alkyl , CO-Ci- 4 -alkyl , NH 2 , NHCi_ 4 -alkyl , or N (Ci_ 4 -alkyl ) 2 , phenoxy optionally substituted by F, Cl , Br, Ci- 4 -alkyl , cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl , CO-C ⁇ -alkyl , NH 2 , NHCi_ 4 -alkyl , N (Ci_
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 1 is benzyl , phenethyl , phenpropyl , or naphthylmethyl , in each case optionally substituted by F, Cl , Br, Ci- 4 -alkyl , cyano , hydroxy, carboxy, COO-Ci- 4 -alkyl , CO-Ci_ 4 - alkyl , NH 2 , NHCi- 4 -alkyl , N (Ci_ 4 -alkyl ) 2 , CONH 2 , CONHC 1 _ 4 -alkyl , or CON ( Ci_ 4 -alkyl ) 2 ; and R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g .
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 1 is benzyl optionally substituted by F, Cl, Br, Ci- 4 -alkyl , cyano, hydroxy, carboxy, COO-
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, Ci_ 4 - alkyl, hydroxyalkyl having 1 to 4 carbon atoms, C 2 _ 4 -alkenyl, COOH, C00-Ci_ 4 -alkyl, NH 2 ,
  • R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-Ci- 4-alkyl, NH 2 , NHCi_ 4 -alkyl , or N (Ci-4-alkyl ) 2 , phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 - alkyl , CO-Ci- 4 -alkyl, NH 2 , NHCi- 4 -alkyl , and R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, Ci_ 4 - alkyl , hydroxyalkyl having 1 to 4 carbon atoms , C 2 - 4 -alkenyl, COOH, COO-Ci_ 4 -alkyl, NH 2 ,
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl, Br, Ci_ 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1 - 4 - alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci- 4 -alkyl) 2 , CONH 2 ,
  • R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl , CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, or N (Ci_ 4 -alkyl ) 2 , phenoxy optionally substituted by F, Cl , Br,
  • Ci- 4 -alkyl cyano, hydroxy, carboxy, COO-C 3. - 4 - alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci- 4 - alkyl ) 2 , CONH 2 , CONHCi_ 4 -alkyl, or CON (Ci- 4 - alkyl) 2 , or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, 1 cyano, hydroxy, carboxy,.
  • COO-Ci_ 4 -alkyl CO-C 1 - 4 - alkyl, NH 2 , NHCi_ 4 -alkyl, N (C 1 _ 4 -alkyl) 2 , CONH 2 , CONHC ⁇ - 4 -alkyl, or CON (Ci_ 4 -alkyl) 2 .
  • A is a single bond
  • R 2 , R' 2 , R 3 , and R' 3 are each H/
  • R is hydrogen; and R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl , tetrahydrofuranyl, and pyrazinyl) optionally substituted by ' F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl , or N (Ci_ 4 -alkyl) 2 , phenoxy optionally substituted by F, Cl , Br, Ci_ 4 -alkyl, cyano, hydroxy, carboxy, COO-C 1 -.
  • R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrroli
  • A is a single bond
  • R 2 , R' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-Ci_ 4 ⁇ alkyl, NH 2 , NHCi- 4 -alkyl, N (Ci_ 4 -alkyl) 2 , CONH 2 , CONHCi- 4 -alkyl, or CON (Ci- 4 -alkyl) 2 ; and R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g .
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H;
  • R 5 is hydrogen
  • R 1 is benzyl optionally substituted by F, Cl,
  • Ci- 4 -alkyl cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl , N (Ci- 4 -alkyl) 2 , CONH 2 , CONHCi-4-alkyl, or CON (Ci- 4 -alkyl) 2 ; and R 4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g .
  • A is a single bond
  • R 4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -O-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . piperidinyl, morpholinyl, pyrrolidinyl , tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-Ci_ 4 -alkyl , NH 2 , NHC 1 - 4 - alkyl, or N (Ci- 4 -alkyl) 2, phenoxy optionally substituted by F, Cl , Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1 - 4 - alkyl,
  • Ci- 4 -alkyl cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHC ⁇ - 4 -alkyl, N (C 1 - 4 -alkyl ) 2 , CONH 2 , CONHCi_ 4 -alkyl, or CON (Ci- 4 -alkyl ) 2 .
  • R 2 , R' 2 , R 3 , and R ' 3 are each H;
  • R 4 is an -O-heterocycle wherein the heterocycle group has 5-10 members, or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e . g . piperidinyl , morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-j-a'lkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl , or N (Ci- 4 -alkyl) 2 , phenoxy optionally substituted by F, Cl, Br,
  • Ci- 4 -alkyl cyano, hydroxy, carboxy, COO-Ci_ 4 - alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci- 4 - alkyl ) 2 , CONH 2 , CONHCi_ 4 -alkyl , or CON (C ⁇ 4 - alkyl) 2 f or benzyloxy, phenethoxy, or phenpropoxy, in, each case optionally substituted 1 by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl , CO-Ci_ 4 - " alkyl , NH 2 , NHCi_ 4 -alkyl , N (Ci- 4 -alkyl) 2 , CONH 2 , CONHCi- 4 -alkyl, or CON (Ci_ 4 -alkyl ) 2
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 1 is benzyl, phenethyl , phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl , CO-Ci_ 4 - alkyl , NH 2 , NHCi_ 4 -alkyl , N (Ci- 4 -alkyl) 2 , CONH 2 , CONHCi_ 4 -alkyl, or CON (Ci_ 4 -alkyl) 2 ; and R 4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e .
  • Iv A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H;
  • R 1 is benzyl optionally substituted by F, Cl, Br, Ci- 4 -alkyl , cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl, CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci- 4 -alkyl) 2 , CONH 2 , CONHCi_ 4 -alkyl, or CON (Ci_ 4 -alkyl ) 2 ; and R 4 is an -O-heterocycle wherein the heterocycle group has 5-10 members, or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • A is a single bond
  • R 2 , R' 2 , R 3 , and R' 3 are each H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, Ci_ 4 - alkyl, hydroxyalkyl having 1 to 4 carbon atoms, C 2 _ 4 -alkenyl, COOH, COO-Ci_ 4 -alkyl, NH 2 , NHCi- 4 -alkyl, or N (Ci- 4 -alkyl) 2 ; and R 4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -O- heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, C 1 - 4 - alkyl, hydroxyalkyl having 1 to 4 carbon atoms , C 2 - 4 -alkenyl, COOH, COO-Ci- 4 -alkyl, NH 2 , NHCi-4-alkyl, or N (Ci-4-alkyl) 2 ;
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C 1 - 4 - alkyl, NH 2 , NHCi- 4 -alkyl, N (Ci-4-alkyl) 2 , CONH 2 ,
  • R 4 is an -0-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has
  • 5-10 members e . g . piperidinyl, morpholinyl, pyrrolidinyl , tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl ) optionally substituted by F,- Cl, Br, methoxy, ethoxy, - cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl , CO-Ci- 4-alkyl, NH 2 , NHCi_ 4 -alkyl, or N (Ci-4-alkyl ) 2 , phenoxy optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-C 1 - 4 - alkyl , CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci_ 4 - • alkyl ) 2, CONH 2 , CONHCi- 4
  • A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H; R 5 is hydrogen; and
  • R 4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has
  • 5-10 members e . g . piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl
  • Iz A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen;
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, C00-Ci- 4 -alkyl, CO-C 1 - 4 - alkyl, NHf, NHCi_ 4 -alkyl, N (Ci- 4 -alkyl) 2 , CONH 2 ,
  • R 4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has
  • 5-10 members e . g . piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-Ci-
  • Iaa A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H; R is hydrogen;
  • R 1 is benzyl optionally substituted by F, Cl, - Br, Ci_ 4 -alkyl, cyano, hydroxy, carboxy, COO- C ⁇ - 4 -alkyl , CO-Ci_ 4 -alkyl, NH 2 , NHCi_ 4 -alkyl,
  • R 4 is an -0-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e . g. piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, C00-Ci_ 4 -alkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi- 4 -alkyl, or N (Ci_ 4 -alkyl) 2 , phenoxy optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 - alkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4
  • Ibb A is a single bond; and FLj is an -O-Cl-4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O- Cl-4-alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy,
  • Ice A is a single bond
  • R 2 , R ' 2 , R 3 , and R' 3 are each H; and R4 is an -0-Ci- 4 -alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C 1 - 4 - alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • Idd A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-C 1 I 4 - alkyl, NH 2 , NHCi- 4 -alkyl, N (Ci_ 4 -alkyl) 2 , CONH 2 ,
  • R 4 is an -O-Ci- 4 -alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C 1 - 4 - alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • R 2 , R ' 2 , R 3 , and R' 3 are each H;
  • R 1 is benzyl optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci- 4 -alkyl, NH 2 , NHCi_ 4 -alkyl, N (Ci_4-alkyl ) 2 , CONH 2 , CONHCi_ 4 -alkyl, or CON (Ci-4-alkyl ) 2 ; and
  • R 4 is an -O-Ci- 4 -alkyl-heterocycle wherein the heterocycle group has 5-10 members, -O-Ci_ 4 -alkyl- heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, Ci_ 4 - alkyl, hydroxyalkyl having 1 to 4 carbon atoms , C 2 - 4 ⁇ alkenyl, COOH, COO-Ci- 4 -alkyl , NH 2 , NHCi- 4 -alkyl, or N (Ci_ 4 -alkyl) 2 ; and R 4 is an -0-Ci_ 4 -alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-Ci- 4 -alkyl- heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • R 2 , R ' 2 , R 3 , and R' 3 are each >H;
  • R 5 is hydrogen, halogen, cyano, hydroxy, Ci_ 4 - alkyl , hydroxyalkyl having 1 to 4 carbon atoms , C 2 - 4 -alkenyl, COOH, COO-Ci- 4 -alkyl , NH 2 , NHCi- 4 -alkyl, or N (Ci- 4 -alkyl )' 2 ;
  • R 1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, C ⁇ - 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-C 1 - 4 - alkyl, NH 2 , NHCi- 4 -alkyl , N (Ci_ 4 -alkyl ) 2 , CONH 2 , CONHCi- 4 -alkyl, or CON (Ci- 4 -alkyl) 2 ; and
  • R 4 is an wherein the heterocycle group has 5-10 members , -O-C 1 -. 4 - alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1, 3- dioxanylmethoxy, dimethyl-1, 3- dioxanylmethoxy, 1 , 3-dioxolanylmethoxy, piperidinyIethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, ' cyano, hydroxy, carboxy, COO-Ci- 4 -alkyl, CO-Ci- 4-alkyl, NH 2 , NHCi_ 4 -alkyl , or N (Ci_ 4 -alkyl) 2 ,
  • Ihh A is a single bond
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen; and R 4 is an -0-Ci_ 4 -alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C 1 - 4 - alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • A is a single bond
  • R 2 , R' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen;
  • R 1 is benzyl, phenethyl , phenpropyl , or naphthylmethyl, ' in each case optionally substituted by F, Cl, Br, Ci- 4 -alkyl, cyano, hydroxy, carboxy, COO-Ci_ 4 -alkyl, CO-C 1 - 4 - alkyl, NH 2 , NHCi- 4 -alkyl, N (Ci-4-alkyl ) 2 , CONH 2 ,
  • R 4 is an -O-Ci- 4 -alkyl-heterocycle wherein the • heterocycle group has 5-10 members , -O-C 1 - 4 - alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • R 2 , R ' 2 , R 3 , and R ' 3 are each H;
  • R 5 is hydrogen
  • R 1 is benzyl optionally substituted by F, Cl , Br, Ci_ 4 -alkyl , cyano, hydroxy, carboxy, COO- Ci- 4 -alkyl , CO-Ci- 4 -alkyl , NH 2 , NHCi_ 4 -alkyl , N ( Ci- 4 -alkyl ) 2 , CONH 2 , CONHCi-4-alkyl , or
  • R 4 is an -O-Ci-4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C 1 - 4 - alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g .
  • the present invention provides novel compounds including :
  • novel compounds including :
  • ACETAMIDE 76 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(PYRIDIN- 3-YLOXY)-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
  • Reference hereinafter to a compound according to the invention includes compounds of the general formula ( I ) and their pharmaceutically acceptable salts , hydrates and solvates .
  • the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 99% .
  • the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 95% .
  • the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 90% .
  • the compounds of the present invention are the (-) enantiomer having an enantiomeric excess of 99% .
  • the compounds of the present invention are the ( -) enantiomer having an enantiomeric excess of 95% .
  • the compounds of the present invention are the (-) enantiomer having an enantiomeric excess of 90% .
  • alkyl represents a linear, branched or cyclic hydrocarbon moiety having 1 to 10 carbon atoms , which may have one or more double bonds or triple bonds in the chain, and is optionally substituted .
  • Examples include but are not limited to methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , tert-pentyl, hexyl, isohexyl, neohexyl, allyl , vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl , butenyl, isobutenyl, hexenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexat
  • alkyl is also meant to include haloalkyls in which one or more hydrogen atom is replaced by a halogen, i . e . an alkylhalide .
  • alkylhalide examples include but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl , chloromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloroethyl, dichloroethyl , chloroethyl, chlorofluoromethyl, chlorodifluoromethyl, dichlorofluoroethyl .
  • alkyl groups can also be optionally substituted by, for example, hydroxy, amino, amido, and/or carboxy .
  • cycloalkyl represents a cyclic alkyl moiety having 3 to 10 carbon atoms , which is optionally substituted ( (e . g . , cyclopropyl, cyclobutyl , cyclopentyl, and cyclohexyl ) .
  • Suitable substituents are, for example, halogens , hydroxy, amino, amido, and/or carboxy .
  • alkoxy represents an alkyl which is covalently bonded to the adj acent atom through an ⁇ oxygen atom. Like the alkyl groups, the alkoxy groups can also be optionally substituted. Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy.
  • the alkoxy groups can be optionally substituted by, for example, halogens, hydroxy, amino, amido, and/or carboxy.
  • aryl represents a carbocyclic moiety containing at least one benzenoid-type ring (i . e . may be monocyclic or polycyclic) , and which may be optionally substituted with one or more substituents .
  • substituents include but are not limited to phenyl, tolyl , dimethylphenyl, aminophenyl, anilinyl, naphthyl, anthryl, phenanthryl or biphenyl .
  • the aryl groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy .
  • aralkyl represents an aryl group attached to the adj acent atom by a C 1 - I0 alkyl . Like the aryl groups , the aralkyl groups can also be optionally substituted. Examples include but are not limited to benzyl, benzhydryl, trityl , phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl and naphthylmethyl . The aralkyl groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy .
  • Alkyloxy represents an aralkyl which is covalently bonded to the . adj acent atom through an oxygen atom.
  • the aralkyloxy groups can also be optionally substituted. Examples include but are not limited to benzyloxy, benzhydryloxy, trityloxy, phenethyloxy, 3-phenylpropyloxy, 2-phenylpropyloxy, 4- phenylbutyloxy and naphthylmethoxy.
  • the aralkyloxy groups can be optionally substituted by, for example, halogens, hydroxy, amino, amido, and/or carboxy.
  • Halogen atom is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom.
  • the term "amido" represents -CONH 2 , -CONHR d , -CONR d R e , - NHCOR d , -NR d C0R e , wherein R d and R e are each independently selected from Ci-10 alkyl, C6-12 aryl or C 7 - 12 aralkyl, or R d and R e are taken together with the nitrogen to which they are attached to form a 4 to 10 member heterocycle .
  • amino represents a derivative of ammonia obtained by substituting one or more hydrogen atom and include -NH 2 , -NHR d and -NR d R e , wherein R d and R e are each independently selected from Ci-10 alkyl, C 6 - 12 aryl or C 7 - I2 aralkyl , or R d and R e are taken together with the nitrogen to which they are attached to form a 4 to 10 member heterocycle .
  • sulfonamido represents -SO 2 NH 2 , -SO 2 NHR d , - SO 2 NR d R e , and -NR d SO 2 R e , wherein R d and R e are each independently selected from Ci- 10 alkyl, C6- 12 aryl or C 7 - i 2 aralkyl, or R d and R e are taken together with the nitrogen to which they are attached to form a 5 to 10 member heterocycle .
  • urea represents -N (R d ) CONR e R f wherein R d is H or Ci-io alkyl and wherein R d and R e are each independently selected from the group consisting of H, Ci-io alkyl, C 6 -io aryl, 3-10 member heterocycle, and C 7 - I2 aralkyl, or R e and Rf are taken together with the nitrogen to which they are attached to form a C 3 -. 10 heterocycle .
  • heterocycle represents an optionally substituted, saturated, partially saturated, or aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0) , sulfur ( S ) or nitrogen (N) .
  • Heterocycles may be monocyclic or polycyclic rings . Examples include but are not limited to azepinyl, aziridinyl , azetyl, azetidinyl, diazepinyl, dithiadiazinyl, dioxazepinyl, .
  • dioxolanyl dithiazolyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, morpholinyl, morpholino, oxetanyl, oxadiazolyl, oxiranyl, oxazinyl, oxazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl , piperidyl, piperidino, pyridyl, pyranyl , pyrazolyl, pyrrolyl, pyrrolidinyl , thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl , thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, thiopyranyl, furoisoxazolyl, imidazothiazolyl, imid
  • heteroaryl represents an optionally substituted aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0) , sulfur (S ) or nitrogen (N) .
  • Heteroaryls may be monocyclic or polycyclic rings .
  • Examples include but are not limited to azepinyl, aziridinyl, azetyl , diazepinyl, dithiadiazinyl , dioxazepinyl, dithiazolyl, furanyl , isooxazolyl, isothiazolyl, ] imidazolyl, oxadiazolyl, oxiranyl, oxazinyl , oxazolyl, ' pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl ⁇ pyranyl , pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl , triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, thiopyranyl, furoisox
  • heteroaralkyl represents an optionally substituted heteroaryl group attached to the adj acent atom by a Ci_io alkyl .
  • the heteroaralkyl groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy.
  • substitutgd represents a group which is substituted by one or more substituents selected from: halogen, amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro, nitroso, urea,
  • Rb is H, C x -I 0 alkyl, C 6 - 10 aryl , C 7 _ 12 aralkyl or 3-10 member heterocycle
  • NR b S ⁇ 2 NR' b R c (wherein R b , R' b and R c are each independently H, Ci_io alkyl, C ⁇ -io aryl, C 7 _ 12 aralkyl or ' 3-10 member heterocycle, or R ' b and R c are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
  • Ci-io alkyl, C 6 -io aryl, C 7 _ 12 aralkyl or 3-10 member heterocycle) are Ci-io alkyl, C 6 -io aryl, C 7 _ 12 aralkyl or 3-10 member heterocycle.
  • enantiomers of the present invention . It will be appreciated that the compounds in accordance with the present invention can contain a chiral center . The compounds in accordance with the present invention may thus exist in the form of two different optical isomers , that is (+) or (-) enantiomers . All such enantiomers and mixtures thereof, including racemic or other ratio mixtures of individual enantiomers , are included within the scope of the invention . The single enantiomer can be obtained by methods well known to those of ordinary skill in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary derivatization .
  • the compounds in accordance with the present invention can contain more than one chiral centers .
  • the compounds of the present invention may thus exist in the form of different diastereomers . All such diastereomers and mixtures thereof are included within the scope of the invention .
  • the single diastereomer can be obtained by method well known in the art, such as HPLC, crystallization and chromatography.
  • the optical purity is numerically equivalent to the "enantiomeric excess” .
  • the term ''enantiomeric excess is defined in percentage (%) value as follows : . [mole fraction (maj or enantiomer) - mole fraction (minor enantiomer) ] x 100.
  • An example of ee of 99% represents a ratio of . 99.5% . of one enantiomer and 0.5% of the opposite enantiomer .
  • salts of the compounds of the present invention .
  • the salt (s ) must be “acceptable” in the sense of not being deleterious to the recipient thereof .
  • pharmaceutically acceptable salts of compounds are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases .
  • acids include but are not limited to hydrochloric, hydrobromic, sulphuric, ⁇ nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids .
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts .
  • salts derived from appropriate bases include alkali metal, alkaline earth metal or ammonium salts .
  • Non- limiting examples of such salts known by those of ordinary skill include without limitation calcium, potassium, sodium, choline, ethylenediamine, tromethamine, arginine, glycinelysine, lysine, magnesium and meglumine .
  • hydrates of the compounds of the present invention there is also provided pharmaceutically acceptable hydrates of the compounds of the present invention .
  • the hydrate ( s) must be "acceptable” in the sense of not being deleterious to the recipient thereof .
  • "Hydrates" exist when the compound of the invention incorporates water .
  • the hydrate may contain one or more molecule of water per molecule of compound of the invention .
  • Illustrative non-limiting examples include monohydrate, dihydrate, trihydrate and tetrahydrate .
  • the hydrate may contain one or more molecule of compound of the invention per molecule of water .
  • An illustrative non- limiting example includes semi-hydrate .
  • the water may be held in the crystal in various ways and thus, the water molecules may occupy lattice positions in the crystal, or they may form bonds with salts of the compounds as described herein .
  • the hydrate must be "acceptable” in the sense of not being deleterious to the recipient thereof .
  • the hydration may be assessed by methods known in the art such as Loss on Drying techniques (LOD) and Karl Fisher titration .
  • Solvate means that compound of the invention incorporates one or more pharmaceutically acceptable solvent (e . g . , when the solvent is water the solvate is a hydrate) .
  • the solvate ( s ) must be "acceptable” in the sense of not being deleterious to the recipient thereof .
  • the solvate may contain one or more molecule of solvent per molecule of compound of the invention or may contain one or more molecule of compound of the invention per molecule of solvent .
  • the solvent may be held in the crystal in various ways and thus , the solvent molecule may occupy lattice positions in the crystal, or they may form bonds with salts of the compounds as described herein .
  • the solvate (s ) must be “acceptable” in the sense of not being deleterious to the recipient thereof .
  • the solvation may be assessed by methods known in the art such as Loss on Drying techniques (LOD)
  • Polymorphs & pseudopolymorphs It will be appreciated by those skilled in the art that the compounds in accordance with the present invention can exist in several different crystalline forms due to a different arrangement of molecules in the crystal lattice . This may include solvate or hydrate (also known as pseudopolymorphs ) and amorphous forms . All such crystalline forms and polymorphs are included within the scope of the invention .
  • the polymorphs may be characterized by methods well known in the art . Examples of analytical procedures that may be used to determine whether polymorphism occurs include : melting point (including hot-stage microscopy) , infrared (not in solution) , X-ray powder diffraction, thermal analysis methods (e . g . differential scanning calorimetry ( DSC) differential thermal analysis (DTA) , thermogravimetric analysis (TGA) ) , Raman spectroscopy, comparative intrinsic dissolution rate, scanning electron microscopy (SEM) .
  • DSC differential scanning calorimetry
  • the sulfur atom can be at different oxidation levels , i . e . S, SO, or SO 2 . All such oxidation levels are within the scope of the present invention .
  • the nitrogen atom can be at different oxidation levels , i . e . N or NO . All such oxidation levels are within the scope of the present invention.
  • a method of preventing or treating HIV infection in a subject which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
  • a method of preventing or treating HIV infection in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or pharmaceutical composition of the present invention .
  • a method of preventing, delaying or treating AIDS in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
  • a method of preventing, delaying or treating AIDS in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
  • a method of preventing HIV replication in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
  • a method of preventing HIV replication in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
  • a method of inhibiting HIV integrase in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
  • a method of inhibiting HIV integrase in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
  • a method of preventing integration of HIV DNA into host cell DNA in a subj ect which comprises administering to the subj ect a , therapeutically effective amount of a compound of the present invention .
  • a method of preventing integration of HIV DNA into host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
  • a method of preventing the 3' -end processing of HIV DNA in a subj ect the method comprising administering to the subj ect a therapeutically effective amount of a compound of the present invention .
  • a method of preventing the 3' -end processing of HIV DNA in a subj ect which comprises administering to the subj ect a combination or a pharmaceutical composition of the present invention .
  • a method of preventing the HIV DNA strand transfer to the host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
  • a method of preventing the HIV DNA strand transfer to the host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
  • combinations of the present invention comprise those wherein the following embodiments are present, either independently or in combination .
  • the pharmaceutical combinations of this invention may contain at least one further therapeutic agent chosen from an agent used in inflammatory diseases , immunoregulatory diseases and in organ transplantation reactions .
  • the pharmaceutical combination of this invention may contain at least one further therapeutic agent which is an antiviral agent .
  • the pharmaceutical combination of this invention may contain at least one further antiviral agent which is chosen ( from nucleoside and nucleotide analog reverse transcriptase inhibitors , non-nucleoside reverse transcriptase inhibitors , protease inhibitors , integrase inhibitors attachment and fusion inhibitors, entry inhibitors or maturation inhibitors .
  • at least one further antiviral agent which is chosen ( from nucleoside and nucleotide analog reverse transcriptase inhibitors , non-nucleoside reverse transcriptase inhibitors , protease inhibitors , integrase inhibitors attachment and fusion inhibitors, entry inhibitors or maturation inhibitors .
  • the pharmaceutical combinations of this invention may contain at least one other antiviral agent which is a nucleoside and nucleotide analog
  • the pharmaceutical combination of this inyention may contain at least one other antiviral agent which is a non-nucleoside reverse transcriptase inhibitor chosen from Nevirapine (Viramune®, NVP, BI-RG-587 ) , delavirdine (Rescriptor®, DLV) , efavirenz ( DMP 266, Sustiva®) , (+) -Calanolide A, Capravirine (AG1549, formerly S-1153 ) , DPC083 , MIV-150 , TMC120 , TMC125 or BHAP (delavirdine) , calanolides or L- 697 , 661 (2-Pyridinone 3benzoxazolMeNH derivative) .
  • a non-nucleoside reverse transcriptase inhibitor chosen from Nevirapine (Viramune®, NVP, BI-RG-587 ) , delavirdine (Rescriptor®, DLV) , efavirenz ( D
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a protease inhibitor chosen from nelfinav ' ir (Viracept®, NFV) , amprenavir ( 141W94 ,
  • Agenerase® indinavir (MK-639 , IDV, Crixivan®) , saquinavir ( Invirase®, Fortovase®, SQV) , ritonavir
  • Atazanavir BMS232632
  • mozenavir DMP-450
  • fosamprenavir GW433908
  • RO033-4649 Tipranavir
  • TMC114 TMC114 or VX-385.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an attachment and fusion inhibitor chosen from T-20 (enfuvirtide, Fuzeon®) , T- 1249 , Schering C ( SCH-C) , Schering D (SCH-D) , FP21399 , PRO-140 , PRO 542 , PRO 452 , TNX-355, GW873140 (AK602 ) , TAK-220 , TAK-652 , UK-427 , 857 or soluble CD4 , CD4 fragments , CD4-hybrid molecules, BMS-806, BMS-488043 , AMD3100 , AMD070 or KRH-2731.
  • an attachment and fusion inhibitor chosen from T-20 (enfuvirtide, Fuzeon®) , T- 1249 , Schering C ( SCH-C) , Schering D (SCH-D) , FP21399 , PRO-140 , PRO 542 , PRO 45
  • the pharmaceutical combination of this invention may contain- at least one other antiviral agent which is an integrase inhibitor chosen from S-1360 , JKT 303 , L-870 , 810 , L-870, 812 or C-2507.
  • an integrase inhibitor chosen from S-1360 , JKT 303 , L-870 , 810 , L-870, 812 or C-2507.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a maturation inhibitor and is PA-457.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA) .
  • ADA azodicarbonamide
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an antisense drug and is , HGTV43.
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an immun ⁇ modulator, immune stimulator or cytokine chosen from interleukin-2 (IL-2 , Aldesleukin, Proleukin) , granulocyte macrophage colony stimulating factor (GM-CSF) , erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscarnet, HE2000 , Reticulose, Murabutide, Resveratrol, HRG214 , HIV-I Immunogen (Remune) or EP HIV J 1090.
  • IL-2 interleukin-2
  • Proleukin granulocyte macrophage colony stimulating factor
  • GM-CSF granulocyte macrophage colony stimulating factor
  • erythropoietin erythropoietin
  • Multikine erythropoietin
  • Ampligen thymomodulin
  • the pharmaceutical combination of this invention may contain at least one other antiviral agent chosen from 2 ' , 3 ' -dideoxyadenosine, 3 ' - deoxythymidine, 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir, ganciclovir; interferons such as alpha-, beta-and gamma-interferon; glucuronation inhibitors such as probenecid; or TIBO drugs, HEPT, TSAO derivatives .
  • at least one other antiviral agent chosen from 2 ' , 3 ' -dideoxyadenosine, 3 ' - deoxythymidine, 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydrocytidine and ribavirin; acyclic nucleosides such as
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprises a further aspect of the invention .
  • the individual' components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations .
  • the said compound of formula ( I ) and said therapeutic agent are administered sequentially . In a further embodiment, the said compound of formula ( I ) and said therapeutic agent are administered simultaneously .
  • the subj ect to which the compounds are administered can be, for example, a mammal or a human .
  • the subj ect is a human .
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound having the formula ( I ) or pharmaceutically acceptable salts or pharmaceutically acceptable hydrates or pharmaceutically acceptable solvates thereof and at least one pharmaceutically acceptable carrier or excipient .
  • the opportunistic infection is selected from CMV retinitis, Pneumocystis carinii pneumonia, Mycobacterium avium complex, cryptococcal meningitis , or herpes simplex .
  • the invention provides the use of a compound of the present invention for the manufacture of a medicament for preventing or treating HIV infection or preventing, delaying or treating AIDS .
  • the invention provides the use of a compound of the present invention for the manufacture of a medicament for preventing or treating
  • HIV infection or preventing, delaying or treating AIDS .
  • the invention provides the use of a combination of the invention for the manufacture of a medicament for preventing or treating HIV infection or preventing, delaying or treating AIDS .
  • the invention provides the use of a compound of the present invention for the manufacture of a medicament for preventing anyone of HIV replication, integration of HIV DNA into host cell DNA, 3' -end processing of HIV DNA or HIV DNA strand transfer to the host cell DNA.
  • the invention provides the use of a combination of the invention for the manufacture of a medicament for preventing anyone of HIV replication, integration of HIV DNA into host cell DNA, 3' -end processing of HIV DNA or HIV DNA strand transfer to the host cell DNA.
  • the invention provides the use of a compound of the present invention for the manufacture of a medicament for inhibiting HIV integrase .
  • the invention provides the use of a combination of the invention for . the manufacture of a medicament for inhibiting HIV integrase .
  • the subj ect in the above-mentioned methods and uses is a human .
  • the present invention provides a combination comprising a therapeutically effective amount of a compound of the present invention, and a therapeutically effective amount of at least one further antiviral agent wherein said compound and said antiviral agent are present in a synergistic ratio .
  • compositions may be administered as pharmaceutical compositions .
  • a further aspect of the invention is therefore presented as a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention together with at least one pharmaceutically acceptable carrier or excipient thereof .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salts, hydrates or solvates thereof or combination as defined herein together with one or more pharmaceutically acceptable carrier or excipient thereof .
  • the carrier (s ) or excipient (s ) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not being deleterious to the recipient thereof .
  • a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, alternatively in the range of 0.5 to 60 mg/kg/day, in a further alternative in the range of 1 to 20 mg/kg/day.
  • the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
  • the compound is conveniently administered in unit dosage form; for example containing 1 to 1500 mg, as a further example the unit dosage form is containing 10 to 1000 mg, as a further example the unit dosage form is containing 50 to 750 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 ⁇ M, preferably about 2 to 50 ⁇ M, most preferably about 3 to about 30 ⁇ M. This may be achieved, for example, by the intravenous inj ection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient . Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient .
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual ) , transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous ) administration or in a form suitable for administration by inhalation or insufflation .
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation .
  • compositions suitable for oral administration may conveniently 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 a solution, a suspension or as an emulsion .
  • the active ingredient may also be presented as 'a bolus, electuary or paste .
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents , fillers , lubricants , disintegrants, or wetting agents .
  • the tablets may be coated according to methods well known in the art .
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions , solutions , emulsions, syrups or elixirs , or may be presented as a dry product for constitution with water or other suitable vehicle before use .
  • Such liquid preparations may contain conventional additives such as suspending agents , emulsifying agents, non-aqueous vehicles (which may include edible oils ) , or preservatives .
  • the compounds and combinations according to the invention may also be formulated for parenteral administration (e . g . by inj ection, for example bolus inj ection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes , small volume infusion or in multi-dose containers with an added preservative .
  • the compositions may take such forms as suspensions , solutions, or emulsions in oily or aqueous vehicles , and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents .
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e . g . sterile, pyrogen-free water, before use .
  • the compounds and combinations according to the invention may be formulated as ointments, creams or lotions , or as a transdermal patch .
  • Such transdermal patches may contain penetration enhancers such as linalool , carvacrol, thymol, citral, menthol and t-anethole .
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents .
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents , dispersing agents , suspending agents , thickening agents, or coloring agents .
  • compositions suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier .
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories .
  • suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier ( s ) followed by chilling and shaping in moulds .
  • compositions suitable for vaginal administration may be presented as pessaries , tampons, creams , gels , pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate .
  • the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops .
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one more dispersing agents, solubilising agents or suspending agents .
  • Liquid sprays are conveniently- delivered from pressurized packs .
  • the compounds and combinations according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas .
  • the dosage unit may be determined by providing a valve to deliver a metered amount .
  • the compounds and combinations according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch .
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e . g . gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator .
  • the above described formulations adapted to give sustained release of the active ingredient may be employed.
  • the compounds of the invention have been found to have activity in the inhibition of HIV integrase, as described in example 30 , generally with an observed inhibitory activity at 50 ⁇ M.
  • Certain compounds of the present invention have also been tested in an assay for HIV activity, as described in Example 31 , and generally having an IC 50 value of less than 10 ⁇ M.
  • the compound was prepared starting from 5-bromo-3- methoxy-2-methyl-lH-pyridin-4-one in a similar manner as described above .
  • Acetic acid 4-benzyloxy-5-bromo-3-methoxy-pyridin-2- ylmethyl ester .
  • the compound was prepared starting from acetic acid 4- benzyloxy-5-bromo-3-methoxy-pyridin-2-ylmethyl ester in a similar manner using the procedure described above .
  • the compound was prepared starting from 3-benzyloxy-4- methoxy- ⁇ -bromo-pyridine-2-carboxylic acid (WO0105769 ) in a similar manner using the procedure described above .
  • the compound was prepared starting from 4-benzyloxy-3- methoxy-5-bromo-pyridine-2-carboxylic acid [2- (tert- butyl-dimethyl-silanyloxy) -ethyl] - ( 4-fluoro-benzyl ) - amide in a similar manner using the procedure described above .
  • the compound was prepared starting from 3-benzyloxy ⁇ 4- methoxy-6-bromo-pyridine-2-carboxylic acid [2- (tert- butyl-dimethyl-silanyloxy) -ethyl] - ( 4-fluoro-benzyl ) - amide in a similar manner using the procedure described above .
  • reaction mixture was stirred at rt for overnight, filtered and the residue was washed with methylene chloride (20 ml ) .
  • methylene chloride (20 ml )
  • the combined methylene chloride solution was washed with 5% sodium thiosulfate solution, water, and brine and dried over Na 2 SO 4 .
  • the solvent was removed under reduced pressure and the residue was purified on silica gel using CH 2 Cl 2 : MeOH 95 : 5 as eluent to give 140 mg of a solid product in 72% yield.
  • the 1 H-NMR indicated the cyclic product .
  • reaction mixture was stirred at rt for 12 h . After removal of the solvent under reduced pressure, the residue was suspended into 30 ml of water and the pH was adj usted to 3. The mixture was extracted with methylene chloride ( 3 x 15 ml ) . The combined organic phases were washed with brine, dried over anhydrous sodium sulfate . Evaporation of the solvent under reduced pressure afforded a white solid of 730 mg, which was used in the next step without further purification .
  • the mixture was then dissolved into methanol ( 5 ml) and the solution was neutralized with N, N' -diisopropylethyl amine (DIPEA) .
  • DIPEA N, N' -diisopropylethyl amine
  • the mixture was heated to 70 0 C for 2 h . After removal of the solvent under reduced pressure, the residue was purified on a silica gel column using 5% methanol in dichloromethane to give a white solid ( 20 mg) .
  • R vinyl, furan, sultam, thiazole, phenyl, SCH 3
  • step 1 The product from step 1 (73 mg) was dissolved into a mixture of 10 ml of methanol and 10 ml of ethyl acetate . To the solution was added 7 mg of 10% Pd/C and the mixture was stirred was stirred under hydrogen at atmospheric pressure . After stirring for 1 h at rt, the mixture was filtered to remove the catalyst . The filtrate was concentrated to dryness under reduced pressure to afford ⁇ -cyclohexylmethoxy-2- ( 4-fluoro- benzyl) -9-hydroxy-3, 4-dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1, 8-dione as a white solid ( 60 mg) .
  • Step 2 The product ( 148 mg) from Step 1 was deprotected by hydrogenolysis as described for Example XXX to provide 9-benzyloxy-6-cyclopropylmethoxy-2- ( 4-fluoro-benzyl ) - 3 , 4-dihydro-2H ⁇ pyrido [ 1, 2-a] pyrazine-1, 8-dione as a white solid ( 110 mg) .
  • Anti-HIV-1 replication Assay in H9 cells for anti-HIV-1 integrase compounds were tested by employing HIV-IIIIB in H9 cells .
  • the prepared cells were suspended at 5XlO6/ml in complete medium (RPMI 1640, 10%FBS , 2mM glutamine, 100 units penicillin/ml , 100 ⁇ g streptomycin/ml ) , incubated with virus at a multiplicity of infection of 0.1 for 2h in an atmosphere of 5 % C02 and 37°C .
  • the infected cells were washed twice with PBS to remove residual virus and cultured at presence of inhibitors at serial concentrations for 7-8 days .
  • the anti-HIV-1 efficacy was determined by testing for HIV-I RT activity in the cell culture supernatants . All assays were performed in duplicate with Merck compound L-731988 and Shionogi compound S-1360 as control . The 50% effective concentrations (IC50s) were calculated from the linear portion of the dose-response curve .

Abstract

Bi-or tricyclic compounds of formula (I) wherein R1, R4 and R5 are as herein defined, A represents a single or double bond and two R2, R2’, R3 and R3’ can be joined to form a condensed or spiro ring. These compounds and their pharmaceutical acceptable salt are used in combinations or pharmaceutical compositions and are useful in methods for preventing or treatin human immunodeficiency virus (HIV) infection or in methods for preventing, delaying or treating acquired immunodeficiency syndrome (AIDS).

Description

HYDROXYDIHYDROPYRIDOPYRAZINE-1 , 8-DIONES AND METHODS FOR
INHIBITING HIV INTEGRASE
This application claims the benefit of U . S . Provisional Application Serial No . 60/638 , 180 , filed December 23, 2004 , the entire disclosure of which is hereby incorporated by reference .
FIELD OF THE INVENTION The present invention relates to novel compounds and method for the treatment or prevention of HIV infection/ AIDS .
BACKGROUND OF THE INVENTION HIV integrase is an attractive therapeutic target for the development of drugs to treat HIV infection
( Pommier Y et al : Antiviral . Chem. Chemother . 1997 , 8 ,
463-83 ; De Clercq, E : Med Res Rev 2002 , 22 , 531-565 ;
Nair V: Rev. Med. Virol . 2002 , Ϊ2 , 179-193) . It is a protein of Mr 32000 encoded at the 3 ' -end of pol gene . This viral enzyme catalyses the integration of viral DNA into host cell chromosomal DNA to form a provirus . This essential step in the viral life cycle proceeds by integrase recognizing and binding to attachment sites located at the ends of linear viral DNA, followed by the cleavage of highly conserved CA dinucleotides from the 5' and 3' long-terminal repeats . This reaction, known as 3' -processing, occurs in the cytoplasm and exposes the 3 ' -0H group from the CA unit . This OH group subsequently acts as a nucleophile by attacking the host DNA in a transesterification reaction . This second
i reaction, referred to as strand transfer or integration, occurs in the nucleus . These reactions are
• adequately represented in vitro using purified integrase, a double-stranded DNA template matching the viral DNA ends as a substrate surrogate along with a divalent metal ion (Mn2+ or Mg2+) cofactor . It has been reported that selective inhibition of strand transfer reaction results in the inhibition of HIV viral replication ( Pais GCG & Burke TR Jr : Drugs of the Future, 2002 , 27 , 1101-1111 ) .
HIV integrase is further attractive as a target for the development of anti-HIV drugs because there is apparently no functional equivalent of this enzyme in human cells . It has also been reported that integrase inhibitors in combination with either reverse transcriptase or protease inhibitors are potently synergistic against both wild-type HIV and reverse transcriptase inhibitor resistant viruses (Robinson WE Jr et al Antiviral Res . 1998 , 39, .101-111 ; Beale K et al Antiviral Res 2000 , 46, 223-232 ) .
A number of integrase inhibitors have been reported, including nucleotide-based inhibitors, DNA binders, catechols , hydrazides, etc (Neamati N : Expert Opin Ther Patents 2002 , 12 , 709-724 ) . Most of these compounds inhibit integrase function in extracellular oligonucleotide assays but often lack inhibitory potency when assayed using fully assembled preintegration complexes or fail to show antiviral effects against HIV-infected cells . A class of diketo- containing int'egrase inhibitors has been found to inhibit viral replication by blocking the strand transfer step of integrase reactions ( Pais GCG & Burke TR Jr : Drugs of the Future, 2002 , 27 , 1101-1111 ) . An inhibitor of this class has been in clinical trials for the treatment of HIV infection (Billich A: Curr . Opin . Investig . Drugs 2003 , 4 , 206-209 ) . However, in spite of their high integrase inhibitory potencies , diketo- containing compounds are electrophilic and they bind covalently to human cellular proteins leading to potential cytotoxicity. In addition, it has been reported recently that some diketo-containing compounds interfere with DNA cleavage and disintegration activities of RAG1/2 which are essential for the development of mammalian immune system (Melek M et al : Proc . Natl . Acad . Sci . USA 2002 , 99, 134-7 ) .
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a compound of formula I :
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof , wherein
A is a single or double bond, and when A is a double bond R.2 or R'2 and R3 or R' 3 are absent ; '
Ri is H, OH, optionally substituted C6-io aryl , optionally substituted 5-10 member heteroaryl , optionally substituted 4-10 member heterocycle, or Ci-10 alkyl optionally substituted , with one or more substituents selected from optionally substituted C3-10 cycloalkyl, optionally substituted C6_io aryl , optionally substituted 5-1O 1 member heteroaryl, or optionally substituted 4-10 member heterocycle ( e . g . , R1 can be optionally substituted (CH2) 1-4 phenyl ) ;
R2, R' 2 ι R3 and R' 3 are each, independently, hydrogen, optionally substituted Ci-10 alkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C6_io aryl, optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member heterocycle, COOR6, CONR7R' 7, or CR6=NOR' 6;
R2 or R'2 can also be taken together with R3 or R' 3, and the atoms to which they are attached, to form an optionally substituted C3-10 cycloalkyl, an optionally substituted 4-10 member heterocycle, an optionally substituted C6_io aryl or an optionally substituted 5-10 member heteroaryl;
R2 and R' 2 or R3 and R' 3 can also be j oined together, with the atoms to which they are attached, to form an optionally substituted C3-10 cycloalkyl or an optionally substituted 5-10 member heterocycle;
R2 and R' 2 or R3 and R' 3 can also be j oined together to form a carbonyl (C=O) ;
R4 is halogen, CN, azido, NO2, amino, amido, sulfonamido, urea, guanidino, amidino, SOnR6, OCONR7R' 7, NR6SO2NR7R' η NR6COOR7, NR6COCONR7R' 7, CR6=NOR7, Ci_i0alkoxy, optionally substituted C6_io aryloxy, optionally substituted C6aryl-Ci-ioalkyloxy, optionally substituted C6-Io aryl, optionally substituted 5-10 member heterocycle, or optionally substituted 5-10 member heteroaryl ;
n is 0 , 1 , or 2 ;
R5 is hydrogen, halogen, OH, CN, azido, NO2, COOR6, Ci-10 alkyl, amino, amido, sulfonamido, urea, guanidino, amidino, SOnR6, OCONR7R' 7, NR6SO2NR7R' 7 NR6COOR7, CR6=NOR7, Ci-ioalkoxy, optionally substituted C6_io aryl , optionally substituted 5-10 member heterocycle, or optionally substituted 5-10 member heteroaryl ;
R4 and R5 can also be taken together, with the atoms to which they are attached, to form an optionally substituted C5-10 cycloalkyl, optionally substituted 5- 10 member heterocycle, optionally substituted 5-10 member heteroaryl, or optionally substituted C6-io aryl ; Re, R7, R' 7 are each independently hydrogen, optionally substituted Ci-io alkyl, optionally substituted C6-10 aryl, or optionally substituted C7_i2aralkyl;
R6 can also be taken together with R7 or R' 7, with the atoms to which they are attached, to form a 5-10 member heterocycle; and
R7 and R' 7 can be taken together, with the atom to which they are attached, to form a 4-10 member heterocycle .
The compound of formula I can also be in the form of a pharmaceutically acceptable solvate or a solvate of a pharmaceutically acceptable salt thereof
In one embodiment, there is provided a method of preventing or treating HIV infection in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention .
In one embodiment, there is provided a method of preventing, delaying or treating AIDS in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention . In one embodiment, there is provided a method of inhibiting HIV integrase in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention .
In one embodiment, there is provided a method of preventing integration of HIV DNA into host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition of the present invention .
In one embodiment, there is provided a method of preventing HIV DNA strand transfer to the host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound, a combination or a pharmaceutical composition
' of the present invention .
In another embodiment, the invention provides the use of a compound or combination of the present invention for the manufacture of a medicament for preventing or treating HIV infection or preventing, delaying or treating AIDS .
In another embodiment, the invention provides the use of a compound or combination of the present invention for the manufacture of a medicament for preventing any one of HIV replication, integration of HIV DNA into host cell DNA, 3' -end processing of HIV DNA or HIV DNA strand transfer to the host cell DNA. In another aspect, the present invention provides a combination comprising a therapeutically effective amount of compound of the present invention, and a therapeutically effective amount of at least one antiviral agent .
A further aspect of the invention is therefore presented as a pharmaceutical composition comprising a compound or combination of the present invention together with at least one pharmaceutically acceptable carrier or excipient thereof .
DETAILED DESCRIPTION OF THE INVENTION In one embodiment, compounds of the present invention comprise those wherein the following embodiments are present, either independently or in combination.
In accordance with the present invention, there is provided a compound of formula I :
Figure imgf000009_0001
I or a pharmaceutically acceptable salt thereof,
wherein A is a single or double bond, and when A is a double bond R2 or R' 2 and R3 or R' 3 are absent ;
Ri is H, OH, optionally substituted C6-I0 aryl , optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member heterocycle, or Ci_i0 alkyl optionally substituted with one or more substituents selected from optionally substituted C3-I0 cycloalkyl, optionally substituted C6-I0 . aryl, optionally substituted 5-10 member heteroaryl, or optionally substituted 4-10 member heterocycle (e . g . , Ri can be optionally substituted (CH2) 1-4 phenyl ) ;
R2, R' 2, R3 and R' 3 are each, independently, hydrogen, optionally substituted Ci-I0 alkyl, optionally substituted C3-I0 cycloalkyl , optionally substituted C6-I0 aryl, optionally substituted 5-10 member heteroaryl, optionally 'substituted 4-10 member heterocycle, COOR6, CONR7R' 7, or CR6=NOR' 6;
R2 or R'2 can also be taken together with R3 or R' 3, and the atoms to which they are ' attached, to form an optionally substituted C3-I0 cycloalkyl, an optionally substituted 4-10 member heterocycle, an optionally substituted C6-I0 aryl or an optionally substituted 5-10 member heteroaryl ;
R2 and R' 2 or R3 and R' 3 can also be j oined together, with the atoms to which they are attached, to form an optionally .substituted ,C3_io cycloalkyl or an optionally substituted 5-10 member heterocycle ;
R2 and R' 2 or R3 and R' 3 can also be j oined together to form a carbonyl (C=O) ;
R4 is halogen, CN, azido, NO2, amino, amido, sulfonamido, urea, guanidino, amidino, SOnRg/ OCONR7R' 7, NR6SO2NR7R' 7 NR6COOR7, NR6COCONR7R' 7, CR6=NOR7, Ci_i0alkoxy, optionally substituted Cδ-io aryl, optionally substituted 5-10 member heterocycle, or optionally substituted 5-10 member heteroaryl;
n is 0 , 1 , or 2 ;
R5 is hydrogen, halogen, OH, CN, azido, NO2, COOR6, Ci-10 alkyl, amino, amido, sulfonamido, urea, guanidino, amidino, SOnR6, OCONR7R' 7, NR6SO2NR7R' ? NR6COOR7, CR6=NOR7, Ci-ioalkoxy, optionally substituted Cβ-io aryl , optionally substituted 5-10 member heterocycle, or optionally substituted 5-10 member heteroaryl;
R4 and R5 can also be taken together, with the atoms to which they are attached, to form a optionally substituted C5-.10 cycloalkyl, optionally substituted 5- 10 member heterocycle, optionally substituted 5-10 member heteroaryl, or optionally substituted Cδ-io aryl ;
R6, R7, R' 7 are each independently hydrogen, optionally substituted Cχ_io alkyl, optionally substituted Cβ-io aryl, or optionally substituted C7_χ2aralkyl; R6 can also be taken together with R7 or R' 7, with the atoms to which they are attached, to form a 5-10 member heterocycle; and
R7 and R' 7 can be taken together, with the atom to which they are attached, to form a 4-10 member heterocycle .
The compound of formula I can also be in the form of a pharmaceutically acceptable solvate or a solvate of a pharmaceutically acceptable salt thereof
In one embodiment of the invention, A is a single bond .
Ri can be H, OH, optionally substituted Cε-io aryl, optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member heterocycle, optionally substituted cycloalkylalkyl wherein the cycloalkyl portion has 3 to 10 carbon atoms and the alkyl portion has 1 to 10 carbon atoms, optionally substituted aralkyl wherein the aryl portion has 6 to carbon atoms and the alkyl portion has 1 to 10 carbon atoms, optionally substituted heteroaralkyl wherein the heteroaryl portion is a 5-10 member heteroaryl and the alkyl portion has 1 to 10 carbon atoms , or optionally substituted hetefocycle-alkyl wherein the heterocyclic portion is a 4-10 member heterocycle and the alkyl portion has 1 to 10 carbon atoms .
In one embodiment of the invention, R1 is hydrogen . In one embodiment of the invention, Ri is hydroxy.
In one embodiment of the invention, Ri is C1-4 alkyl substituted by an optionally substituted aryl group .
In another embodiment of the invention, Ri is (CH2) i-4 phenyl where phenyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro, nitroso, urea,
S(O) o-2Ra (wherein Ra is H, Ci-10 alkyl, Cβ-io aryl or 3-10 member heterocycle) ,
Ci-ioalkyl, C7-I0 aralkyl,
C6-I0 aryl,
5-10 member heteroaryl
Ci-ioalkoxy,
C6-ioaryl-Ci-i0alkyloxy, C6-Io aryloxy,
3-10 member heterocycle, C (O) Rb (wherein Rb is H, C1-I0 alkyl, C6-I0 aryl, C7_i2 aralkyl or 3-10 member heterocycle) , C (O) ORb (wherein Rb is H, Ci-io alkyl, Cβ-io aryl, C7-i2 aralkyl—or 3-10 member heterocycle) , NRbC (O) Rb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, C6-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , SO2NRbRb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, Cδ-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle ) , NRbSO2Rb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, Ce-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , NRbSO2NRb ' Rc (wherein Rb, Rb ' and Rc are each independently H, Ci-io alkyl , C6-io aryl, C7_i2 aralkyl or 3-10 member heterocycle, or Rb ' and Rc are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , CRbN=ORb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, Ce-io aryl, C7-I2 aralkyl or 3-10 member heterocycle) , and
NRbCOO Rb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, C6-io aryl, C7-I2 aralkyl or 3-10 member heterocycle) . In another embodiment Ri is (CH2) i_4phenyl where phenyl is unsubstituted or substituted with one or more substituents "independently selected from: halogen, amino, amido, cyano, hydroxyl, urea, OCi-io alkyl,
S(O) o-2Ra #(wherein Ra is H, Ci_i0 alkyl, C6-I0 aryl or 3-10 member heterocycle) ,
Ci_io alkyl,
C6_,io aryl, 5-10 member heteroaryl
3-10 member heterocycle,
C (O) ORb (wherein Rb is H, Ci-io alkyl , C7-I2 aralkyl or 3-
10 member heterocycle) ,
NRbC (O) Rb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl,' C7-I2 aralkyl or 3-10 member heterocycle, or
Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
NRbSO2Rb ' (wherein Rb and Rb ' are each independently H,
Ci_io alkyl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which
•they are attached to form a 5-10 member heterocycle ) ,
CRbN=ORb ' (wherein Rb and Rb ' are each independently H,
Ci-io alkyl, Cε-io aryl , C7-I2 aralkyl or 3-10 member heterocycle ) , and NRbCOORb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, C6_10 aryl, C7_i2 aralkyl or 3-10 member heterocycle) .
In another embodiment Ri is (CH2) i-4phenyl where phenyl is substituted with one or more substituents independently selected from: fluoro, bromo, chloro,
CONHCH3,
CON (CH3) 2,
CF3,
NHCOCH3 , NHCONHCH3 , and
SO2NHCH3 .
In another embodiment Ri is CH2- ( 4-fluorophenyl) .
In another embodiment Ri is CH2- ( 3 , 4 dichlorophenyl ) . In another embodiment Ri is CH2- ( 3-chloro-4- fluorophenyl) .
In another embodiment Ri is CH2- (2-N-methylamido-4- fluorophenyl) .
In one embodiment, R2 and R' 2 are each independently chosen from:
optionally substituted phenyl, optionally substituted Ci_6alkyl, COOCi_6alkyl, CONR7R' 7, and CR6=NOIV 6.
In one embodiment , R2 and R' 2 are each independently chosen from: H;
unsubstituted phenyl or phenyl substituted by one or more substituents independently selected from halogens , hydroxy, -NH2, -NHRd and -NRdRe, -CONH2 , -CONHRd, - CONRdR6, -NHCORd, -NRdCORe, carboxy, CF3, NRdCORd, NRdCONRdRe, and SO2NRdRe wherein Rd and Re are each independently selected from Ci-10 alkyl ;
unsubstituted Ci_6alkyl or Ci_6alkyl substituted by one1 or more substituents independently selected from halogens, hydroxy, -NH2, -NHRd and -NRdRe, wherein Rd and Re are each independently selected from Ci-10 alkyl, -CONH2, - C0NHRd, -CONRdRe, -NHC0Rd, -NRdC0Re, and carboxy, wherein Rd and Re are each independently selected from C1-I0 alkyl ;
COOCi_6alkyl ;
CONR7R' 7 ; and
CR6=NOR' 6.
In one embodiment , R2 and R' 2 are each independently chosen from: H,
Phenyl , Ci_6alkyl, COOCi-ealkyl, CONR7R' η, and CR6=NOR' 6.
In one embodiment , R3 and R' 3 are each independently chosen from:
optionally substituted phenyl, optionally substituted Ci_6alkyl,
COOCi_6alkyl , ' CONR7R' 7, and CR6=NOR' 6. '
In one embodiment, R3 and R' 3 are each independently chosen from:
H;
unsubstituted phenyl or phenyl substituted by one or more substituents independently selected from halogens , hydroxy, -NH2 , -NHRd and -NRdRe , -CONH2 , -CONHRd, - CONRdRe/ -NHCORd, -NRdCORe, carboxy, CF3 , NRdCORd, ' NRdC0NRdRe , and SO2NRdRe wherein Rd and Re are each independently selected from Ci-10 alkyl ;
unsubstituted Ci-6alkyl or Ci_6al kyl substituted by one or more substituents independently selected from halogens , hydroxy, -NH2, -NHRd and -NRdRe, wherein Rd and Re are each independently selected from Ci_10 alkyl , -CONH2, - CONHRd, -CONRdRe/ -NHC0Rd, -NRdCORe , and carboxy, wherein Rd and Re are each independently selected from Ci-io alkyl ;
COOCx-ealkyl ;
CONR7R' 7 ; and
CR6=NOR' 6 .
In another embodiment R3 and R' 3 are each independently chosen from:
H,
Phenyl,
Figure imgf000019_0001
COOCx-eal kyl ,
CONR7R' 7 , and
CR6=NOR' 6 .
In one embodiment, R4 is : H, halogen, amino, amidino, amido, azido, cyano, guanidino, nitro, nitroso, urea, S(0)o-2Ra (wherein Ra is H, Ci-I0 alkyl, C6-I0 aryl or 3-10 member heterocycle) ,
Ci-ioalkyl,
C7-I2 aralkyl, C6-ioaryl,
5-10 member heteroaryl
Ci-i0alkoxy,
Cβaryl-Ci-ioalkyloxy,
C6-I0 aryloxy, 3-10 member heterocycle,
C (O) Rb (wherein Rb is H, Ci_io alkyl, C6-I0 aryl, C7-I2 aralkyl—or 3-10 member heterocycle) ,
C (O) ORb (wherein Rb is H, Ci-io alkyl, C6-I0 aryl, C7_i2 aralkyl or 3-10 member heterocycle) , NRbC (O) Rb ' (wherein Rb and Rb ' are each independently H,
Ci-io alkyl, Cε-io aryl , C7_i2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , SO2NRbRb ' (wherein Rb and Rb ' are each independently H,
Ci-io alkyl, C6-I0 aryl , C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , NRbSO2Rb ' (wherein Rb and Rb ' b are each independently H,
Ci-io alkyl, C6-I0 aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , NRbSO2NRb'Rc (wherein Rb, Rb' and Rc are each independently H, Ci-I0 alkyl, C6-I0 aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rc are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
CRbN=ORb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, C6_10 aryl, C7_i2 aralkyl or 3-10 member heterocycle ) ,
NRbCOORb ' wherein Rb and Rb ' are each independently H or Ci-io alkyl, C6-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or NRbCOCONRb ' Rc (wherein Rb, Rb ' and Rc are each independently H or Ci_i0 alkyl, Cδ-io aryl, C7-i2 aralkyl or 3-10 member heterocycle, or Rb ' and Rc are taken together with the atoms to which they are attached to form a 4-10 member heterocycle) .
In another embodiment R4 is halogen, amino, amido, cyano, urea,
Ci-βalkoxy,
S(O) o-2Ra (wherein R3 is H, Ci-io alkyl, C6_i0 aryl or 3-10 member heterocycle) ,
Ce-ioaryl,
5-10 member heteroaryl,
3-10 member heterocycle,
NRbC (O) Rb ' (wherein Rb and Rb ' are each independently H, Ci-io alkyl, Cδ-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
NRbSO2Rb ' (wherein Rb and Rb ' are each independently H, C1-IO alkyl , C6-I0 aryl , C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
NRbSO2NRb ? RC (wherein Rb, Rb ' and Rc are each independently H, Ci_io alkyl, C6_io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb ' and Rc are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
NRbCOORb ' wherein Rb and Rb ' are each independently H, Ci-io alkyl, C6-Io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or
NRbCOCONRb ' Rc (wherein Rb, Rb ' and Rc are each independently H, Ci-I0 alkyl, C6-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb f and Rc are taken together with the atoms to which they are attached to form a 4-10 member he'terocycle) .
In another embodiment, R4 is halogen, NRbSO2Rb ' (wherein Rb and Rb ' are each independently H,
Ci-10 alkyl , C6-I0 aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle ) , NRbSO2NRb ' Rc (wherein Rb, Rb ' and Rc are each independently H, Ci-10 alkyl , C6-I0 aryl , C7-I2 aralkyl or 3-10 member heterocycle, or Rb ' and Rc are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
NRbC (O) Rb'b (wherein Rb and Rb' are each independently H, Ci-io alkyl, Cε-io aryl, C7-i2 aralkyl or 3-lθ member' heterocycle, or Rb and Rb' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) , or
NRbCOCONRb 1 Rc (wherein Rb, Rb 1 and Rc are each independently H, Ci_io alkyl, Cβ-io aryl, C7_i2 aralkyl or 3-10 member heterocycle, or Rb ' and Rc are taken together with the atoms to 'which they are attached to form a 4-10 member heterocycle) .
In another embodiment, R4 is Br, NHCOCON ( CHS ) 2 ,
Figure imgf000023_0001
In another embodiment, R4 is optionally substituted Ci- io alkoxy (e . g . , Ci-ealkoxy) , optionally substituted Cβ-io aryloxy, or optionally sμbstituted C6aryl-Ci_i0alkyloxy.
In another embodiment, R4 is optionally substituted Ci- io alkoxy (e . g . , Ci-βalkoxy) .
In another embodiment, R4 is optionally substituted C&- io aryloxy (e . g . , phenoxy, 4-fluorophenoxy) . In another embodiment, R4 is optionally substituted C6aryl-Ci_10alkyloxy .
In another embodiment, R4 is optionally halogenated Ci- 10 alkoxy (e . g . , Ci_6alkoxy) .
In another embodiment, R4 is optionally halogenated CQ- 10 aryloxy.
In another embodiment, R4 is optionally halogenated Cβaryl-Ci-ioalkyloxy .
According to a further aspect of the invention, R4 is an optionally substituted 5-10 member heterocycle, or optionally substituted 5-10 member heteroaryl . Suitable heterocycle and heteroaryl for R4 include : piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, and pyrazinyl .
According to a further aspect of the invention, R4 is an amino group selected from NH2, monoalkylamino in which the alkyl group has 1 to 6, preferably 1 to 4 , carbon atoms , and dialkylamino in which each alkyl group has , independently, 1 to 6, preferably 1 to 4 , carbon atoms , and -N (Ci-4-alkyl) -aryl wherein the aryl j is optionally substituted (e . g . , phenylamino wherein the phenyl group is substituted by halogen such as F) .
According to a further aspect of the invention, R4 is an optionally substituted -O-heterocycle wherein the heterocycle group has 5-10 members , or optionally substituted -O-heteroaryl wherein the heteroaryl group has 5-10 members . Suitable heterocycle and heteroaryl for R4 include : piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl)
According to a further aspect of the invention, R4 is , an optionally substituted -0-Ci_4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , or optionally substituted -0-Ci-4-alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1 , 3- dioxanylmethoxy, dimethyl-1, 3-dioxanylmethoxy, 1 , 3- dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo-tetrahydrofuranylmethoxy) .
In one embodiment, R5 is
Halogen,
Amino, Hydroxy,
C1-6 alkyl, ;,
5-10 member heteroaryl,
C6-Io aryl, or
CONR6R' 6.
In another embodiment, R4 and R5 are j oined to form a 5-
10 member heterocycle, or C6-I0 member aryl . In accordance with a further embodiment of the invention, the compounds are selected from subformulas Ia-Ij j , which correspond, respectively, to Formula I , but which exhibit the following groups :
Ia A is a single bond; and
R4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, or N (Ci-4-alkyl) 2 Λ phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHd-4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl,
N (Ci_4-alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (Ci-4-alkyl) 2.
Ib A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H; and R4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, or
N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl , NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, N(Ci_4-alkyl)2, CONH2, CONHCi_4-alkyl, or
CON(Ci-4-alkyl)2.
A is a single bond;
R2, R'2, R3, and R'3 are each H; R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl, Br, Cx-^-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (d-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci_4-alkyl ) 2; and
(
R4 is Ci-10 alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-.4- alkyl, CO-C^-alkyl, NH2, NHC^-alkyl, or N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl , CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci_4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl , CO-Ci_4-alkyl , NH2, NHCi_4-alkyl,
N (Ci-4-alkyl) 2, CONH2, CONHCi_4-alkyl , or CON (Ci_4-alkyl ) 2.
A is a single bond; R2 , R ' 2 , R3 , and R ' 3 are each H ;
R1 is benzyl optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci_4-alkyl , NH2, NHCi_4-alkyl ,
N (C1_4-alkyl) 2, CONH2, CONHCi-4-alkyl , or CON (Ci-4-alkyl) 2; and
R4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, or N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl , N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-
Ci-4-alkyl, CO-Ci-4~alkyl, NH2, NHCχ-4-alkyl, N (Ci-4-alkyl) 2f CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2.
A is a single bond; R2, R'2, R3, and R'3 are each H;
R5 is hydrogen, halogen, cyano, hydroxy, C1-.4- alkyl, hydroxyalkyl having 1 to 4 carbon atoms, C2-4-alkenyl, COOH, COO-Ci-4-alkyl, NH2,
NHCi-4-alkyl, or N (Ci-4-alkyl ) 2; and R4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl, NH2, NHCi-4-alkyl, or
N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, ■ hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl ).2>, CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci-4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or
CON (Ci_4-alkyl) 2.
A is a single bond;
R2, R ' 2, R3, and R' 3 are each H; R5 is hydrogen, halogen, cyano, hydroxy, C1-4- alkyl, hydroxyalkyl having 1 to 4 carbon atoms , C2-4-alkenyl , COOH, C00-Ci-4-alkyl, NH2, NHCi-4-alkyl, or N (Ci_4-alkyl ) 2;
R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- ■ . alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl ) 2; and R4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyaho, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci_4-alkyl , NH2, NHCi-4-alkyl, or
' , N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Cα_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- • Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl , N (Ci-4-alkyl) 2, CONH2, CONHCχ_4-alkyl, or
CON (Ci-4-alkyl ) 2. Ig A is a single bond;
R2, R' 2, R3, and R ' 3 are each H;
R5 is hydrogen; and
R4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, ' difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl, NH2, NHCi-4-alkyl, or N (Ci_4-alkyl ) 2 A phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl ,
N (Ci-4-alkyl) 2, CONH2, CONHCa.-4-alkyl, or CON (Ci_4-alkyl) 2.
Ih A is a single bond;
R2, R' 2, R3, and R' 3 are each H; R5 is hydrogen;
R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, In1 each case optionally substituted by F, Cl, Br, Ci-4-alkyl , cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2; and
R4 is Ci-io alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexyimethoxy) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, or N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl , ' Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl , or CON (Ci_4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Cχ-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCr_4-alkyl , or CON (C1_4-alkyl) 2. A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H;
R5 is hydrogen;
R1 is benzyl optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl , N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or
CON (Ci-4-alkyl) 2; and
R4 is Ci-10 alkoxy (e . g . , methoxy, ethoxy, propoxy, isopropoxy, fluoroethoxy, difluoroethoxy, trifluoromethoxy, fluoropropoxy, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, or
N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl , CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl , cyano, hydroxy, carboxy, COO- Ci_4-alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or
CON (Ci_4-alkyl ) 2. Ij A is a single bond; and
R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (C^4- alkyl) 2, CONH2, CONHC1_4-alkyl , or CON (Ci-4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl , cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci~4-alkyl) 2, CONH2, CONHCα_4-alkyl, or CON (Ci_4-alkyl) 2.
Ik A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H; and
R4 is an a 5-10 member heterocycle , or 5-10 member heteroaryl ( e . g . piperidinyl , morpholinyl, pyrrolidinyl , pyridinyl , tetrahydrofuranyl , and pyrazinyl ) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano , hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci- 4-alkyl , NH2 , NHCi_4-alkyl , or N (Ci_4-alkyl ) 2 , phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl , cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-C^-alkyl , NH2 , NHCi_4-alkyl , N (Ci_4- alkyl ) 2 , CONH2 , CONHCi-4-alkyl , or CON (C^4- alkyl ) 2 / or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl , Br, Ci_4-alkyl , cyano , hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci-4- alkyl , NH2 , NHC1_4-alkyl , N (Ci_4-alkyl ) 2, CONH2 , CONHCχ-4-alkyl, or CON ( Ci_4-alkyl ) 2.
A is a single bond;
R2, R ' 2 , R3, and R ' 3 are each H;
R1 is benzyl , phenethyl , phenpropyl , or naphthylmethyl , in each case optionally substituted by F, Cl , Br, Ci-4-alkyl , cyano , hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci_4- alkyl , NH2 , NHCi-4-alkyl , N (Ci_4-alkyl ) 2 , CONH2, CONHC1_4-alkyl , or CON ( Ci_4-alkyl ) 2 ; and R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl , morpholinyl, pyrrolidinyl , pyridinyl, - tetrahydrofuranyl, and pyrazinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, • carboxy, COO-Ci-4-alkyl , CO-Ci- 4-alkyl, NH2, NHCi-4-alkyl, or N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci_4-alkyl, NH2, NHCi-4-alkyl , N (Ci_4- alkyl) 2, CONH2, CONHCi_4-alkyl , or CON (C3.-4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2.
A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H;
R1 is benzyl optionally substituted by F, Cl, Br, Ci-4-alkyl , cyano, hydroxy, carboxy, COO-
Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (Ci_4-alkyl ) 2; and R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl , pyridinyl, tetrahydrofuranyl, and pyrazinyl) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4- alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON (Ci_4- alkyl ) 2, or benzyloxy, phenethpxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy', carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl / NH2, NHCi-4-alkyl , N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2.
A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H;
R5 is hydrogen, halogen, cyano, hydroxy, Ci_4- alkyl, hydroxyalkyl having 1 to 4 carbon atoms, C2_4-alkenyl, COOH, C00-Ci_4-alkyl, NH2,
NHCi-4-alkyl, or N (Ci-4-alkyl) 2; and R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl , or N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4- alkyl , CO-Ci-4-alkyl, NH2, NHCi-4-alkyl, N (Cχ-4- alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (C1_4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl , NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (Ci_4-alkyl ) 2.
A is a single bond;
R2, R ' 2, R3, and R' 3 are each H;
R5 is hydrogen, halogen, cyano, hydroxy, Ci_4- alkyl , hydroxyalkyl having 1 to 4 carbon atoms , C2-4-alkenyl, COOH, COO-Ci_4-alkyl, NH2,
NHCi-4-alkyl, or N (Ci-4~alkyl) 2; R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2; and
R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl , Br,
Ci-4-alkyl , cyano, hydroxy, carboxy, COO-C3.-4- alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci-4- alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON (Ci-4- alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl,1 cyano, hydroxy, carboxy,. COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (C1_4-alkyl) 2, CONH2, CONHCα-4-alkyl, or CON (Ci_4-alkyl) 2.
A is a single bond;
R2, R' 2, R3, and R' 3 are each H/
R is hydrogen; and R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl , tetrahydrofuranyl, and pyrazinyl) optionally substituted by ' F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl , or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl , Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-C1-.4- alkyl, CO-C^-alkyl, NH2, NHCi-4-alkyl , N (C^4- alkyl) 2/ CONH2, CONHCi-4-alkyl, or CON (Ci_4- alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, In each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C^-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2.
A is a single bond;
R2, R' 2, R3, and R ' 3 are each H;
R5 is hydrogen;
R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci_4~ alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2; and R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl, pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi-4-alkyl, or N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci_4-alkyl , NH2, NHC^-alkyl, N-(C1-4- alkyl ) 2, CONH2, CONHCi-4-alkyl , or CON (Ci_4- alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl , Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl),2.
A is a single bond;
R2, R ' 2, R3, and R' 3 are each H;
R5 is hydrogen;
' R1 is benzyl optionally substituted by F, Cl,
Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl , N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2; and R4 is an a 5-10 member heterocycle, or 5-10 member heteroaryl (e . g . piperidinyl, morpholinyl , pyrrolidinyl, pyridinyl, tetrahydrofuranyl, and pyrazinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1- 4-alkyl, NH2, NHCi-4-alkyl , or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, - cyano, hydroxy, carboxy, COO-Cχ_4- alkyl/ C0-Ci-4-alk:yl, NH2, NHCi_4-alkyl, N (Ci_4- alkyl )-2, CONH2, CONHC1_4-alkyl, or CON (Ci-4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl , cyano, hydroxy, carboxy, COO-Ci_4-alkyl , CO-Ci_4- alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl , or CON (Ci_4-alkyl ) 2.
A is a single bond; and
R4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -O-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . piperidinyl, morpholinyl, pyrrolidinyl , tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci_4-alkyl , NH2, NHC1-4- alkyl, or N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (C^-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl,
Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCχ-4-alkyl, N (C1-4-alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON (Ci-4-alkyl ) 2.
It A is a single bond;
R2, R' 2, R3, and R ' 3 are each H; and
R4 is an -O-heterocycle wherein the heterocycle group has 5-10 members, or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e . g . piperidinyl , morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-j-a'lkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl , or N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br,
Ci-4-alkyl , cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci-4- alkyl ) 2, CONH2, CONHCi_4-alkyl , or CON (C^4- alkyl) 2 f or benzyloxy, phenethoxy, or phenpropoxy, in, each case optionally substituted1 by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl , CO-Ci_4- " alkyl , NH2, NHCi_4-alkyl , N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl ) 2.
A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H;
R1 is benzyl, phenethyl , phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl , CO-Ci_4- alkyl , NH2, NHCi_4-alkyl , N (Ci-4-alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (Ci_4-alkyl) 2; and R4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e . g . piperidinyl, morpholinyl, pyrroiidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl , and pyridinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl , or N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br,
Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci_4-alkyl, NH2, NHd_4-alkyl, N (Ci_4- alkyl ) 2 / CONH2, ' CONHCi-4-alkyl , or CON (Ci_4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl , NH2, NHCi-4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl , or CON (Ci-4-alkyl) 2.
Iv A is a single bond;
R2, R ' 2, R3, and R' 3 are each H;
R1 is benzyl optionally substituted by F, Cl, Br, Ci-4-alkyl , cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (Ci_4-alkyl ) 2; and R4 is an -O-heterocycle wherein the heterocycle group has 5-10 members, or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e . g . piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHC^-alkyl, or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br,
Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci_4-alkyl, NH2, NHC1_4-alkyl, N (Cχ_4- alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON ( C;L-4- alkyl ) 2Λ or benzyloxy, ■ phenethoxy, or phenpropoxy, in each case' optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-C1_4-alkyl, CO-Ci_4- alkyl, ' NH2, NHC^-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl/ or CON (Ci_4-alkyl) 2.
A is a single bond;
R2, R' 2, R3, and R' 3 are each H;
R5 is hydrogen, halogen, cyano, hydroxy, Ci_4- alkyl, hydroxyalkyl having 1 to 4 carbon atoms, C2_4-alkenyl, COOH, COO-Ci_4-alkyl, NH2, NHCi-4-alkyl, or N (Ci-4-alkyl) 2; and R4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -O- heteroaryl wherein the heteroaryl group has 5-10 members (e . g . piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi-4-alkyl, or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl , Br,
Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl, NH2, NHCi-4-alkyl, N (C1-Z1- alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON (C1_4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl , Br, Ci_4-alkyl , cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCχ-4-alkyl, or CON (Ci-4-alkyl) 2.
A is a single bond;
R2, R ' 2, R3, and R' 3 are each H;
R5 is hydrogen, halogen, cyano, hydroxy, C1-4- alkyl, hydroxyalkyl having 1 to 4 carbon atoms , C2-4-alkenyl, COOH, COO-Ci-4-alkyl, NH2, NHCi-4-alkyl, or N (Ci-4-alkyl) 2; R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl , in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi_4-alkyl , or CON (Ci-4-alkyl) 2; and
R4 is an -0-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has
5-10 members (e . g . piperidinyl, morpholinyl, pyrrolidinyl , tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl ) optionally substituted by F,- Cl, Br, methoxy, ethoxy, - cyano, hydroxy, carboxy, COO-Ci-4-alkyl , CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, or N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4- • alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (C1-4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-.4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (C^-alkyl ) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2 •
A is a single bond;
R2, R ' 2, R3, and R' 3 are each H; R5 is hydrogen; and
R4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has
5-10 members (e . g . piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci-
4-alkyl, NH2, NHCi_4-alkyl, or N (Ci-4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4- alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (Ci_4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl , Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2.
Iz A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H;
R5 is hydrogen; R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, C00-Ci-4-alkyl, CO-C1-4- alkyl, NHf, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2; and
R4 is an -O-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has
5-10 members (e . g . piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl ) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci-
4-alkyl, NH2, NHCi-4-alkyl , or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (C^4- alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (C1^- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl , cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci-4- -alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2.
Iaa A is a single bond;
R2, R ' 2, R3, and R' 3 are each H; R is hydrogen;
R1 is benzyl optionally substituted by F, Cl, - Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO- Cχ-4-alkyl , CO-Ci_4-alkyl, NH2, NHCi_4-alkyl,
N (Ci-4-alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (C1_4-alkyl) 2; and
R4 is an -0-heterocycle wherein the heterocycle group has 5-10 members , or -0- heteroaryl wherein the heteroaryl group has 5-10 members (e . g. piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazinyl, dioxanyl, and pyridinyl) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, C00-Ci_4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi-4-alkyl, or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4- alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON (Ci_4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl , or CON (Ci_4-alkyl) 2.
Ibb A is a single bond; and FLj is an -O-Cl-4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O- Cl-4-alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy,
1, 3-dioxanylmethoxy, dimethyl-1, 3- dioxanylmethoxy, 1 , 3-dioxolanylmethoxy, piperidinyIethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy,
\ cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci-
4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-C^-alkyl, NH2, NHCi_4-alkyl, N (C1^- alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON (Ci-4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl , cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl , N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2.
Ice A is a single bond;
R2, R ' 2, R3, and R' 3 are each H; and R4 is an -0-Ci-4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C1-4- alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1 , 3- dioxanylmethoxy, dimethyl-1 , 3- dioxanylmethoxy, 1, 3-dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi-4-alkyl, or N (Ci-4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, N (C^4- alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2.
Idd A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H; R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1I4- alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2; and
R4 is an -O-Ci-4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C1-4- alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1 , 3- dioxanylmethoxy, dimethyl-1, 3- dioxanylmethoxy, 1, 3-dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4- alkyl) 2, CONH2, CONHCi_4-alkyl, or CON (C^4- alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl , cyano, hydroxy, carboxy, COO-Cα-4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2. lee A is a single bond;
R2, R ' 2, R3, and R' 3 are each H;
R1 is benzyl optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO- Ci-4-alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl ) 2, CONH2, CONHCi_4-alkyl, or CON (Ci-4-alkyl ) 2; and
R4 is an -O-Ci-4-alkyl-heterocycle wherein the heterocycle group has 5-10 members, -O-Ci_4-alkyl- heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy,' 1 , 3-dioxanylmethoxy, dimethyl-1 , 3-dioxanylmethoxy, 1 , 3- dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci-4-alkyl, NH2, NHC1-4- alkyl, or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4-alkyl , cyano, hydroxy, carboxy, COO-Ci_4-alkyl , CO-Ci-4-alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHC1-4- alkyl, or CON (Ci-4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2. Iff A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H;
R5 is hydrogen, halogen, cyano, hydroxy, Ci_4- alkyl, hydroxyalkyl having 1 to 4 carbon atoms , C2-4~alkenyl, COOH, COO-Ci-4-alkyl , NH2, NHCi-4-alkyl, or N (Ci_4-alkyl) 2; and R4 is an -0-Ci_4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-Ci-4-alkyl- heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1 , 3-dioxanylmethoxy, dimethyl-1 , 3-dioxanylmethoxy, 1 , 3- dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci_4-alkyl, NH2, NHC1-4- alkyl, or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHC1-4- alkyl, or CON (Ci_4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, C00-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (C1_4-alkyl) 2. Igg A is a single bond;
R2, R ' 2, R3, and R' 3 are each >H;
R5 is hydrogen, halogen, cyano, hydroxy, Ci_4- alkyl , hydroxyalkyl having 1 to 4 carbon atoms , C2-4-alkenyl, COOH, COO-Ci-4-alkyl , NH2, NHCi-4-alkyl, or N (Ci-4-alkyl )'2 ;
R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Cχ-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl , N (Ci_4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2; and
R4 is an
Figure imgf000059_0001
wherein the heterocycle group has 5-10 members , -O-C1-.4- alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1, 3- dioxanylmethoxy, dimethyl-1, 3- dioxanylmethoxy, 1 , 3-dioxolanylmethoxy, piperidinyIethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, ' cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl , or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci_4-alkyl , NH2, NHCi_4-alkyl, N (C'i_4- alkyl) 2 / CONH2, CONHCi_4-alkyl, or CON (Ci_4- alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHd-4-alkyl , N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl , or CON (Ci-4-alkyl ) 2.
Ihh A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H;
R5 is hydrogen; and R4 is an -0-Ci_4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C1-4- alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1 , 3- dioxanylmethoxy, dimethyl-1 , 3- dioxanylmethoxy, 1 , 3-dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl , NH2, NHCi_4-alkyl, or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, N (C1_4- alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (C1-Z1- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2.
A is a single bond;
R2, R' 2, R3, and R ' 3 are each H;
R5 is hydrogen; R1 is benzyl, phenethyl , phenpropyl , or naphthylmethyl,' in each case optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl ) 2, CONH2,
CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2; and
R4 is an -O-Ci-4-alkyl-heterocycle wherein the • heterocycle group has 5-10 members , -O-C1-4- alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1 , 3- dioxanylmethoxy, dimethyl-1 , 3- dioxanylmethoxy, 1 , 3-dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrofuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4-alkyl) 2, phenoxy optionally substituted by F, Cl , Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, N (Cχ-4- alkyl) 2/ CONH2, CONHCi-4-alkyl, or CON(Ci_4- alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Cχ-4- alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2. Ij j A is a single bond;
R2 , R ' 2, R3, and R ' 3 are each H;
R5 is hydrogen;
R1 is benzyl optionally substituted by F, Cl , Br, Ci_4-alkyl , cyano, hydroxy, carboxy, COO- Ci-4-alkyl , CO-Ci-4-alkyl , NH2, NHCi_4-alkyl , N ( Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl , or
CON (Ci-4-alkyl ) 2 ; and
R4 is an -O-Ci-4-alkyl-heterocycle wherein the heterocycle group has 5-10 members , -O-C1-4- alkyl-heteroaryl wherein the heteroaryl group has 5-10 members (e . g . , morpholinylethoxy, tetrahydropyranylmethoxy, 1, 3- dioxanylmethoxy, dimethyl-1, 3- dioxanylmethoxy, 1, 3-dioxolanylmethoxy, piperidinylethoxy, thienylethoxy, pyridinylmethoxy, and oxo- tetrahydrόfuranylmethoxy) optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci-
4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4-alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci-4-alkyl, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci_4-alkyl, NH2, NHCi_4-alkyl, N (C1_4- alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4- alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4-alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl , N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl , or CON (Ci_4-alkyl ) 2.
In one aspect, the present invention provides novel compounds including :
6-Bromo-2- ( 4-fluoro-benzyl ) -9-hydroxy- 3, 4-dihydro-2H-pyrido [1 , 2-a] pyrazine- 1, 8-dione; 6- (1, 1-Dioxo- [1, 2] thiazinan-2-yl) -2- (4- fluoro-benzyl) -9-hydroxy-3, 4-dihydro-2H- pyrido [1, 2-a] pyrazine-1, 8-dione;
2- (4-Fluoro-benzyl) -9-hydroxy-6- (tetrahydro-furan-2-yl) -3, 4-dihydro-2H- pyrido (1, 2-a) pyrazine-1, 8-dione;
8 2- (4-Fluoro-benzyl) -6-furan-2-yl-9- hydroxy-3, 4-dihydro-2H-pyrido (1,2- a) pyrazine-1, 8-dione;
2- (4-Fluoro-benzyl) -9-hydroxy-6-thiazol- 2-yl-3, 4-dihydro-2H-pyrido (1, 2- a) pyrazine-1, 8-dione;
10 2- (4-Fluoro-benzyl) -9-hydroxy-6-phenyl-
3, 4-dihydro-2H-pyrido (1, 2-a) pyrazine- 1, 8-dione; l
16 2- (4-Fluoro-benzyl) -9-hydroxy-6- methanesulfonyl-3, 4-dihydro-2H- pyrido (1, 2-a) pyrazine-1, 8-dione;
35 6-AZIDO-2-(4-FLUORO-BENZYL)-9-HYDRO
XY-3,4-DIHYDRO-2H-PYRIDO[1 ,2-A]PYRA ZINE-1, 8-DIONE; 36 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-PIPERIDIN-1 -YL-3,4-
DIHYDRO-2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
37 6-CYCLOHEXYL-2-(4-FLUORO-BENZYL)-9-
HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
38 4-FLUORO-N-(4-FLUORO-BENZOYL)-N-[2-(4-
FLUORO-BENZYL)-9-HYDROXY-1 ,8-DIOXO-i ,3,4,8-
TETRAYDRO-2H-PYRIDO[1 ,2-A]PYRAZIN-6-YL]-
BENZAMIDE;
39 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
MORPHOLIN-4-YL-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
40 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
PYRROLIDIN-1-YL-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
41 FURAN-2-CARBOXYLIC ACID [2-(4-FLUORO-
BENZYL)-9-HYDROXY-1 ,8-DIOXO-i ,3,4,8- TETRAHYDRO-2H-PYRIDO[1 ,2-A]PYRAZIN-6-YL]- (FURAN-2-CARBONYL)-AMIDE;
42 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
(TETRAHYDRO-FURAN-S-YLJ-S^-DIHYDRO^H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE; 43 2-(4-FLUORO-BENZYL)-6-(4-FLUORO-
PHENYLAMINO)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
44 6-DIMETHYLAMINO-2-(4-FLUORO-BENZYL)-9- HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
46 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
[1,2,3]TRIAZOL-1-YL-3,4-DIHYDRO-2H-PYRIDO[1,2- A]PYRAZINE-1,8-DIONE;
47 1-[2-(4-FLUORO-BENZYL)-9-HYDROXY-1,8-DIOXO- 1,3,4,8-TETRAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN- 6-L]-1H-[1,2,3]TRIAZOLE-4-CARBOXYLIC ACID METHYL ESTER;
and pharmaceutically acceptable salts thereof, pharmaceutically solvates thereof, and solvates of pharmaceutically acceptable salts thereof.
According to a further embodiment, the present invention provides novel compounds including :
45 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
METHOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE; 48 6-ETHOXY-2-(4-FLUORO-BENZYL)-9-HYDROXY- 3,4-DIHYDRO-2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8- DIONE;
49 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
ISOPROPOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
50 6-(2,2-DIFLUORO-ETHOXY)-2-(4-FLUORO-
BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
51 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
PROPOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
52 2-(4-FLUORO-BENZYL)-6-(2-FLUORO-ETHOXY)-
Θ-HYDROXY-S^-DIHYDRO^H-PYRIDOCI ^- A]PYRAZINE-1 ,8-DIONE;
53 δ-CYCLOPROPYLMETHOXY^^-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
54 6-CYCLOHEXYLMETHOXY-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE; 55 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2,2,2- TRIFLUORO-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
56 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
MORPHOLIN-4-YL-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
57 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
PHENOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
58 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
ISOBUTOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
59 2-(4-FLUORO-BENZYL)-6-(4-FLUORO-PHENOXY)-
9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
60 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
(TETRAHYDRO-PYRAN-4-YLMETHOXY)-3,4- DIHYDR0-2H-PYRID0[1 ,2-A]PYRAZINE-1 ,8- DIONE;
61 7-FLUORO-2-(4-FLUORO-BENZYL)-9-HYDROXY-
6-METHOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE; 62 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2- METHOXY-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
63 6-(2,2-DIMETHYL-[1 ,3]DIOXOLAN-4-
YLMETHOXY)-2-(4-FLUORO-BENZYL)-9- HYDROXY-3,4-DIHYDRO-2HPYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
64 6-(2-DIMETHYLAMINO-ETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
65 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
METHANESULFONYL-ETHOXY)-S^-DIHYDRO- 2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
66 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-[2-(4-
METHOXY-PHENYL)-ETHOXY]-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
67 2-(4-FLUORO-BENZYL)-G-(S-FLUORO-PROPOXY)- 9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
68 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(PYRIDIN- 2-YLMETHOXY)-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE; 69 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
PHENETHYLOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
70 6-([1 ,3]DIOXOLAN-4-YLMETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
71 6-([1 ,3]DIOXAN-5-YLOXY)-2-(4-FLUORO-BENZYL)-
9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
72 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
PIPERIDIN-1-YL-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
73 6-CYCLOPENTYLMETHOXY-2-(4-FLUORO-
BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
74 6-CYCLOBUTYLMETHOXY-2-(4-FLUORO-
BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
75 2-[2-(4-FLUORO-BENZYL)-9-HYDROXY-1 ,8-
DIOXO-1 ,3,4,8-TETRAHYDRO^H-PYRIDO[I ,2-
A]PYRAZIN-6-YLOXY]-N,N-DIMETHYL-
ACETAMIDE 76 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(PYRIDIN- 3-YLOXY)-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
77 6-(2-CYCLOPROPYL-ETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
78 6-BROMO-2-(3,4-DICHLORO-BENZYL)-9-
HYDROXY-3,4-DIHYDRO-2H-PYRIDO(1 ,2-A)- PYRAZINE-1 ,8-DIONE;
79 6-BROMO-2-(3-CHLORO-4-FLUORO-BENZYL)-9-
HYDROXY-3,4-DIHYDRO-2H-PYRIDO-(1 ,2-A)- PYRAZINE-1 ,8-DIONE;
80 6-(4,4-DIFLUORO-CYCLOHEXYL-METHOXY)-2-(4-
FLUORO-BENZYL)-9-HYDROXY-3,4-DIHYDRO- 2H-PYRIDO-[1 ,2-A]PYRAZINE-1 ,8-DIONE;
81 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
HYDROXY-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
82 6-(2,2-DIMETHOXY-ETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE; 83 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-((R)-5-
OXO-TETRAHYDRO-FURAN-2-YLMETHOXY)-3,4- DIHYDRO-2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8- DIONE;
84 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-((S)~5-
OXO-TETRAHYDRO-FURAN-2-YLMETHOXY)-3,4- DIHYDRO-2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8- DIONE;
85 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
THIOPHEN-2-YL-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
86 2-BENZYL-9-HYDROXY-6-METHOXY-3,4-
DIHYDR0-2H-PYRID0(1 ,2-A)-PYRAZINE-1 ,8- DIONE;
87 2-(3,4-Dichloro-benzyl)-9-hydroxy-6-methoxy-3,4- dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,8-dione;
88 2-BENZYL-6-(2-FLUORO-ETHOXY)-9-HYDROXY- 3,4-DIHYDRO-2H-PYRIDO-(1 ,2-A)-PYRAZINE-1 ,8- DIONE;
89 2-(3,4-DICHLORO-BENZYL)-6-(2-FLUORO-
ETHOXY)-9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO- (1 ,2-A)-PYRAZINE-1 ,8-DIONE; f# pi 90 6-(2-CYCLOPENTYL-ETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
91 2-(3,4-Dich loro-benzyl )-9-hyd roxy-6-( pyrid i n-3- yloxy)-3,4-dihydro-2H-pyrido[1 ,2~a]pyrazine-1 ,8- dione;
92 2-(3-Chloro-4-fluoro-benzyl)-9-hydroxy-6-(pyridin-3- yloxy)-3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,8- dione;
93 2-(3,4-Dichloro-benzyl)-9-hydroxy-6-(2-methoxy- ethoxy)-3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,8- dione; and
94 2-(3-Chloro-4-fluoro-benzyl)-9-hydroxy-6-(2- methoxy-ethoxy)-3,4-dihydro-2H-pyrido[1 ,2- a]pyrazine-1 ,8-dione;
and pharmaceutically acceptable salts thereof, pharmaceutically solvates thereof, and solvates of pharmaceutically acceptable salts thereof .
• Reference hereinafter to a compound according to the invention includes compounds of the general formula ( I ) and their pharmaceutically acceptable salts , hydrates and solvates . < In one embodiment, the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 99% .
In one embodiment , the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 95% .
In one embodiment, the compounds of the present invention are the (+) enantiomer having an enantiomeric excess of 90% .
In one embodiment, the compounds of the present invention are the (-) enantiomer having an enantiomeric excess of 99% .
In one embodiment, the compounds of the present invention are the ( -) enantiomer having an enantiomeric excess of 95% .
In one embodiment, the compounds of the present invention are the (-) enantiomer having an enantiomeric excess of 90% .
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . All publications , patent applications , patents, and other references mentioned herein are incorporated by reference in their entirety . In case of conflict, the present specification, including definitions, will control . In addition, the materials , methods , and examples are illustrative only and not intended to be limiting .
The term "alkyl" represents a linear, branched or cyclic hydrocarbon moiety having 1 to 10 carbon atoms , which may have one or more double bonds or triple bonds in the chain, and is optionally substituted . Examples include but are not limited to methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , tert-pentyl, hexyl, isohexyl, neohexyl, allyl , vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl , butenyl, isobutenyl, hexenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexatrienyl, heptenyl, heptadienyl, heptatrienyl, octenyl, octadienyl, octatrienyl, octatetraenyl , propynyl , butynyl , pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclohexenyl, cyclohexdienyl and cyclohexyl . The term alkyl is also meant to include haloalkyls in which one or more hydrogen atom is replaced by a halogen, i . e . an alkylhalide . Examples include but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl , chloromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloroethyl, dichloroethyl , chloroethyl, chlorofluoromethyl, chlorodifluoromethyl, dichlorofluoroethyl . Aside from halogens , the alkyl groups can also be optionally substituted by, for example, hydroxy, amino, amido, and/or carboxy . The term "cycloalkyl" represents a cyclic alkyl moiety having 3 to 10 carbon atoms , which is optionally substituted ( (e . g . , cyclopropyl, cyclobutyl , cyclopentyl, and cyclohexyl ) . Suitable substituents are, for example, halogens , hydroxy, amino, amido, and/or carboxy .
The term "alkoxy" represents an alkyl which is covalently bonded to the adj acent atom through an } oxygen atom. Like the alkyl groups, the alkoxy groups can also be optionally substituted. Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy. The alkoxy groups can be optionally substituted by, for example, halogens, hydroxy, amino, amido, and/or carboxy.
The term "aryl" represents a carbocyclic moiety containing at least one benzenoid-type ring (i . e . may be monocyclic or polycyclic) , and which may be optionally substituted with one or more substituents . Examples include but are not limited to phenyl, tolyl , dimethylphenyl, aminophenyl, anilinyl, naphthyl, anthryl, phenanthryl or biphenyl . The aryl groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy .
The term "aralkyl" represents an aryl group attached to the adj acent atom by a C1-I0 alkyl . Like the aryl groups , the aralkyl groups can also be optionally substituted. Examples include but are not limited to benzyl, benzhydryl, trityl , phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl and naphthylmethyl . The aralkyl groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy .
"Aralkyloxy" represents an aralkyl which is covalently bonded to the . adj acent atom through an oxygen atom.
Like the aryl groups , the aralkyloxy groups can also be optionally substituted. Examples include but are not limited to benzyloxy, benzhydryloxy, trityloxy, phenethyloxy, 3-phenylpropyloxy, 2-phenylpropyloxy, 4- phenylbutyloxy and naphthylmethoxy. The aralkyloxy groups can be optionally substituted by, for example, halogens, hydroxy, amino, amido, and/or carboxy.
The term "acceptable" means that it must not be deleterious to the recipient thereof . "
"Halogen atom" is specifically a fluorine atom, chlorine atom, bromine atom or iodine atom.
The term "independently" means that a substituent can be the same or a different definition for each item.
The term ' "amidino" represents -C (=NRd) NReRf wherein Rd, Re and Rf are each independently selected from H, Cχ-io alkyl, C6-I2 aryl or C7-I2 aralkyl, or Re and Rf are taken together with the nitrogen to which they are attached to form a 4 to 10 member heterocycle .
The term "guanidino" represents -N (Rd) C (=NRe) NRfRg wherein Rd, Re, Rf and Rg are each independently selected from H, Ci_io alkyl, C6-12 aryl or C7_12 aralkyl, or Rf and R9 are taken together with the nitrogen to which they are attached to form a 4 to 10 member heterocycle .
The term "amido" represents -CONH2, -CONHRd, -CONRdRe, - NHCORd, -NRdC0Re, wherein Rd and Re are each independently selected from Ci-10 alkyl, C6-12 aryl or C7- 12 aralkyl, or Rd and Re are taken together with the nitrogen to which they are attached to form a 4 to 10 member heterocycle .
The term "amino" represents a derivative of ammonia obtained by substituting one or more hydrogen atom and include -NH2, -NHRd and -NRdRe, wherein Rd and Re are each independently selected from Ci-10 alkyl, C6-12 aryl or C7-I2 aralkyl , or Rd and Re are taken together with the nitrogen to which they are attached to form a 4 to 10 member heterocycle .
The term "sulfonamido" represents -SO2NH2, -SO2NHRd, - SO2NRdRe, and -NRdSO2Re, wherein Rd and Re are each independently selected from Ci-10 alkyl, C6-12 aryl or C7- i2 aralkyl, or Rd and Re are taken together with the nitrogen to which they are attached to form a 5 to 10 member heterocycle . The term "urea" represents -N (Rd) CONReRf wherein Rd is H or Ci-io alkyl and wherein Rd and Re are each independently selected from the group consisting of H, Ci-io alkyl, C6-io aryl, 3-10 member heterocycle, and C7-I2 aralkyl, or Re and Rf are taken together with the nitrogen to which they are attached to form a C3-.10 heterocycle .
The term "heterocycle" represents an optionally substituted, saturated, partially saturated, or aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0) , sulfur ( S ) or nitrogen (N) . Heterocycles may be monocyclic or polycyclic rings . Examples include but are not limited to azepinyl, aziridinyl , azetyl, azetidinyl, diazepinyl, dithiadiazinyl, dioxazepinyl, . dioxolanyl , dithiazolyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, morpholinyl, morpholino, oxetanyl, oxadiazolyl, oxiranyl, oxazinyl, oxazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl , piperidyl, piperidino, pyridyl, pyranyl , pyrazolyl, pyrrolyl, pyrrolidinyl , thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl , thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, thiopyranyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl, thiazolothiazinyl , thiazolopyrimidinyl , thiazolopyridinyl, oxazolopyrimidinyl, oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, imidazopyrazinyl, purinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl , furopyridyl, benzofuranyl, isobenzofuranyl , thienopyrimidinyl , thienopyridyl , benzothienyl, cyclopentaoxazinyl, cyclopentafuranyl, benzoxazinyl, benzothiazinyl , quinazolinyl , naphthyridinyl, quinolinyl, isoquinolinyl, benzopyranyl, pyridopyridazinyl and pyridopyrimidinyl . The heterocyclic groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy.
The term "heteroaryl" represents an optionally substituted aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0) , sulfur (S ) or nitrogen (N) . Heteroaryls may be monocyclic or polycyclic rings . Examples include but are not limited to azepinyl, aziridinyl, azetyl , diazepinyl, dithiadiazinyl , dioxazepinyl, dithiazolyl, furanyl , isooxazolyl, isothiazolyl, ] imidazolyl, oxadiazolyl, oxiranyl, oxazinyl , oxazolyl, ' pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl^ pyranyl , pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl , triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, thiopyranyl, furoisoxazolylv imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl , thiazolothiazinyl, thiazolopyrimidinyl , thiazolopyridinyl , oxazolopyrimidinyl, oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, imidazopyrazinyl , purinyl, pyrazolopyrimidinyl , imidazopyridinyl, benzimidazolyl, indazolyl , benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl , indolinyl, isoindolinyl, furopyrimidinyl , furopyridyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl, thienopyridyl, benzothienyl , benzoxazinyl, , benzothiazinyl, quinazolinyl , naphthyridinyl, quinolinyl, isoquinolinyl, benzopyranyl, pyridopyridazinyl and pyridopyrimidinyl . The heteroaryl groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy.
The term "heteroaralkyl" represents an optionally substituted heteroaryl group attached to the adj acent atom by a Ci_io alkyl . The heteroaralkyl groups can be optionally substituted by, for example, halogens , hydroxy, amino, amido, and/or carboxy.
The term "optionally substitutgd" represents a group which is substituted by one or more substituents selected from: halogen, amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro, nitroso, urea,
S(O) o-∑Ra (wherein Ra is H, Ci-io alkyl, Cε-io aryl or 3-10 member heterocycle) ,
Ci-ioalkyl,
C7-I2 aralkyl,
C6-ioaryl,
5-10 member heteroaryl, Ci_ioalkoxy,
C6_ioaryl-Ci-10alkyloxy,
C6-i0aryloxy,
3-10 member heterocycle,
C (O) Rb (wherein Rb is H, Cx-I0 alkyl, C6-10 aryl , C7_12 aralkyl or 3-10 member heterocycle) ,
C (O) ORb (wherein Rb is H, Cx_xo alkyl, C6-10 aryl, C7_12 aralkyl or 3-10 member heterocycle) ,
NRbC (O) R' b (wherein Rb and R' b are each independently H,
Cx-Xo alkyl, C6-Xo aryl, C7-X2 aralkyl or 3-10 member heterocycle, or Rb and R ' b are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
SO2NRbR ' b (wherein Rb and R ' b are each independently H,
Ci-io alkyl, Cβ-io aryl , C7-I2 aralkyl or 3-10 member heterocycle, or Rb and R 'b are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
NRbSθ2R ' b (wherein Rb and Rb are each independently H,
C1-I0 alkyl, C6-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and R ' b are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
NRbSθ2NR' bRc (wherein Rb, R' b and Rc are each independently H, Ci_io alkyl, Cβ-io aryl, C7_12 aralkyl or ' 3-10 member heterocycle, or R ' b and Rc are taken together with the atoms to which they are attached to form a 5-10 member heterocycle) ,
CRbN=OR ' b (wherein Rb and R ' b are each independently H,
Ci-io alkyl, Cβ-io aryl, 3-10 member heterocycle or C7_i2 aralkyl ) , and
NRbCOOR ' b (wherein Rb and R ' b are each independently H,
Ci-io alkyl, C6-io aryl, C7_12 aralkyl or 3-10 member heterocycle) .
There is also provided "enantiomers" of the present invention . It will be appreciated that the compounds in accordance with the present invention can contain a chiral center . The compounds in accordance with the present invention may thus exist in the form of two different optical isomers , that is (+) or (-) enantiomers . All such enantiomers and mixtures thereof, including racemic or other ratio mixtures of individual enantiomers , are included within the scope of the invention . The single enantiomer can be obtained by methods well known to those of ordinary skill in the art, such as chiral HPLC, enzymatic resolution and chiral auxiliary derivatization .
It will also be appreciated that the compounds in accordance with the present invention can contain more than one chiral centers . The compounds of the present invention may thus exist in the form of different diastereomers . All such diastereomers and mixtures thereof are included within the scope of the invention . The single diastereomer can be obtained by method well known in the art, such as HPLC, crystallization and chromatography.
The optical purity is numerically equivalent to the "enantiomeric excess" . The term ''enantiomeric excess" is defined in percentage (%) value as follows : . [mole fraction (maj or enantiomer) - mole fraction (minor enantiomer) ] x 100. An example of ee of 99% represents a ratio of . 99.5% . of one enantiomer and 0.5% of the opposite enantiomer .
There is also provided "pharmaceutically acceptable salts" of the compounds of the present invention . The salt (s ) must be "acceptable" in the sense of not being deleterious to the recipient thereof . By the term pharmaceutically acceptable salts of compounds are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases . Examples of suitable acids include but are not limited to hydrochloric, hydrobromic, sulphuric, ■ nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids . Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts .
Also meant by "pharmaceutically acceptable salts" are salts derived from appropriate bases include alkali metal, alkaline earth metal or ammonium salts . Non- limiting examples of such salts known by those of ordinary skill include without limitation calcium, potassium, sodium, choline, ethylenediamine, tromethamine, arginine, glycinelysine, lysine, magnesium and meglumine .
^ There is also provided pharmaceutically acceptable hydrates of the compounds of the present invention . The hydrate ( s) must be "acceptable" in the sense of not being deleterious to the recipient thereof . "Hydrates" exist when the compound of the invention incorporates water . The hydrate may contain one or more molecule of water per molecule of compound of the invention . Illustrative non-limiting examples include monohydrate, dihydrate, trihydrate and tetrahydrate . The hydrate may contain one or more molecule of compound of the invention per molecule of water . An illustrative non- limiting example includes semi-hydrate . In one embodiment, the water may be held in the crystal in various ways and thus, the water molecules may occupy lattice positions in the crystal, or they may form bonds with salts of the compounds as described herein . The hydrate must be "acceptable" in the sense of not being deleterious to the recipient thereof . The hydration may be assessed by methods known in the art such as Loss on Drying techniques (LOD) and Karl Fisher titration .
The term "Solvate" means that compound of the invention incorporates one or more pharmaceutically acceptable solvent (e . g . , when the solvent is water the solvate is a hydrate) . The solvate ( s ) must be "acceptable" in the sense of not being deleterious to the recipient thereof . The solvate may contain one or more molecule of solvent per molecule of compound of the invention or may contain one or more molecule of compound of the invention per molecule of solvent . In one embodiment , the solvent may be held in the crystal in various ways and thus , the solvent molecule may occupy lattice positions in the crystal, or they may form bonds with salts of the compounds as described herein . The solvate (s ) must be "acceptable" in the sense of not being deleterious to the recipient thereof . The solvation may be assessed by methods known in the art such as Loss on Drying techniques (LOD)
Polymorphs & pseudopolymorphs : It will be appreciated by those skilled in the art that the compounds in accordance with the present invention can exist in several different crystalline forms due to a different arrangement of molecules in the crystal lattice . This may include solvate or hydrate (also known as pseudopolymorphs ) and amorphous forms . All such crystalline forms and polymorphs are included within the scope of the invention . The polymorphs may be characterized by methods well known in the art . Examples of analytical procedures that may be used to determine whether polymorphism occurs include : melting point (including hot-stage microscopy) , infrared (not in solution) , X-ray powder diffraction, thermal analysis methods (e . g . differential scanning calorimetry ( DSC) differential thermal analysis (DTA) , thermogravimetric analysis (TGA) ) , Raman spectroscopy, comparative intrinsic dissolution rate, scanning electron microscopy (SEM) .
When there is a sulfur atom present , the sulfur atom can be at different oxidation levels , i . e . S, SO, or SO2. All such oxidation levels are within the scope of the present invention .
When there is a nitrogen atom present, the nitrogen atom can be at different oxidation levels , i . e . N or NO . All such oxidation levels are within the scope of the present invention.
The following Table lists compounds in accordance with the invention .
Figure imgf000088_0001
2- ( 4-Fluoro-benzyl ) -6-furan- 2-yl-9-hydroxy-3, 4-dihydro--
8. 2H-pyrido ( 1, 2-a) pyrazine- 1, 8-dione
2- ( 4-Fluoro-benzyl ) -9- hydroxy-6-thiazol-2-yl-3 , 4-
9. dihydro-2H-pyrido ( 1 , 2- a) pyrazine-1 , 8-dione
2- ( 4-Fluoro-benzyl ) -9- hydroxy-6-phenyl-3 , 4-
10 dihydro-2H-pyrido ( 1 , 2- a) pyrazine-1, 8-dione
2- ( 4-Fluoro-benzyl ) -9- hydroxy-6-methyl-3, 4-
11 dihydro-2H-pyrido ( 1 , 2- a) pyrazine-1 , 8-dione
6-Ethyl-2- ( 4-Fluoro-benzyl ) • 9-hydroxy-3, 4-dihydro-2H-
12 pyrido ( 1, 2-a) pyrazine-1, 8- dione
2- ( 4-Fluoro-ben.zyl ) -9- hydroxy-6-vinyl-3 , 4-dihydro-
13 2H-pyrido ( 1 , 2-a) pyrazine- 1 , 8-dione
6- ( l, 2-Dihydroxy-ethyl ) -2- ( 4-Fluoro-benzyl ) -9-hydroxy-
14 3 , 4-dihydro-2H-pyrido ( 1 , 2- a) pyrazine-1, 8-dione
Figure imgf000089_0001
2- ( 4-Fluoro-benzyl) -9- hydroxy-1, 8-dioxo-l , 3, 4 , 8-
15 tetrahydro-2H-pyrido (1, 2- a) pyrazine-6-carboxylic acid
2- ( 4-Fluoro-benzyl ) -9- hydroxy-6-methanesulfonyl-
16 3, 4-dihydro-2H-pyrido ( l , 2- a) pyrazine-l , 8-dione
2- ( 4-fluoro-benzyl ) -7 , 9- dihydroxy -3 , 4-dihydro-2H-
17 pyrido [1, 2-a] pyrazine-1, 8- dione,
7-Amino-2- ( 4-fluoro-benzyl ) 9-hydroxy-3, 4-dihydro-2H-
18 pyrido [1, 2-a] pyrazine-1, 8- dione,
2-'(4-fluoro-benzyl) -9- hydroxy-7-methyl-3, 4-
19 dihydro-2H-pyrido [1,2- a] pyrazine-1, 8-dione,
2- ( 4-fluoro-benzyl) -9- hydroxy-7-hydroxymethyl-3, 4-
20 dihydro-2H-pyrido [ 1 , 2- a] pyrazine-1, 8-dione,
Figure imgf000090_0001
2- ( 4-fluoro-benzyl ) -9- hydroxy-1, 8-dioxo-l , 3, 4 , 8- tetrahydro-2H-pyrido [ 1, 2-
21 a] pyrazine-7-carboxylic acid,
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000092_0001
,2-A]PYRA
Figure imgf000093_0001
Figure imgf000094_0001
,8-
Figure imgf000095_0001
Figure imgf000096_0001
6-CYCLOPROPYLMETHOXY-2-(4- FLUORO-BENZYL)-9-HYDROXY-3,4- DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE
6-CYCLOHEXYLMETHOXY-2-(4- FLUORO-BENZYL)-9-HYDROXY-3,4- DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE
2-(4-FLUORO-BENZYL)-9-HYDROXY 6-(2,2,2-TRIFLUORO-ETHOXY)-3,4- DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE
2-(4-FLUORO-BENZYL)-9-HYDROXY- 6-(2-MORPHOLIN-4-YL-ETHOXY)- 3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE
2-(4-FLUORO-BENZYL)-Q-HYDROXY- 3-PHENOXY-3.4-DIHYDRO-2H- YRIDO[1 ,2-A]PYRAZiNE-1 ,8-DIONE
2-(4-FLUORO-BENZYL)-9-HYDROXY- 6-ISOBUTOXY-3,4-DIHYDRO-2H- 1YRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE
2-(4-FLUORO-BENZYL)-6-(4- FLU0R0-PHEN0XY)-9-HYDR0XY- 3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
,8-
,8-
Figure imgf000102_0001
In one embodiment, there is provided a method of preventing or treating HIV infection in a subject which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
In one embodiment, there is provided a method of preventing or treating HIV infection in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or pharmaceutical composition of the present invention .
In one embodiment, there is provided a method of preventing, delaying or treating AIDS in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
In one embodiment , there is provided a method of preventing, delaying or treating AIDS in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
In one embodiment , there is provided a method of preventing HIV replication in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention . In one embodiment, there is provided a method of preventing HIV replication in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
In one embodiment, there is provided a method of inhibiting HIV integrase in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
In one embodiment, there is provided a method of inhibiting HIV integrase in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
In one embodiment, there is provided a method of preventing integration of HIV DNA into host cell DNA in a subj ect which comprises administering to the subj ect a , therapeutically effective amount of a compound of the present invention .
In one embodiment, there is provided a method of preventing integration of HIV DNA into host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention . In one embodiment, there is provided a method of preventing the 3' -end processing of HIV DNA in a subj ect , the method comprising administering to the subj ect a therapeutically effective amount of a compound of the present invention .
In one embodiment, there is provided a method of preventing the 3' -end processing of HIV DNA in a subj ect which comprises administering to the subj ect a combination or a pharmaceutical composition of the present invention .
In one embodiment, there is provided a method of preventing the HIV DNA strand transfer to the host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention .
In one embodiment, there is provided a method of preventing the HIV DNA strand transfer to the host cell DNA in a subj ect which comprises administering to the subj ect a therapeutically effective amount of a combination or a pharmaceutical composition of the present invention .
In one embodiment , combinations of the present invention comprise those wherein the following embodiments are present, either independently or in combination . In • a further embodiment, the pharmaceutical combinations of this invention may contain at least one further therapeutic agent chosen from an agent used in inflammatory diseases , immunoregulatory diseases and in organ transplantation reactions .
In another embodiment, the pharmaceutical combination of this invention may contain at least one further therapeutic agent which is an antiviral agent .
In one embodiment, the pharmaceutical combination of this invention may contain at least one further antiviral agent which is chosen ( from nucleoside and nucleotide analog reverse transcriptase inhibitors , non-nucleoside reverse transcriptase inhibitors , protease inhibitors , integrase inhibitors attachment and fusion inhibitors, entry inhibitors or maturation inhibitors .
In one embodiment, the pharmaceutical combinations of this invention may contain at least one other antiviral agent which is a nucleoside and nucleotide analog
'reverse transcriptase inhibitors chosen from 3TC
(lamivudine, Epivir®) , AZT ( zidovudine, Retrovir®) , Emtricitabine (Coviracil®, formerly FTC) , d4T ( 2 ' , 3 ' - dideoxy-2 ' , 3 ' -didehydro-thymidine, stavudine and Zerit®) , tenofovir (Viread®) , 2 ' , 3 ' -dideoxyinosine (ddl , didanosine, Videx®) , 2 ' , 3 ' -dideoxycytidine (ddC, zalcitabine, Hivid®) , Combivir® (AZT/3TC or zidovudine/lamivudine combination) , Trivizir® (AZT/3TC/abacavir or zidovudine/lamivudine/abacavir combination) , abacavir ( 1592U89, Ziagen®) , SPD-754 ,
ACH-126, 443 (Beta-L-Fd4C) , Alovudine (MIV-310 ) ,. DAPD
(amdoxovir) , Racivir, 9- [ (2-hydroxymethyl) -1, 3- dioxolan-4-yl] guanine or 2-amino-9- [ (2-hydroxymethyl ) - 1 , 3-dioxolan-4-yl] adenine .
In another embodiment, the pharmaceutical combination of this inyention may contain at least one other antiviral agent which is a non-nucleoside reverse transcriptase inhibitor chosen from Nevirapine (Viramune®, NVP, BI-RG-587 ) , delavirdine (Rescriptor®, DLV) , efavirenz ( DMP 266, Sustiva®) , (+) -Calanolide A, Capravirine (AG1549, formerly S-1153 ) , DPC083 , MIV-150 , TMC120 , TMC125 or BHAP (delavirdine) , calanolides or L- 697 , 661 (2-Pyridinone 3benzoxazolMeNH derivative) .
In another embodiment , the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a protease inhibitor chosen from nelfinav'ir (Viracept®, NFV) , amprenavir ( 141W94 ,
Agenerase®) , indinavir (MK-639 , IDV, Crixivan®) , saquinavir ( Invirase®, Fortovase®, SQV) , ritonavir
(Norvir®, RTV) , lopinavir (ABT-378 , Kaletra®) ,
Atazanavir (BMS232632 ) , mozenavir ( DMP-450 ) , fosamprenavir (GW433908 ) , RO033-4649, Tipranavir ( PNU- 140690 ) , TMC114 or VX-385.
In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an attachment and fusion inhibitor chosen from T-20 (enfuvirtide, Fuzeon®) , T- 1249 , Schering C ( SCH-C) , Schering D (SCH-D) , FP21399 , PRO-140 , PRO 542 , PRO 452 , TNX-355, GW873140 (AK602 ) , TAK-220 , TAK-652 , UK-427 , 857 or soluble CD4 , CD4 fragments , CD4-hybrid molecules, BMS-806, BMS-488043 , AMD3100 , AMD070 or KRH-2731.
In another embodiment, the pharmaceutical combination of this invention may contain- at least one other antiviral agent which is an integrase inhibitor chosen from S-1360 , JKT 303 , L-870 , 810 , L-870, 812 or C-2507.
In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a maturation inhibitor and is PA-457.
In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is a zinc finger inhibitor and is azodicarbonamide (ADA) .
In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an antisense drug and is , HGTV43.
In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent which is an immunόmodulator, immune stimulator or cytokine chosen from interleukin-2 ( IL-2 , Aldesleukin, Proleukin) , granulocyte macrophage colony stimulating factor (GM-CSF) , erythropoietin, Multikine, Ampligen, thymomodulin, thymopentin, foscarnet, HE2000 , Reticulose, Murabutide, Resveratrol, HRG214 , HIV-I Immunogen (Remune) or EP HIVJ1090.
In another embodiment, the pharmaceutical combination of this invention may contain at least one other antiviral agent chosen from 2 ' , 3 ' -dideoxyadenosine, 3 ' - deoxythymidine, 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir, ganciclovir; interferons such as alpha-, beta-and gamma-interferon; glucuronation inhibitors such as probenecid; or TIBO drugs, HEPT, TSAO derivatives .
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprises a further aspect of the invention .
The individual' components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations .
In a further embodiment, the said compound of formula ( I ) and said therapeutic agent are administered sequentially . In a further embodiment, the said compound of formula ( I ) and said therapeutic agent are administered simultaneously .
The subj ect to which the compounds are administered can be, for example, a mammal or a human . Preferably, the subj ect is a human .
In one embodiment , the present invention further provides a pharmaceutical composition comprising at least one compound having the formula ( I ) or pharmaceutically acceptable salts or pharmaceutically acceptable hydrates or pharmaceutically acceptable solvates thereof and at least one pharmaceutically acceptable carrier or excipient .
In one embodiment , there is provided a method of
' preventing, or delaying opportunistic infections in HIV-infected subj ect which comprises administering to the subj ect a therapeutically effective amount of a compound of the present invention.
In one embodiment, the opportunistic infection is selected from CMV retinitis, Pneumocystis carinii pneumonia, Mycobacterium avium complex, cryptococcal meningitis , or herpes simplex .
In another embodiment, the invention provides the use of a compound of the present invention for the manufacture of a medicament for preventing or treating HIV infection or preventing, delaying or treating AIDS .
In another embodiment, the invention provides the use of a compound of the present invention for the manufacture of a medicament for preventing or treating
HIV infection or preventing, delaying or treating AIDS .
In another embodiment, the invention provides the use of a combination of the invention for the manufacture of a medicament for preventing or treating HIV infection or preventing, delaying or treating AIDS . ,
In another embodiment, the invention provides the use of a compound of the present invention for the manufacture of a medicament for preventing anyone of HIV replication, integration of HIV DNA into host cell DNA, 3' -end processing of HIV DNA or HIV DNA strand transfer to the host cell DNA.
In another embodiment, the invention provides the use of a combination of the invention for the manufacture of a medicament for preventing anyone of HIV replication, integration of HIV DNA into host cell DNA, 3' -end processing of HIV DNA or HIV DNA strand transfer to the host cell DNA.
In another embodiment, the invention provides the use of a compound of the present invention for the manufacture of a medicament for inhibiting HIV integrase . In another embodiment, the invention provides the use of a combination of the invention for . the manufacture of a medicament for inhibiting HIV integrase .
According to a further -embodiment, the subj ect in the above-mentioned methods and uses is a human .
In another embodiment, the present invention provides a combination comprising a therapeutically effective amount of a compound of the present invention, and a therapeutically effective amount of at least one further antiviral agent wherein said compound and said antiviral agent are present in a synergistic ratio .
It will be clear to a person of ordinary skill that if a further additional therapeutic agent is required or desired, ratios will be readily adjusted. It will be understood that the scope of ■ combinations described herein is not limited to the antiviral agents listed above, but includes in principles any therapeutic agent useful for the prevention and treatment of HIV infection and AIDS .
The compound and combinations referred to above as well as individual components of such combinations may be administered as pharmaceutical compositions .
A further aspect of the invention is therefore presented as a pharmaceutical composition comprising a compound of the present invention together with at least one pharmaceutically acceptable carrier or excipient thereof .
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salts, hydrates or solvates thereof or combination as defined herein together with one or more pharmaceutically acceptable carrier or excipient thereof .
The carrier (s ) or excipient (s ) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not being deleterious to the recipient thereof .
It will be appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age' and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian . In general however a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, alternatively in the range of 0.5 to 60 mg/kg/day, in a further alternative in the range of 1 to 20 mg/kg/day. The desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
The compound is conveniently administered in unit dosage form; for example containing 1 to 1500 mg, as a further example the unit dosage form is containing 10 to 1000 mg, as a further example the unit dosage form is containing 50 to 750 mg of active ingredient per unit dosage form.
Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75μM, preferably about 2 to 50 μM, most preferably about 3 to about 30 μM. This may be achieved, for example, by the intravenous inj ection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 500 mg of the active ingredient . Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient .
While it is possible that, for use in therapy, a compound or combination of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical composition . Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual ) , transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous ) administration or in a form suitable for administration by inhalation or insufflation . The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation .
Pharmaceutical compositions suitable for oral administration may conveniently 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 a solution, a suspension or as an emulsion . The active ingredient may also be presented as 'a bolus, electuary or paste . Tablets and capsules for oral administration may contain conventional excipients such as binding agents , fillers , lubricants , disintegrants, or wetting agents . The tablets may be coated according to methods well known in the art . Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions , solutions , emulsions, syrups or elixirs , or may be presented as a dry product for constitution with water or other suitable vehicle before use . Such liquid preparations may contain conventional additives such as suspending agents , emulsifying agents, non-aqueous vehicles (which may include edible oils ) , or preservatives .
The compounds and combinations according to the invention may also be formulated for parenteral administration (e . g . by inj ection, for example bolus inj ection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes , small volume infusion or in multi-dose containers with an added preservative . The compositions may take such forms as suspensions , solutions, or emulsions in oily or aqueous vehicles , and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents . Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e . g . sterile, pyrogen-free water, before use .
For topical administration to the epidermis , the compounds and combinations according to the invention may be formulated as ointments, creams or lotions , or as a transdermal patch . Such transdermal patches may contain penetration enhancers such as linalool , carvacrol, thymol, citral, menthol and t-anethole . Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents . Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents , dispersing agents , suspending agents , thickening agents, or coloring agents .
Compositions suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier .
Pharmaceutical compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories . Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier ( s ) followed by chilling and shaping in moulds .
Compositions suitable for vaginal administration may be presented as pessaries , tampons, creams , gels , pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate .
For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops . Drops may be formulated with an aqueous or non-aqueous base also comprising one more dispersing agents, solubilising agents or suspending agents . Liquid sprays are conveniently- delivered from pressurized packs .
For administration by inhalation the compounds and combinations according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas . In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount .
Alternatively, for administration by inhalation or insufflation, the compounds and combinations according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch . The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e . g . gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator .
When desired the above described formulations adapted to give sustained release of the active ingredient may be employed. The compounds of the invention have been found to have activity in the inhibition of HIV integrase, as described in example 30 , generally with an observed inhibitory activity at 50 μM.
Certain compounds of the present invention have also been tested in an assay for HIV activity, as described in Example 31 , and generally having an IC50 value of less than 10 μM.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius ; and, unless otherwise indicated, all parts and percentages are by weight .
The entire disclosures of all applications , patents and publications , cited above and below, are hereby incorporated by reference .
The following general schemes and examples are provided to illustrate various embodiments of the present invention and shall not be considered as limiting in scope .
EXAMPLES
Scheme 1 :
THF1PPh3 1)mCPBA, CH2CI2, 100%
Figure imgf000120_0003
BnOH, DiAD, 77%
Figure imgf000120_0002
2) Ac2O, 1000C, 80%
Figure imgf000120_0001
Figure imgf000120_0004
R=H, Br
TBDMSO
Figure imgf000120_0005
Example 1
5-Bromo-3-methoxy-2-methyl-lH-pyridin-4-one.
Figure imgf000120_0006
To a solution of 3-methoxy-2-methyl-lH-pyridone ( 7g, 50.3 mmol) in chloroform (100 ml) ..was added N- bromosuccinimide (NBS, 9.9 g, l.leq.) portionwise. The reaction mixture was stirred at rt for Ih and the precipitate was removed by filtration . The filtrate was concentrated under reduced pressure and was purified on silica gel using CH2Cl2 : MeOH 9 : 1 as eluent to give 9.7 g of desired product in 89% yield.
1H NMR ( 400 MHz , CDCl3) : δ [ppm] 8.0 ( s , IH) , 3.82 ( s , 3H) , 2.43 ( s, 3H) .
Example 2
4-Benzyloxy-3-methoxy-2-methyl-pyridine .
Figure imgf000121_0001
To a stirring solution of 3-methoxy-2-methyl-lH- pyridone ( 3g, 21.5 mmσl ) , triphenyl phosphine ( 6.8 g, 1.2 eq) , benzyl alcohol (2.6 g, 1.1 eq) in THF ( 40 ml ) was added dropwise diisopropyl azodicarboxylate ( 5g, l . leq) . The mixture was stirred at rt for Ih and refluxed for 18 hrs . After cooling to rt, the solvent was removed under reduced pressure . The residue was suspended in water, acidified with 6N-HC1 solution to pH 1 and washed with diethyl ether . The pH of the aqueous solution was then increased to 8 with sodium hydroxide and extracted with ethyl acetate (3x100 ml) . The organic phase was washed with water, dried with Na- 2SO4 and evaporated under reduced pressure to give 3.8 g ( 77% ) of desired product as oil which was used in the next step without further purification . 1H NMR ( 400 MHz, CDCl3) : δ [ppm] 8.12 (d, IH) , 7.40 (m, 5H) , 6.75 (d, IH) , 5.18 ( s , 2H) , 3.85 ( s, 3H) , 2.48 ( s , 3H) .
Example 3
4-Benzyloxy-3-methoxy-5-bromo-2-methyl-pyridine .
Figure imgf000122_0001
The compound was prepared starting from 5-bromo-3- methoxy-2-methyl-lH-pyridin-4-one in a similar manner as described above .
1H NMR ( 400 MHz, CDCl3) : δ [ppm] 8.32 ( s , IH) , 7.50 (m, 2H) , 7.40 (m, 3H) , 5.18 ( s , 2H) , 3.80 ( s, 3H) , 2.40 ( s, 3H) .
Example 4
4-Benzyloxy-3-methoxy-2-methyl-pyridine N-oxide .
Figure imgf000122_0002
To a solution of 4-benzyloxy-3-methoxy-2-methyl- pyridine ( 3.8 g, 16.6 mmol) in dichloromethane ( 50 ml ) was added portionwise m-chloroperoxybenzoic acid ( 75% MCPBA, 4.6 g, 1.2 eq. ) . The reaction mixture was stirred at rt for overnight, washed with 5% sodium carbonate solution ( 3x50ml ) , water and dried over Na2SO4. The solvent was removed under reduced pressure to give 4.2 g of product as oil which was used in the next step without further purification .
1H NMR ( 400 MHz , CDCl3) : δ [ppm] 8.22 (d, IH) , 7.40 (m, 5H) , 6.70 (d, IH) , 5.18 ( s , 2H) , 3.82 ( s, 3H) , 2.48 ( s , 3H) .
Example 5
Acetic acid 4-benzyloxy -3-methoxy-pyridin-2-ylmethyl ester .
Figure imgf000123_0001
A solution of 4-benzyloxy-3-methoxy-2-methyl-pyridine N-oxide ( 4 , 2g, 17.1 iranol ) in acetic anhydride ( 35 ml ) was stirred at 1000C for 2h and cooled to rt . The reaction mixture was evaporated to dryness under reduced pressure . The residue was dissolved in methylene chloride ( 150 ml ) , washed with saturated NaHCO3 solution, water and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified on silica gel using hexane : EtOAc 7 : 3, 3 : 2 • and 1 : 1 as eluent to give 3.9 g of pure product in 80% yield.
1H NMR ( 400 MHz, CDCl3) : δ [ppm] 8.22 (d, IH) , 7.40 (m, 5H) , 6.84 (d, IH) , 5.22 ( s, 2H) , 5.18 ( s, 2H) , 3.82 ( s , 3H) , 2.12 ( s , 3H) . Example 6
Acetic acid 4-benzyloxy-5-bromo-3-methoxy-pyridin-2- ylmethyl ester .
Figure imgf000124_0001
The compound was prepared starting from 4-benzyloxy-3- methoxy-5-bromo-2-methyl-pyridine in a similar manner as described above . 1H NMR ( 400 MHz, CDCl3) : δ [ppm] 8.44 (s, IH)', 7.50 (m, 2H) , 7.40 (m, 3H) , 5.22 ( s , 2H) , 5.19 ( s , 2H) , 3.92 (s , 3H) , 2.14 ( s , 3H) .
Example 7
(4-Benzyloxy-3-methoxy-pyridin-2-yl) -methanol ,
Figure imgf000124_0002
To a solution of acetic acid 4-benzyloxy -3-methoxy- pyridin-2-ylmethyl ester ( 1.8 g, 6.27 mmol ) in dioxarie
( 15 ml ) -water ( 5 ml) was added a solution of lithium hydroxide ( 300mg, 1.2 eq . ) in water ( 3 ml) . The reaction mixture was stirred as rt for 3 h and evaporated under reduced pressure . The residue was dissolved in methylene chloride ( 100 ml) , washed with water, brine solution and dried over Na2SO4. The solvent was removed under reduced pressure to give 1.56 g of desired product in 100% yield . The1 1H-NMR indicated pure product which was used in the next step without further purification .
1H NMR ( 400 MHz , CDCl3) : δ [ppm] 8.20 (d, IH) , 7.40 (m, 5H) , 6.84 (d, IH) , 5.20 ( s , 2H) , 4.78 ( s., 2H) , 3.90 ( s , 3H) .
Example 8
4-BenzylQxy-3-methoxy-5-bromo-pyridin-2-yl) -methanol .
Figure imgf000125_0001
The compound was prepared starting from acetic acid 4- benzyloxy-5-bromo-3-methoxy-pyridin-2-ylmethyl ester in a similar manner using the procedure described above .
1H NMR (400 MHz, CDCl3) : δ [ppm] 8.39 (s, IH) , 7.50 (m, 2H) , 7.40 (m, 3H) , 5.20 ( s , 2H) , 4.73 ( s, 2H) , 3.89 ( s, 3H) .
Example 9
4-Benzyloxy-3-methoxy-pyridine-2-carbaldehyde .
Figure imgf000125_0002
MnO2 ( 85% , 2.5 g, 5 eq. ) was added to a solution of 4- benzyloxy-3-methoxy-pyridin-2-yl) -methanol ( 1.23 g, 5 iratiol) in methylene chloride ( 40 ml ) . The mixture was stirred at rt for 3 h and an additional portion of MnO2 was added. The mixture was stirred for overnight and filtered through celite . The residue was washed with methylene chloride-methanol 4 : 1 mixture (20 ml ) . The combined organic solution was evaporated to dryness under reduced pressure . The residue was purified on silica gel using hexane : EtOAc 1 : 1 as eluent to give 970 mg of product in 79% yield.
1H NMR ( 400\ MHz , CDCl3) : δ [ppm] 10.36 ( s , IH) , 8.39 (d, IH) , 7.40 (m, 5H) , 7.05 (d, IH) , 5.22 ( s , 2H) , 4.02 ( s , 3H) .
Example 10
4-Benzyloxy-3-methoxy-5-bromo-pyridine-2-carbaldehyde .
Figure imgf000126_0001
The compound was prepared starting from 4-benzyloxy-3- methoxy-5-bromo-pyridin-2-yl ) -methanol in a similar manner using the procedure described above . 1H NMR ( 400 MHz , CDCl3) : δ [ppm] 10.22 ( s , IH) , 8.60 ( s , IH) , 7.50 (m, 2H) , 7.40 (m, 3H) , 5.28 ( s , 2H) , 4.01 ( s , 3H) . Example 11 /
4-Benzyloxy-3-methoxy-pyridine-2-σarboxylic acid.
Figure imgf000127_0001
To a ' solution of 4-benzyloxy-3-methoxy-pyridine-2- carbaldehyde ( 970 mg, 4 iranol) in a 1 : 1 mixture of acetonitrile (20 ml ) and water (20 ml) was added sodium dihydrogen phosphate NaH2PC^ ( 720 mg, 1.3eq. ) , followed by sodium chlorite NaClO2 ( 80% , 1.1 g, 3eq . ) . The mixture was stirred for 3hrs and evaporated to dryness under reduced pressure ._ The solid residue was triturated with methanol and filtered. The filtrate was , evaporated to dryness to give 725 mg of product in 70% yield. The 1H-NMR indicated pure product which used in the next step without purification .
1H NMR ( 400 MHz , DMSO-d6) : δ [ppm] 8.37 (d, IH) , 7.52 (m, 3H) , 7.43 (m, 3H) , 5.37 ( s , 2H) , 3.83 ( s , 3H) .
Example 12
4-Benzyloxy-3-methoxy-5-brobo-pyridine-2-carboxylic acid.
Figure imgf000128_0001
The compound was prepared in a similar manner using the procedure described above . 1H NMR ( 400 MHz , . CDCl3) : δ [ppm] 8.43 ( s, IH) , 7.50 (m, 2H) , 7.40 (m, 3H) , 5.34 ( s , 2H) , 4.01 ( S, 3H) .
Example 13
[2- (tert-Butyl-dimethyl-silanyloxy-ethyl] - (4-fluoro- benzyl) -amine
Figure imgf000128_0002
To a solution of (tert-butyl-dimethyl-silanyloxy) - acetaldehyde ( 90% , 195mg, 1 irunol ) and 4-fluoro- benzylamine ( 137 mg, l . leq. ) in 1 , 2-dichloroethane ( 15 ml) was added sodium triacetoxyborohydride (300 mg,
1.4eq . ) under stirring . The solution became cloudy and stirring was continued at rt for overnight . The reaction mixture was then poured in saturated NaHCO3 solution and the product was extracted with methylene chloride, dried over Na2SO4 and evaporated. The residue was purified on silica gel using hexane : EtOAc 7 : 3 as eluent to give 240 mg of product in 85% yield. 1H NMR ( 400 MHz, CDCl3) : δ [ppm] 7.25 (m, 2H) , 6.95 (m,
2H) , 3.75 ( s , 3H) , 3.70 (tt, 2H) , 2.67" (tt , 2H) . Example 14
4-Benzyloxy-3-methoxy-pyridine-2-carboxylic acid [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] - (4-fluoro- benzyl) -amide .
Figure imgf000129_0001
To a solution of 4-benzyloxy-3-methoxy-pyridine-2- carboxylic acid ( 259 mg, lmmol ) in anhydrous DMF ( 5 ml) were added N, N-diisopropylethylamine (260 μl, 1.5eq. ) and [2- (tert-Butyl-dimethyl-silanyloxy-ethyl] - ( 4- fluoro-benzyl) -amine (312 mg, l . leq) . The mixture was stirred for 5 min . and 0- ( 7-azabenzotriazol-l-yl) - N, N, N' , N' -tetramethyluronium hexafluoro-phosphate
(HATU, 418 mg, l . leq. ) was added. The mixture was stirred at rt for overnight and DMF was removed under reduced pressure . The residue was dissolved in methylene chloride ( 50 ml) , washed with water (2x20 ml ) , brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified on silica gel using hexane-EtOAc 9 : 1 , 4 : 1 , 7 : 3 , 3 : 2 , 1 : 1 and 2 : 3 each 50 ml as eluent . It gave 242 mg of pure product in 46% yield. The 1H-NMR indicated the presence of two rotamers in a 45 : 55 ratio .
1H NMR ( 400 MHz , CDCl3) : δ [ppm] 8.28 (t ) 7.5 (m) , 7.35 (m) , 7.08 (m) , 6.95 (m) , 5.27 (s ) , 5.24 ( s ) , 4.95 (s ) , 4.52 (s), 4.03 (s), 4.00(s), 3.93 (t) , 3.70 (t) , 3.58 (t), 3.22 (t), 0.98 (s), 0.88 (s) , 0.15 (s) , 0.00 (s) .
Example 15
4-Benzyloxy-3-methoxy-5-bromo-pyridine-2-carboxylic acid [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] - (4- fluoro-benzyl) -amide.
Figure imgf000130_0001
The compound was prepared starting from 4-benzyloxy-3- methoxy-5-brobo-pyridine-2-carboxylic acid in a similar manner using the procedure described above . 1H NMR ( 400 MHz , CDCl3) : δ [ppm] 8.45 ( s ) , 8.40 ( s ) , 7.5 (m) , 7.35 (m) , 7.08 (m) , 6.95 (m) , 5.27 ( s ) , 5.24 ( s ) , 4.95 ( s ) , 4.52 ( s ) , 4.03 ( s ) , 4.00 ( s ) , 3.93 (t) , 3.70 (t ) , 3.58 (t) , 3.22 (t ) , 0.98 ( s ) , 0.88 ( s ) , 0.15 ( s ) , 0.00 ( s ) .
Example 16
3-Benzyloxy-4-methoxy-6-bromo-pyridine-2-carboxylic acid [2- (tert-butyl-dimethyl-silanyloxy) -ethyl] - (4- fluoro-benzyl) -amide .
Figure imgf000131_0001
The compound was prepared starting from 3-benzyloxy-4- methoxy-β-bromo-pyridine-2-carboxylic acid (WO0105769 ) in a similar manner using the procedure described above .
1H NMR ( 400 MHz, CDCl3) : δ [ppm] , 7.5 (m) , 7.30 (m) , 7.10 ( s ) , 7.06 ( s ) , 6.95 (m) , 6.82 (m) , 5.15 ( s ) , 5.11
( s ) , 4.85 ( s ) , 4.42 ( s ) , „4.00 ( s ) , 3.98 ( s ) , 3.83 (t) , 3.70 (t ) , 3.50 (t) , 3.12 (t) , 0.98 ( s ) , 0.88 ( s ) , 0.15
( s ) , 0.00 ( s ) .
Example 17
4-Benzyloxy-3-methoxy-pyridine-2-carboxylic acid (4- fluoro-benzyl) - (2-hydroxy-ethyl) -amide .
Figure imgf000131_0002
To a solution of 4-benzyloxy~3-methoxy-pyridine-2- carboxylic acid ' [2- (tert-butyl-dimethyl-silanyloxy) - ethyl] - ( 4-fluoro-benzyl) -amide (240 mg, 0.46 mmol ) in THF ( 5ml ) was added a , THF solution of tetrabutylammonium fluoride (TBAF, IM, 0.5ml, l . leq. ) . The mixture was stirred at rt for 3 hrs and solvent was removed under reduced pressure . The residue was dissolved in methylene chloride ( 50 ml ) , washed with water ( 3x20ml ) , brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified on silica gel using CH2Cl2 : MeOH 95 : 5 , 9 : 1 as eluent to give 180 mg of desired product in 96% yield. The 1H-NMR indicated the presence of two rotamers in a 35 : 65 ratio . 1H NMR ( 400 MHz, CDCl3) : δ [ppm] 8.20 (d ) , 8.16 (d) , 7.45 (m) , 7.35 (m) , 7.27 (m) , 7.03 (m) , 6.95 (m) , 5.2 ( s ) , 5.17 ( s ) , 4.8 (MbS ) , 3.97 ( s ) , 3.95 ( s ) , 3.80 (t) , 3.67 (t) , 3.55 (t) , 3.25 (t) . ' '
Example 18
4-Benzyloxy-3-methoxy-5-bromo-pyridine-2-carboxylic acid (4-fluoro-benzyl) - (2-hydroxy-ethyl) -amide .
Figure imgf000132_0001
The compound was prepared starting from 4-benzyloxy-3- methoxy-5-bromo-pyridine-2-carboxylic acid [2- (tert- butyl-dimethyl-silanyloxy) -ethyl] - ( 4-fluoro-benzyl ) - amide in a similar manner using the procedure described above . 1H NMR ( 400 MHz, CDCl3) : δ [ppm] 8.40 ( s ) , 7.5 (m) , 7.35 (m) , 7.08 (m) , 6.95 (m) , 5.27 (s ) , 4.80 ( s) , 4.30 ( s ) , 3.97 ( s ) , 3.80 (t) , 3.65 (t ) , 3.58 (t ) , 3.22 (t ) .
Example 19
3-Benzyloxy-4-methoxy-6-bromo-pyridine-2-carboxylic acid (4-fluoro-benzyl) - (2-hydroxy-ethyl) -amide .
Figure imgf000133_0001
The compound was prepared starting from 3-benzyloxy~4- methoxy-6-bromo-pyridine-2-carboxylic acid [2- (tert- butyl-dimethyl-silanyloxy) -ethyl] - ( 4-fluoro-benzyl ) - amide in a similar manner using the procedure described above .
1H NMR ( 400 MHz , DMSOd5) : δ [ppm] 7.45 (m) , 7.40 (m) , 7.13 (m) , 7.05 (m) , 5.07 ( s ) , 4.78 ( s ) , 4.33 ( s ) , 4.03 ( s ) , 4.00 ( s ) , 3.50 (t ) , 3.40 (t) , 3.38 (t) , 3.02 (t) .
Example 20
2- (4-Fluoro-benzyl) -9 -hydroxy- 3 , 4-dihydro-2H- pyrido [l,2-a]pyrazine-l, 8-dione .
Figure imgf000134_0001
To a suspension of polystyryldiphenylphosphine ( 1 mmol/g, 634 mg, 1.3 eq) in methylene chloride ( 10 ml) were added imidazole ( 43 mg, 1.3 eq) and iodine ( 161 mg, 1.3eq. ) . The mixture was stirred for 5 min . and a solution of 4-benzyloxy-3-methoxy-pyridine-2-carboxylic acid ( 4-fluoro-benzyl) - (2-hydroxy-ethyl) -amide ( 200 mg, 0.48 iranol ) in methylene chloride ( 5 ml) was added. The reaction mixture was stirred at rt for overnight, filtered and the residue was washed with methylene chloride (20 ml) . The combined methylene chloride solution was washed with 5% sodium thiosulfate solution, water, brine and dried over Na2SCU . The solvent was removed under reduced pressure to give 189 mg of a foam residue . The 1H-NMR indicated that the residue is a quaternary cyclic product .
1H NMR ( 400 MHz, CDCl3) : δ [ppm] 9.40 (d, IH ) , 7.93 (d, IH) , 7.45 (m, 2H) , 7.40 (m, 3H) , 7.33 (m, 2H) , 7.03 (m, 2H) , 5.50 ( s, 2H) , 5.03 (m, 2H) , 4.73 ( s , 2H) , 4.07 ( s, 3H) , 3.87 (m, 2H) .
The above residue was dissolved in HBr-AcOH solution ( 38% , 5 ml) . The mixture was heated at 1000C for overnight and cooled to rt . A precipitate was formed and collected by filtratipn giving-- 80 mg of desired product as a white solid. -,5*r 1H NMR (400 MHz, DMSO-d6) : δ [ppm] 8.20 (d, IH ) , 7.45 (m, 2H) , 7.24 (m, 2H) , 7.13 (d, IH) , 4.75 (s, 2H) , 4.53 (m, 2H) , 3.80 (m, 2H) .
Example 21
7-Bromo-2- (4-fluoro-benzyl) -9-methoxγ-3 , 4-dihydro-2H- pyrido [l , 2]pyrazine-l , 8-dione .
Figure imgf000135_0001
To a suspension of polystyryldiphenylphosphine ( 1 mmol/g, 722 mg, 1.3eq) in methylene chloride ( 15 ml) were added imidazole ( 50 mg, 1.3eq) and iodine ( 183 mg, 1.3eq. ) . The mixture was stirred for 5min . and a solution of 4-benzyloxy-3-methoxy-5-bromo-pyridine-2- carboxylic acid ( 4-fluoro-benzyl ) - (2-hydroxy-ethyl) - amide ( 250 mg, 0.51 mmol ) in methylene chloride ( 5 ml) was added. The, reaction mixture was stirred at rt for overnight, filtered and the residue was washed with methylene chloride (20 ml ) . The combined methylene chloride solution was washed with 5% sodium thiosulfate solution, water, and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified on silica gel using CH2Cl2 : MeOH 95 : 5 as eluent to give 140 mg of a solid product in 72% yield. The 1H-NMR indicated the cyclic product . 1H - NMR ( 400 MHz , CDCl3) : δ [ppm] 7.55 ( s, IH) , 7.25 (m, 2H) , 7.00 (m, 2H) , 4.62 ( s, 2H) , 4.00 ( s , 3H) , 3.97 (m, 2H) , 3.50 (m, 2H) .
Example 22
7-Bromo-2- (4-fluoro-benzyl) -9-hydroxy-3 , 4-dihydro-2H- pyrido [1 , 2-a]pyrazine-1 , 8-dione .
Figure imgf000136_0001
7-Bromo-2- ( 4-fluoro-benzyl ) -9-methoxy-3, 4-dihydro-2H- pyrido [ 1 , 2 ] pyrazine-1, 8-dione ( 37 mg) was dissolved in HBr-AcOH solution ( 38% , 2 ml ) and heated at 1000C for 3hrs . After cooling to rt the mixture was evaporated to dryness . The residue was titurated with methylene chloride and filtered to give 15 mg of desired product as a white solid. 1H NMR ( 400 MHz , DMSO-d6) : δ [ppm] 8.20 ( s, IH ) , 7.40 (m, 2H) , 7.20 (m, 2H) , 4.63 ( s, 2H) , 4.20 (m, 2H) , 3.63 (m, 2H) . Example 23
6-Bromo-2- (4-f luoro-benzyl) -9-hydroxy-3 , 4-dihydro-2H- pyrido [1 ,2-a]pyrazine-l, 8-dione.
Figure imgf000137_0001
3-Benzyloxy-4-methoxy-6-bromo-pyridine-2-carboxylic acid ( 4-fluoro-benzyl) - (2-hydroxy-ethyl ) -amide ( 35 mg) was dissolved in HBr-AcOH solution ( 38% , 2 ml ) and heated at 1000C for overnight . After cooling to rt the mixture was evaporated to dryness . The residue was titurated with methylene chloride : MeOH and filtered to give 13 mg of a white solid. 1H-NMR spectrum indicated the desired cyclic product . 1H NMR ( 400 MHz , DMSO-d6) : δ [ppm] 7.40 (m, 2H) , 7.20
(m, 2H) , 6.80 ( s , IH ) , 4.70 ( s, 2H) , 4.40 (m, 2H) , 3.68
(m, 2H) .
Scheme 2
Figure imgf000138_0001
amine
Example 24
3-Benzyloxy-6- (tert-butyl-dimethyl-silanyloxymethyl) -4- oxo-4H-pyran-2-carboxylic acid.
Figure imgf000138_0002
Starting from the known koj ic acid, compound 3- benzyloxy-6- (tert-butyl-dimethyl-silanyloxymethyl ) -4- oxo-4H-pyran-2-carbaldehyde was prepared using the procedure described in Kiyama, R. WO 03/016275 Al . To a solution of this aldehyde (774 ing, 2.15 mmol) in acetonitrile/water ( 10 mL/10 ml) were added NaH2PO4
( 516 mg, 4.3 mmol ) and NaClO2 ( 80% , 850 mg, 7.25 mmol) .
The reaction mixture was stirred at rt for 12 h . After removal of the solvent under reduced pressure, the residue was suspended into 30 ml of water and the pH was adj usted to 3. The mixture was extracted with methylene chloride ( 3 x 15 ml ) . The combined organic phases were washed with brine, dried over anhydrous sodium sulfate . Evaporation of the solvent under reduced pressure afforded a white solid of 730 mg, which was used in the next step without further purification .
Example 25
(2- ( (3-Benzyloxy-6- (tert-butyl-dimethyl- silanyloxymethyl) -4-oxo-4H-pyran-2-carbonyl) - (4-fluoro- benzyl) -amino) -ethyl) -carbamic acid tert-butyl ester
Figure imgf000139_0001
To the solution of the above-mentioned acid ( 753 g, 2 mmol) in DMF (20 ml ) were added (2- ( 4- fluorobenzylamino) -ethyl) -carbamic acid tert-butyl ester ( 644 , 2.4 mmol) , DIPEA ( 0.66 mL, 4 mmol ) , DCC
( 619 mg, 3 mmol ) , and HOBt . H20 ( 405 mg, 3 mmol ) . The reaction mixture was stirred at rt for 12 h . After removal of the solvent under reduced pressure, the residue was suspended into 50 mL of water and the mixture was extracted with chloroform ( 3 x 50 ml ) . The combined organic phases were washed with brine, dried over anhydrous sodium sulfate . Evaporation of the solvent under reduced pressure gave ■ a residue, which was purified using silica gel chromatography with hexane and ethyl acetate ( 4 : 1 ) to provide the title compound as a white solid in the form of two rotamers
( 610 mg) .
Example 26
(2- ( (3-Benzyloxy-6- (tert-butyl-dimethyl- silanyloxymethyl) -4-oxo-4H-pyran-2-carbonyl) -amino) - ethyl) -carbamic acid tert-butyl ester
Figure imgf000140_0001
This compound was prepared starting from 3-Benzyloxy-β-
(tert-butyl-dimethyl-silanyloxymethyl ) -4-oxo-4H-pyran-
2-carboxylic acid in a similar manner using the procedure described above .
1H NMR ( 400 MHz , CDCl3) : δ [ppm] 7.81 (bs, IH ) , 7.19
(m, 5H) , 6.48 ( s , IH) , 5.27 ( s, 2H) , 4.56 (bs , IH) , 4.45 (s, 2H), 3.22 (m, 2H), 3.15 (m, 2H), 1.33 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H) .
Example 27
9-Benzyloxy-2- (4-fluoro-benzyl) -6-hydroxymethyl-3 , 4- dihydro-2H-pyrido (l ,2-a)pyrazine-l , 8-dione
Figure imgf000141_0001
The above-mentioned rotameric mixture of (2- ( ( 3- Benzyloxy-6- (tert-butyl-dimethyl-silanyloxymethyl ) -A- oxo-4H-pyran-2-carbonyl ) - ( 4-fluoro-benzyl ) -amino) - ethyl) -carbamic acid tert-butyl ester ( 50 mg) was added to a solution of ethyl acetate saturated with HCl (~3M) . The mixture was stirred at rt for Ih . Slowly the solution became cloudy when the reaction proceeded-. Then the solvent was evaporated under reduced pressure to provide a yellowish solid. NMR showed that both TBDMS and Boc protective groups were removed. The mixture was used directly in the next step without purification .
The mixture was then dissolved into methanol ( 5 ml) and the solution was neutralized with N, N' -diisopropylethyl amine (DIPEA) . The mixture was heated to 700C for 2 h . After removal of the solvent under reduced pressure, the residue was purified on a silica gel column using 5% methanol in dichloromethane to give a white solid ( 20 mg) .
1H NMR ( 400 MHz , CD3OD) : δ [ppm] 7.45 (m, 2H) , 7.36 (m, 2H) , 7.27 (m, 3H) , 7.08 (m, 2H) , 6.67 ( s, IH) , 5.18 ( s , 2H) , 4.66 ( s , 2H) , 4.53 ( s , 2H) , 4.13 (m, 2H) , 3.47 (m, 2H) .
Example 28
2- (4-Fluoro-benzyl) -9-hydroxy-6-hydroxymethyl-3 , 4- dihydro-2H-pyrido (1 , 2-a) pyrazine-1 , 8-dione
Figure imgf000142_0001
To a solution of 9-benzyloxy-2- ( 4-fluoro-benzyl ) -6- hydroxymethyl-3 ,'4-dihydro-2H-pyrido ( 1, 2-a) pyrazine-1 , 8- dione (20 mg) in methanol ( 5 ml) was added 10% Pd-C (-5 mg) '. The hydfogenation reaction was run at rt for Ih . To the suspension was added one drop of diluted HCl to dissolve the precipitate and the mixture was filtered. The filtrate was concentrated to dryness under reduced pressure to afford a yellowish solid ( 10 mg) . 1H NMR ( 400 MHz , CD3OD) : δ [ppm] 7.45 (m, 2H) , 7.10 (m, 3H) , 4.80 -4.60 (m, 6H) , 3.84 (m, 2H) . LC/MS : m/z 318.3 (M + H+) .
Example 29 9-Hydroxy-6-hydroxymethyl-3 , 4-dihydro-2H-pyrido (1 , 2- a) pyrazine-1 , 8-dione
Figure imgf000143_0001
The compound was prepared starting from (2- ( ( 3-
Benzyloxy-6- (tert-butyl-dimethyl-silanyloxymethyl) -A- oxo-4H-pyran-2-carbonyl ) -amino) -ethyl ) -carbamic acid tert-butyl ester in a similar manner using the procedure described above .
1H NMR ( 400 MHz, DMSO-d6) : δ [ppm] 10.72 (bs , IH) , 6.13
( s , IH) , 5.54 (bs, IH) , 4.23 ( s , 2H) , 3.46 (m, 2H) ,
3.34 (m, 2H) .
LC/MS : m/z 210.19 (M + H+) .
Compounds 6-16 can be prepared by Scheme 3 Scheme 3 :
Figure imgf000143_0002
R = vinyl, furan, sultam, thiazole, phenyl, SCH3
Figure imgf000143_0003
Compounds 17-25 can be made by Scheme 4 Scheme 4 :
Figure imgf000144_0001
Example 30
6-Cyclohexylmethoxy-2- (4-fluoro-benzyl) -9-hydroxy-3 , 4- dihydro-2H-pyrido [1 , 2-a] pyrazine-1 , 8-dione
Figure imgf000145_0001
Step 1
To a solution of 9-benzyloxy-6-bromo-2- ( 4-fluoro- benzyl) -3, 4-dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1, 8-dione
( 100 mg, 0.22 mmol ) in DMF ( 3 ml) were added cesium carbonate ( 181 mg, 0.56 mmol) and cyclohexanemethanol
( 135 μL, 1.1 mmol ) in a sealed tube . The mixture was stirred at; 60 0C for 24 h . After removal of the solvent under reduced pressure, the residue was dissolved into water ( 10 mL) and extracted with dichloromethane ( 3 x 10 mL) ; the combined organic layers were dried - over anhydrous sodium sulfate . Evaporation of the solvent under reduced pressure provided a residue which was purified by preparative silica gel TLC eluting with 5% methanol in dichloromethane to afford 9-benzyloxy-6- cyclohexylmethoxy-2- ( 4-fluoro-benzyl) -3 , 4-dihydro-2H~ pyrido [ 1, 2-a] pyrazine-1 , 8-dione as a white solid ( 73 mg) .
Step 2
The product from step 1 (73 mg) was dissolved into a mixture of 10 ml of methanol and 10 ml of ethyl acetate . To the solution was added 7 mg of 10% Pd/C and the mixture was stirred was stirred under hydrogen at atmospheric pressure . After stirring for 1 h at rt, the mixture was filtered to remove the catalyst . The filtrate was concentrated to dryness under reduced pressure to afford β-cyclohexylmethoxy-2- ( 4-fluoro- benzyl) -9-hydroxy-3, 4-dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1, 8-dione as a white solid ( 60 mg) .
Example 31
2- (4-Fluoro-benzyl) -9-hydroxy-6-phenoxy-3 , 4-dihydro-2H- pyrido [1 , 2-a]pyrazine-1 , 8-dione
Figure imgf000146_0001
Step 1
To a solution of 9-benzyloxy-6-bromo-2- ( 4-fluoro- benzyl) -3 , 4-dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1, 8-dione ( 140 mg, 0.31 mmol) in DMF ( 3 ml ) were added cesium carbonate (204 mg, 0.62 mmol ) , and phenol ( 59 mg, 0.62 mmol) in a sealed tube . The mixture was stirred at 50 0C for 12 h . After removal of the solvent under reduced pressure, the residue was taken into water ( 10 mL) and extracted with dichloromethane ( 3 x 10 mL) ; the combined organic layers were dried over anhydrous sodium sulfate . Evaporation of the solvent under reduced pressure provided a residue which was purified by silica gel chromatography eluting with 3% methanol in dichloromethane to afford 9-benzyloxy-2- ( 4-fluoro- benzyl) -β-phenoxy-3 , 4-dihydro-2H-pyrido [ 1 , 2-a] pyrazine- 1 , 8-dione as a white solid ( 130 mg) .
Step 2
The product ( 130 mg) from Step 1 was deprotected by hydrogenolysis as described for Example XXX to provide
2- ( 4-fluoro-benzyl ) -9-hydroxy-β-phenoxy-3 , 4-dihydro-2H- pyrido [1, 2-a] pyrazine-l , 8-dione ( 105 mg) as a white solid.
Example 32
7-Fluoro-2- (4-fluoro-benzyl) -9-hydroxy-6-methoxy-3 , 4- dihydro-2H-pyrido [l , 2-a] pyrazine-1 , 8-dione
Figure imgf000147_0001
Step 1
To a solution of 9-benzyloxy-2- ( 4-fluoro-benzyl) -6- methoxy-3 , 4-dihydro-2H-quinolizine-l ^ 8-dione ( 127 mg, 0.31 mmol ) in acetonitrile ( 3 ml) were added cesium carbonate (201 mg, 0.62 mmol ) and Selectfluor® (219 mg, 0.62 mmol) . The mixture was stirred at rt for 6 h . After removal of the solvent under reduced pressure, the residue was taken into water ( 10 mL) and extracted with dichloromethane ( 3 x 10 mL) ; the combined organic layers were dried over anhydrous sodium sulfate . Evaporation of the solvent under reduced pressure provided a residue which was purified on preparative silica gel TLC using 5% methanol in dichloromethane to afford 9-benzyloxy-7-fluoro-2- ( 4-fluoro-benzyl ) -6- methoxy-3, 4-dihydro-2H-pyrido [ 1, 2-a] pyrazine-1 , 8-dione as a white solid ( 43 mg) .
Step 2
The product ( 44 mg) from Step 1 was deprotected by hydrogenolysis as described for Example XXX to provide 7-fluoro-2- ( 4-fluoro-benzyl) -9-hydroxy-6-methoxy-3 , 4- dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1 , 8-dione as a white solid ( 36 mg) .
Example 33
9-Benzyloxy-β-cyclopropylmethoxy-2- ( 4-fluoro-benzyi ; 3 , 4-dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1 , 8-dione
Figure imgf000149_0001
Step 1
To a solution of 9-benzyloxy-6-bromo-2- ( 4-fluoro- benzyl) -3 , 4-dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1 , 8-dione ( 150 mg, 0.33 mmol ) in cyclopropylmethanol ( 5 ml) was added cesium carbonate ( 217 mg, 0.66 mmol) in a sealed tube . After stirred at rt for 12 h, the reaction mixture was filtered and the solid was further washed with dichloromethane . The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel chromatography using 4% methanol in dichloromethane to provide the title compound 9- benzyloxy-6-cyclopropylmethoxy-2- ( 4-fluoro-benzyl) -3 , 4- dihydro-2H-pyrido [ 1 , 2-a] pyrazine-1 , 8-dione as a white solid ( 138 mg) .
Step 2 The product ( 148 mg) from Step 1 was deprotected by hydrogenolysis as described for Example XXX to provide 9-benzyloxy-6-cyclopropylmethoxy-2- ( 4-fluoro-benzyl ) - 3 , 4-dihydro-2H~pyrido [ 1, 2-a] pyrazine-1, 8-dione as a white solid ( 110 mg) .
Example 34
HIV Integrase Strand Transfer inhibition assay
Methods for evaluating biological activity of HIV and HIV integrase inhibitors are described in : PNAS (2002 ) vol . 19 number 10 , pages 5661-6666 "Diketo acid inhibitor mechanism and HIV-I integrase : Implications for metal binding in the active site of phosphotransferase enzymes" ' Grobler, J. A. et al .
Example 35
Anti-HIV-1 replication Assay in H9 cells for anti-HIV-1 integrase compounds . The anti-HIV-1 activities of the compounds were tested by employing HIV-IIIIB in H9 cells . The prepared cells were suspended at 5XlO6/ml in complete medium (RPMI 1640, 10%FBS , 2mM glutamine, 100 units penicillin/ml , 100 μg streptomycin/ml ) , incubated with virus at a multiplicity of infection of 0.1 for 2h in an atmosphere of 5 % C02 and 37°C . The infected cells were washed twice with PBS to remove residual virus and cultured at presence of inhibitors at serial concentrations for 7-8 days . The anti-HIV-1 efficacy was determined by testing for HIV-I RT activity in the cell culture supernatants . All assays were performed in duplicate with Merck compound L-731988 and Shionogi compound S-1360 as control . The 50% effective concentrations (IC50s) were calculated from the linear portion of the dose-response curve .
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples .
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions .

Claims

We Claim:
1. A compound according to Formula I
Figure imgf000152_0001
wherein
A is a single or double bond, and when A is a double bond R2 or R' 2 and R3 or R' 3 are absent ;
Ri is H, OH, optionally substituted C6_10 aryl , optionally substituted 5-10. member heteroaryl, optionally substituted 4-10 member heterocycle, or Ci_io alkyl optionally substituted with one or more substituents selected from optionally substituted C3-I0 cycloalkyl, optionally substituted Cβ-io aryl, optionally substituted 5-10 member heteroaryl, or optionally substituted 4-10 member heterocycle;
R2, R' 2/ R3 and R' 3 are each, independently, hydrogen, optionally substituted Ci-10 alkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C6-I0 aryl, optionally substituted 5-10 member heteroaryl , optionally substituted 4-10 member heterocycle, COOR6, CONR7R' 7, or CR6=NOR' 6; R2 or R' 2 can also be taken together with R3 or R' 3, and the atoms to which they are attached, to form an optionally substituted C3-I0 cycloalkyl, an optionally substituted 4-10 member heterocycle, an optionally substituted C6-Io aryl or an optionally substituted 5-10 member heteroaryl ;
R2 and R' 2 or R3 and R' 3 can also be j oined together, with the atoms to which they are attached, to form an optionally substituted C3-10 cycloalkyl or an optionally substituted 5-10 member heterocycle;
R2 and R' 2 or R3 and R' 3 can also be j oined together to form a carbonyl (C=O) ;
R4 is optionally substituted Ci_ioalkoxy, optionally substituted C6-10 aryloxy, or optionally substituted C6aryl~C;i__ioalkyloxy;
n is 0 , 1, or 2 ;
R5 is hydrogen, halogen, OH, CN, azido, NO2, COOR6, Ci-10 alkyl, amino, amido, sulfonamido, urea, guanidino, amidino, SOnR6, OCONR7R' 7, NR6SO2NR7R' 7 NR6COOR7, CR6=NOR7, Ci-ioalkoxy, optionally substituted C6-I0 aryl, optionally substituted 5-10 member heterocycle, or optionally substituted 5-10 member heteroaryl; R6, R7, R' 7 are each independently hydrogen, optionally substituted Ci_io alkyl, optionally substituted Ce-io aryl, or optionally substituted C7_i2aralkyl;
Re can also be taken together with R7 or R' 7, with the atoms to which they are attached, to form a 5-10 member heterocycle; and
R7 and R' 7 can be taken together, with the atom to which they are attached, to form a 4-10 member heterocycle;
or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof,
wherein alkyl groups can optionally contain one or more double bonds or triple bonds in their chain, and
optionally substituted means that the radical can be unsubstituted or substituted by one or more substituents selected from: halogen, amino, amidino, amido, azido, cyano, guanidinq, hydroxyl, nitro, nitroso, urea,
S(O) o-2Ra wherein Ra is H, Ci_i0 alkyl, C6_10 aryl or 3-10 member heterocycle, Ci-ioalkyl,
C7-I2 aralkyl,
C6_i0aryl,
5-10 member heteroaryl,
Ci-ioalkoxy,, C6-ioaryl-Ci-i0alkyloxy,
C6-ioaryloxy,
3-10 member heterocycle,
C (O) Rb wherein Rb is H, Ci-io alkyl , C6-I0 aryl, C7-I2 aralkyl or 3-10 member heterocycle, C (O) ORb wherein Rb is H, Ci_io alkyl , C6-io aryl , C7_i2 aralkyl or 3-10 member heterocycle,
NRbC (O) R ' b wherein Rb and R 'b are each independently H,
Ci-io alkyl, C6-io aryl, C7_i2 aralkyl or 3-10 member heterocycle, or Rb and R ' b are taken together with the atoms to which they are attached to form a 5-10 member heterocycle,
SO2NRbR ' b wherein Rb and R ' b are each independently H,
Ci-io alkyl, Cε-io aryl , C7_i2 aralkyl or 3-10 member heterocycle, or Rb and R' b are taken together with the atoms to which they are attached to form a 5-10 member heterocycle,
NRbSO2R' b wherein Rb and Rb are each independently H, Ci- io alkyl, Ce-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and R ' b are taken together with the atoms to which they are attached to form a 5-10 member heterocycle, NRbSO2NR ' bRc wherein Rb, R' b and Rc are each independently H, Ci-io alkyl, C6_io aryl, C7-i2 aralkyl or 3-10 member heterocycle, or R ' b and Rc are taken together with the atoms to which they are attached to form a 5-10 member heterocycle,
CRbN=OR ' b wherein Rb and R' b are each independently H, Ci-io alkyl, Cε-io aryl, 3-10 member heterocycle or C7-12 aralkyl, and
NRbCOOR ' b wherein Rb and R' b are each independently H, Ci-10 alkyl, C6-io aryl, C7-I2 aralkyl or 3-10 member heterocycle .
2. A compound according to claim 1 , wherein Ri is hydrogen .
3. A compound according to claim 1, wherein Ri is hydroxy.
4. A compound according to claim 1, wherein Ri is Ci_4 alkyl substituted by an optionally substituted aryl group .
5. A compound according to claim 1 , wherein Ri is (CH2) 1-4 phenyl where phenyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, amino, amidino, amido, azido, cyano, guanidino, hydroxyl, nitro, nitroso, urea,
S(O) o-2Ra (wherein Ra is H, Ci-io alkyl, Cβ-io aryl or 3-10 member heterocycle) ,
Ci-ioalkyl, C7-Io aralkyl,
C6-Io aryl,
5-10 member heteroaryl
Ci-ioalkoxy,
C6-ioaryl-Ci-i0alkyloxy, C6-I0 aryloxy,
3-10 member heterocycle,
C(O)Rb wherein Rb is H, Ci-io alkyl, Cβ-io aryl, C7_i2 aralkyl or 3-10 member heterocycle,
C (O) ORb wherein Rb is H, Ci-io alkyl, Cδ-io aryl, C7_i2 aralkyl—or 3-10 member heterocycle,
NRbC (O) Rb ' wherein Rb and Rb ' are each independently H,
Ci-io alkyl, Cβ-io aryl, C7-12 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle,
SO2NRbRb ' wherein Rb and Rb ' are each independently H,
Ci-10 alkyl, Cβ-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle, NRbSθ2Rb " wherein Rb and Rb ' are each independently H, C1- io alkyl, C6-io aryl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle,
NRbSO2NRb ' Rc wherein Rb, Rb ' and R0 are each independently H, Ci-io alkyl, C6-io aryl, C7-.12 aralkyl or 3-10 member heterocycle, or Rb ' and Rc are taken together with the atoms to which they are attached to form a 5-10 member heterocycle,
CRbN=ORb ' wherein Rb and Rb ' are each independently H, Ci-io alkyl , C6-io aryl, C7-I2 aralkyl1 or 3-10 member heterocycle, and NRbCOO Rb ' (wherein Rb and Rb ' are each independently H, Ci_io alkyl , Cβ-io aryl , C7-I2 aralkyl or 3-10 member heterocycle .
6. A compound according to claim 1, wherein Ri is (CH2) i_4phenyl where phenyl is unsubstituted or substituted with one or more substituents independently selected from: halogen, amino, amido, cyano, hydroxyl, urea,
OCi-io alkyl ,
S (O) o-2Ra (wherein R3 is H, C1-I0 alkyl, C6-I0 aryl or 3-10 member heterocycle) ,
Ci-io alkyl, C6-I0 aryl,
5-10 member heteroaryl 3-10 member heterocycle,
C (0) 0Rb wherein Rb is H, Ci-I0 alkyl, C7-I2 aralkyl or 3-10 member heterocycle,
NRbC (O) Rb ' wherein Rb and Rb " are each independently H, Ci-io alkyl, C7_i2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle, NRbSO2Rb ' wherein Rb and Rb ' are each independently H, Ci-io alkyl, C7-I2 aralkyl or 3-10 member heterocycle, or Rb and Rb ' are taken together with the atoms to which they are attached to form a 5-10 member heterocycle, CRbN=ORb ' wherein Rb and Rb ' are each independently H, Ci-io alkyl, C6-io aryl, C7_12 aralkyl or 3-10 member heterocycle, and
NRbCOORb ' wherein Rb and Rb ' are each independently H, Ci-io alkyl, Cβ-io aryl, C7-I2 aralkyl or 3-10 member heterocycle .
7. A compound according to claim 1, wherein R1 is (CH2) i-4phenyl where phenyl is substituted with one or more substituents independently selected from: fluoro, bromo, chloro, CONHCH3, CON (CH3) 2, CF3, NHCOCH3, NHCONHCH3, and SO2NHCH3. ■
8. A compound according to claim 1, wherein Ri is CH2 ( 4-fluorophenyl ) .
9." A compound according to claim 1, wherein R2 and R' 2 are each independently selected from: optionally substituted phenyl, optionally substituted Cχ-6alk:yl, COOCi-6alkyl, CONR7R' 7, and CR6=NOR' 6.
10. A compound according to claim 1, wherein R2 and R' 2 are each independently chosen from: H;
unsubstituted phenyl or phenyl substituted by one or more substituents independently selected from halogens , hydroxy, -NH2, -NHRd and -NRdRe, -CONH2, -CONHRd, - CONRdR8, -NHCORd, -NRdCORe, carboxy, CF3, NRdCORd, NRdCONRdRe, and SO2NRdRe wherein Rd and Re are each independently selected from Ci_io alkyl ;
unsubstituted Ci_6alkyl or Ci-ealkyl substituted by one or more substituents independently selected from halogens, hydroxy, -NH2, -NHRd and -NRdRe, wherein Rd and R6, are each independently selected from Ci_10 alkyl, -CONH2, - CONHRd, -CONRdRe, -NHCORd, -NRdCORe, and carboxy, wherein Rd and Re are each independently selected from Ci-io alkyl;
COOCi_6alkyl ;
CONR7R' 7; and
CR6=NOR' 6.
11 . A compound according to claim 1 , wherein R2 and R' 2 are each independently chosen from:
H, phenyl , Ci-6alkyl , COOCi_6alkyl , CONR7R' 7 , and CR6=NOR' 6 . i
12. A compound according to claim 1 , wherein R3 and R' 3 are each independently chosen from:
H, optionally substituted phenyl, optionally substituted Ci-5alkyl,
COOCi_6alkyl,
CONR7R' 7, and
CR6=NOR' 6.
13. A compound according to claim 1, wherein R3 and R' 3 are each independently chosen from:
H;
unsubstituted phenyl or phenyl substituted by one or more substituents independently selected from halogens , hydroxy, -NH2 , -NHRd and -NRdRe , -CONH2 , -C0NHRd, - CONRdRe, -NHCORd, -NRdC0Re , carboxy, CF3 , NRdCORd, NRdC0NRdRe , and S02NRdRe wherein Rd and Re are each independently selected from Ci_i0 alkyl ;
unsubstituted Ci_6alkyl or Ci_6alkyl substituted by one or more substituents independently selected from halogens , hydroxy, -NH2, -NHRd and -NRdRe, wherein Rd and Re are each independently selected from C1-X0 alkyl , -CONH2, - CONHRd, -CONRdRe , -NHCORd, -NRdCORe, and carboxy, wherein Rd and Re are each independently selected from Ci-io alkyl ;
COOCi-6alkyl ; ,
CONR7R' 7 ; and
CR6=NOR' 6.
14. A compound according to claim 1, wherein R3 and R' 3 are each independently chosen from: H, phenyl, Ci-6alkyl, COOCi_6alkyl, CONR7R' 7, and CR6=NOR' 6.
15. A compound according to claim 1 , wherein R4 is optionally substituted Ci_io alkoxy.
16. A compound according to claim 1 , wherein R4 is optionally substituted Ci_6alkoxy.
17. A compound according to claim 1 , wherein R4 is optionally substituted C6-io aryloxy.
18. A compound according to claim 1, wherein R4 is optionally substituted C6aryl-Ci-10alkyloxy.
19. A compound according to claim 1 , wherein R4 is optionally halogenated Ci-io alkoxy.
20. A compound according to claim 1 , wherein R4 is optionally halogenated C6-I0 aryloxy.
21. A compound according to claim 1 , wherein R4 is optionally halogenated Cgaryl-Ci-ioalkyloxy.
22. A compound according to claim 1 , wherein R5 is halogen, amino, hydroxy, Ci-6 alkyl, 5-10 member heteroaryl, Cg-io aryl, or CONR6R' 6.
23. A compound according to claim 1 , wherein : A is a single bond; and
R4 is Ci-10 alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, or N (Ci_4- alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO- Ci- 4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, C1-4- alkyl , cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl ) 2, CONH2, CONHC1-4- alkyl, or CON (Ci_4-alkyl) 2.
24. A compound according to claim 1 , wherein : A is a single bond; R2, R ' 2, R3, and R' 3 are each H; and R4 is Ci-io alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, or N (Ci-4- alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Cα_4- alkyl, cyano, hydroxy, carboxy, COO-C1_4-alkyl, CO-
Ci- ' 4-alkyl, NH2, NHCi-4-alkyl, N (d-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci_4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci-
4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2,
CONHCi-4- alkyl, or CON (Ci-4-alkyl ) 2.
25. A compound according to claim 1 , wherein : A is a single bond; R2, R ' 2, R3, and R' 3 are each H;
R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHC1-4- alkyl , or CON (Ci-4-alkyl) 2; and R4 is Ci-10 alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4- alkyl , CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, or N (Ci_4- alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO- C1- 4-alkyl, NH2, NHCi_4-alkyl, N (d-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4- alkyl, or CON (Ci_4-alkyl) 2.
26. A compound according to claim 1, wherein : A is a single bond;
R2, R ' 2, R3, and R ' 3 are each H; R1 is benzyl optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci_4- alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl ) 2, CONH2, CONHC1-.4- alkyl, or CON (Ci_4-alkyl) 2; and
R4 is Ci-10 alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4- alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO- Ci- 4-alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, N (Cχ_4-alkyl) 2, CONH2, CONHCi-4- alkyl, or CON (Ci-4-alkyl ) 2.
27. A compound according to claim 1 , wherein : A is a single bond; R2, R ' 2, R3, and R ' 3 are each H; R5 is hydrogen, halogen, cyano, hydroxy, Ci-4-alkyl, hydroxyalkyl having 1 to 4 carbon atoms, C2-4-alkenyl,
COOH, COO-Ci-4-alkyl, NH2, NHCi-4-alkyl , or N (Ci_4-alkyl ) 2; and ' 5 R4 is Ci-io alkoxy optionally substituted by F, Cl , Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl , CO-Ci_4-alkyl,, NH2, 'NHC1_4-alkyl, or N (Ci_4- alkyl ) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4- 10 alkyl , cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-
C1- 4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, C1-4- 15 alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci-
4-alkyl, NH2, NHCi_4-alkyl, N (d_4-alkyl ) 2, CONH2,
CONHCi-4- alkyl, or CON (Ci-4-alkyl ) 2.
28. A compound according to claim 1 , wherein :
20 A is a single bond;
R2, R ' 2, R3, and R' 3 are each H;
R5 is hydrogen, halogen, cyano, hydroxy, Ci-4-alkyl , hydroxyalkyl having 1 to 4 carbon atoms, C2-4-alkenyl, COOH, COO-Ci-4-alkyl, NH2, NHCi-4-alkyl , or N (Ci_4-alkyl) 2;
25 R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl ) 2, CONH2, QONHC1-4- alkyl, or CON (Ci_4-alkyl) 2; and R4 is Ci-io alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl, NH2, NHCi_4-alkyl, or N (Ci_4- alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-
Ci- 4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl , CO-Ci-
4-alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl ) 2, CONH2,
CONHC1-4- alkyl, or CON (Ci-4-alkyl )' 2. ■
29. A compound according to claim 1, wherein : A is a single bond; R2, R ' 2, R3, and R ' 3 are each H; R5 is hydrogen; and
R4 is Ci-10 alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci_4- alkyl, CO-d-4-alkyl, NH2, NHCi_4-alkyl , or N (Ci_4- alkyl) 2, phenoxy optionally substituted by F, Cl , Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl , CO- Ci- 4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl) 2, CONH2, CONHCi-4-alkyl , or CON (Ci-4-alkyl ) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case . optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4- alkyl , or CON (Ci-4-alkyl) 2.
30. A compound according to claim 1 , wherein : A is a single bond; R2, R ' 2, R3, and R ' 3 are each H; R5 is hydrogen;
R1 is benzyl, phenethyl, phenpropyl, or naphthylmethyl, in each case optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci_4-alkyl, CO-Ci_4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi_4- alkyl, or CON (Ci-4-alkyl ) 2; and
R4 is Ci-io alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4- alkyl, CO-Ci_4-alkyl, NH2, NHCi-4-alkyl, or N (Ci-4- alkyl) 2, phenoxy optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO- C1- 4-alkyl, NH2, NHCi_4-alkyl, N (Ci_4-alkyl) 2, CONH2,
CONHCi-4-alkyl, or CON (Cχ-4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci- 4-alkyl, NH2, NHCi-4-alkyl, N (C1_4-alkyl) 2, CONH2, CONHC1-4- alkyl, or CON (Ci_4-alkyl ) 2. '
31. A compound according to claim 1 , wherein : A is a single bond; R2, R ' 2, R3, and R ' 3 are each H; R5 is hydrogen; R1 is benzyl optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-C1-4- alkyl, NH2, NHCi_4-alkyl, N (Ci-4-alkyl) 2, CONH2, CONHC1-.4- alkyl, or CON (Ci_4-alkyl) 2; and R4 is Ci-10 alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-C1-4- alkyl, CO-Ci-4-alkyl , NH2, NHCi-4-alkyl, or N (C^4- alkyl) 2, phenoxy optionally substituted by F, Cl, Br, C1-4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-
C1- ' 4-alkyl, NH2, NHCi-4-alkyl, N (Ci-4-alkyl ) 2, CONH2, CONHCi-4-alkyl, or CON (Ci-4-alkyl) 2, or benzyloxy, phenethoxy, or phenpropoxy, in each case optionally substituted by F, Cl, Br, Ci_4- alkyl, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci-
4-alkyl, NH2, NHCi-4-alkyl, N (Ci_4-alkyl ) 2, CONH2,
CONHC1-4- alkyl, or CON (Ci-4-alkyl) 2.
32. A compound according to any one of claims 23 to 31 , wherein R1 is benzyl optionally substituted by F,
Cl, or Br .
\
33. A compound according to any one of claims 23 to 32 , wherein ,R4 is Ci-10 alkoxy optionally substituted by F, Cl, Br, methoxy, ethoxy, cyano, hydroxy, carboxy, COO-Ci-4-alkyl, CO-Ci-4-alkyl, NH2, NHCi-4-alkyl, or N (Cx- 4- alkyl ) 2.
34. A compound wherein said compound is selected from: 6-Bromo-2- ( 4-fluoro-benzyl ) -9-hydroxy- 3, 4-dihydro-2H-pyrido [1 , 2-a] pyrazine- 1, 8-dione;
6- ( 1, 1-Dioxo- [1 , 2] thiazinan-2-yl) -2- (4- fluoro-benzyl ) -9-hydroxy-3, 4-dihydro-2H- pyrido [ 1, 2-a] pyrazine-l , 8-dione;
2- ( 4-Fluoro-benzyl ) -9-hydroxy-6- (tetrahydro-furan-2-yl ) -3 , 4-dihydro-2H- pyrido ( 1, 2-a) pyrazine-1, 8-dione;
8 2- ( 4-Fluoro-benzyl ) -6-furan-2-yl-9- hydroxy-3, 4-dihydro-2H-pyrido ( 1 , 2- a) pyrazine-1, 8-dione;
2- ( 4-Fluoro-benzyl ) -9-hydroxy-6-thiazol- 2-yl-3, 4-dihydro-2H-pyrido (1 , 2- a) pyrazine-1, 8-dione;
10 2- ( 4-Fluoro-benzyl) -9-hydroxy-6-phenyl- 3, 4-dihydro-2H-pyrido ( 1 , 2-a) pyrazine- 1 , 8-dione;
16 2- ( 4-Fluoro-benzyl ) -9-hydroxy-6- methanesulfonyl-3, 4-dihydro-2H- pyrido ( 1 , 2-a) pyrazine-1, 8-dione ; 35 6-AZIDO-2-(4-FLUORO-BENZYL)-9-HYDRO
XY-3,4-DIHYDRO-2H~PYRIDO[1 ,2-A]PYRA ZINE-1 ,8-DIONE;
36 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-PIPERIDIN-1 -YL-3,4-
DIHYDRO-2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE; '
37 6-CYCLOHEXYL-2-(4-FLUORO-BENZYL)-9- HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
38 4-FLUORO-N-(4-FLUORO-BENZOYL)-N-[2-(4-
FLUORO-BENZYL)-9-HYDROXY-1 ,8-DIOXO-i ,3,4,8-
TETRAYDRO-2H-PYRIDO[1 ,2-A]PYRAZIN-6-YL]-
BENZAMIDE;
39 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
MORPHOLIN-4-YL-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
40 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
PYRROLIDIN-1 -YL-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
41 FURAN-2-CARBOXYLIC ACID [2-(4-FLUORO- BENZYL)-9-HYDROXY-1 ,8-DIOXO-i ,3,4,8- TETRAHYDRO-2H-PYRIDO[1 ,2-A]PYRAZIN-6-YL]- (FURAN-2-CARBONYL)-AMIDE; 42 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
(TETRAHYDRO-FURAN-3-YL)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
43 2-(4-FLUORO-BENZYL)-6-(4-FLUORO-
PHENYLAMINO)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
44 6-DIMETHYLAMINO-2-(4-FLUORO-BENZYL)-9-
HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
46 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
[1,2,3]TRIAZOL-1-YL-3,4-DIHYDRO-2H-PYRIDO[1,2- A]PYRAZINE-1,8-DIONE;
47 1-[2-(4-FLUORO-BENZYL)-9-HYDROXY-1,8-DIOXO- 1,3,4,8-TETRAHYDRO-2H-PYRIDO[1,2-A]PYRAZIN- 6-L]-1H-[1,2,3]TRIAZOLE-4-CARBOXYLIC ACID METHYL ESTER;
and pharmaceutically acceptable salts thereof, pharmaceutically solvates thereof, and solvates of pharmaceutically acceptable salts thereof.
35. A compound wherein said compound is selected from: 45 ' 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
METHOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
48 6-ETHOXY-2-(4-FLUORO-BENZYL)-9-HYDROXY- 3,4-DIHYDRO-2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8- DIONE;
49 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
ISOPROPOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
50 6-(2,2-DIFLUORO-ETHOXY)-2-(4-FLUORO-
BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
51 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
PROPOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
52 2-(4-FLUORO-BENZYL)-6-(2-FLUORO-ETHOXY)- 9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
53 θ-CYCLOPROPYLMETHOXY^-^-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE; 54 6-CYCLOHEXYLMETHOXY^-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
55 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2,2,2- TRIFLUORO-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
56 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
MORPHOLIN-4-YL-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
57 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
PHENOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
58 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
ISOBUTOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
59 2-(4-FLUORO-BENZYL)-6-(4-FLUORO-PHENOXY)- 9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
60 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-
(TETRAHYDRO-PYRAN-4-YLMETHOXY)-3,4- DIHYDR0-2H-PYRID0[1 ,2-A]PYRAZINE-1 ,8- DIONE; 61 7-FLUORO-2-(4-FLUORO-BENZYL)-9-HYDROXY- 6-METHOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
62 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2- METHOXY-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
63 6-(2,2-DIMETHYL-[1 ,3]DIOXOLAN-4-
YLM ETHOXY)-2-(4-FLUO RO-BENZYL)-9- HYDROXY-3,4-DIHYDRO-2HPYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
64 6-(2-DIMETHYLAMINO-ETHOXY)-2-(4-FLUORO-
BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
65 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
METHANESULFONYL-I≡THOXY)-3,4-DIHYDRO- 2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
66 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-[2-(4-
METHOXY-PHENYL)-ETHOXY]-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
67 2-(4-FLUORO-BENZYL)-G-(S-FLUORO-PROPOXY)- 9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE; 68 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(PYRIDIN- 2-YLMETHOXY)-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
69 2-(4-FLUORO-BENZYL)-9-H YDROXY-6-
PHENETHYLOXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
70 6-([1 ,3]DIOXOLAN-4-YLMETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
71 6-([1 ,3]DIOXAN-5-YLOXY)-2-(4-FLUORO-BENZYL)-
9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
72 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
PIPERIDIN-1-YL-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
73 δ-CYCLOPENTYLMETHOXY^^-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
74 β-CYCLOBUTYLMETHOXY^-^-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE; 75 2-[2-(4-FLUORO-BENZYL)-9-HYDROXY-1 ,8-
DIOXO-1 ,3,4,8-TETRAHYDRO-2H-PYRIDO[1 ,2-
A]PYRAZIN-6-YLOXY]-N,N-DIMETHYL-
ACETAMIDE
76 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(PYRIDIN- 3-YLOXY)-3,4-DIHYDRO-2H-PYRIDO[1 ,2- A]PYRAZINE-1 ,8-DIONE;
77 6-(2-CYCLOPROPYL-ETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
78 6-BROMO-2-(3,4-DICHLORO-BENZYL)-9-
HYDROXY-3,4-DIHYDRO-2H-PYRIDO(1 ,2-A)- PYRAZINE-1 ,8-DIONE;
79 Θ-BROMO^-CS-CHLORO^-FLUORO-BENZYL)^-
HYDROXY-3,4-DIHYDRO-2H-PYRIDO-(1 ,2-A)- PYRAZINE-1 ,8-DIONE;
80 δ^^-DIFLUORO-CYCLOHEXYL-METHOXY)^^- FLUORO-BENZYLJ-Θ-HYDROXY-S^-DIHYDRO- 2H-PYRIDO-[1 ,2-A]PYRAZINE-1 ,8-DIONE;
81 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
HYDROXY-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE; 82 6-(2,2-DIMETHOXY-ETHOXY)-2-(4-FLUORO- BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRlDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
83 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-((R)-5-
OXO-TETRAHYDRO-FURAN-2-YLMETHOXY)-3,4- DIHYDRO-2H-PYRIDO[1 ,2-A]PYRAZINE-1 ,8- DIONE;
84 2-(4-FLUORO-BENZYL)-9-H YDROXY-6-((S)-5-
OXO-TETRAHYDRO-FURAN^- YLMETHOXY)-3,4- DIHYDR0-2H-PYRID0[1 ,2-A]PYRAZINE-1 ,8- DIONE;
85 2-(4-FLUORO-BENZYL)-9-HYDROXY-6-(2-
THIOPHEN-2-YL-ETHOXY)-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
86 2-BENZYL-9-HYDROXY-6-METHOXY-3,4-
DIHYDR0-2H-PYRID0(1 ,2-A)-PYRAZINE-1 ,8- DIONE;
87 2-(3,4-Dichloro-benzyl)-9-hydroxy-6-methoxy-3,4- dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,8-dione;
88 2-BENZYL-6-(2-FLUORO-ETHOXY)-9-HYDROXY- 3,4-DIHYDRO-2H-PYRIDO-(1 ,2-A)-PYRAZINE-1 ,8- DIONE; 89 2-(3,4-DICHLORO-BENZYL)-6-(2-FLUORO-
ETHOXY)-9-HYDROXY-3,4-DIHYDRO-2H-PYRIDO- (1 ,2-A)-PYRAZINE-1 ,8-DIONE;
90 6-(2-CYCLOPENTYL-ETHOXY)-2-(4-FLUORO-
BENZYL)-9-HYDROXY-3,4-DIHYDRO-2H- PYRIDO[1 ,2-A]PYRAZINE-1 ,8-DIONE;
91 2-(3,4-Dichloro-benzyl)-9-hydroxy-6-(pyridin-3- yloxy)-3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,8- dione;
92 2-(3-Chloro-4-fluoro-benzyl)-9-hydroxy-6-(pyridin-3- yloxy)-3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,8- dione;
93 2-(3,4-Dichloro-benzyl)-9-hydroxy-6-(2-methoxy- ethoxy)-3,4-dihydro-2H-pyrido[1 ,2-a]pyrazine-1 ,8- dione; and
94 2-(3-Chloro-4-fluoro-benzyl)-9-hydroxy-6-(2- methoxy-ethoxy)-3,4-dihydro-2H-pyrido[1 ,2- a]pyrazine-1 ,8-dione;
and pharmaceutically acceptable salts thereof, pharmaceutically solvates thereof, and solvates of pharmaceutically acceptable salts thereof . 36. A compound according to any one of claims 1 to 35 , wherein said compound is in the form of the (+) enantiomer having an enantiomeric excess of 99% .
37. A compound according to any one of claims 1 to 35 , wherein said compound is in the form of the (+) enantiomer having an enantiomeric excess of 95% .
38. A compound according to any one of claims 1 to 35 , wherein said compound is in the form of the (+) enantiomer having an enantiomeric excess of 90% .
39. A compound according to any one of claims 1 to 35 , wherein said compound is in the form of the (- ) enantiomer having an enantiomeric excess of 99% .
40. A compound according to any one of claims 1 to 35 , wherein said compound is in the form of the ( - ) enantiomer having an enantiomeric excess of 95% .
41. A compound according to any one of claims 1 to 35 , wherein said compound is in the form of the (- ) enantiomer having an enantiomeric excess of 90% .
42. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 42 and at least one pharmaceutically acceptable carrier or excipient .
43. A combination comprising at least one compound according to any one of claims 1 to 41 and at least one further therapeutic agent chosen from an agent used in inflammatory diseases , immunoregulatory diseases and in organ transplantation reactions .
44. A combination comprising at least one compound according to any one of claims 1 to 41 and, at least one further antiviral agent .
45. A combination according to claim 44 , wherein said at least one further antiviral agent is selected from nucleoside and nucleotide analog reverse transcriptase inhibitors , non-nucleoside reverse transcriptase inhibitors , protease inhibitors , integrase inhibitors attachment and fusion inhibitors , entry inhibitors or maturation inhibitors .
46. A combination according to claim 44 , wherein said at least one further antiviral agent is a nucleoside and nucleotide analog reverse transcriptase inhibitors selected from lamivudine, zidovudine, emtricitabine, 2 ' , 3 ' -dideoxy-2 ' , 3 ' -didehydro-thymidine, stavudine, tenofovir, 2 ' , 3 ' -dideoxyinosine, 2 " , 3 ' - dideoxycytidine, zidovudine/lamivudine combination, zidovudine/lamivudine/abacavir combination, abacavir, ' SPD-754 , ACH-126, 443 (Beta-L-Fd4C) , Alovudine (MIV- 310 ) , DAPD (amdoxovir) , Racivir, 9- [ (2-hydroxymethyl) - 1, 3-dioxolan-4-yl] guanine or 2-amino-9- [ (2- hydroxymethyl ) -1 , 3-dioxolan-4-yl] adenine .
47. A combination according to claim 44 , wherein said at least one further antiviral agent is a non- nucleoside reverse transcriptase inhibitor selected from Nevirapine, delavirdine, efavirenz , (+) -Calanolide A, Capravirine, DPC083 , MIV-150 , TMC120 , TMC125 , delavirdine, calanolides or L-697 , 661.
■48. A combination according to claim 44 , wherein said at least one further antiviral agent a protease inhibitor chosen from nelfinavir, amprenavir, indinavir, saquinavir, ritonavir, lopinavir, Atazanavir, mozenavir, fosamprenavir, RO033-4649, Tipranavir, TMC114 or VX-385.
49. A method of preventing or treating HIV infection in a subj ect, comprising administering to said subj ect a therapeutically effective amount of a compound according to any one of claims 1 to 41.
50. A method of preventing, delaying or treating AIDS in a subj ect, comprising administering to the subj ect a therapeutically effective amount of a compound according to any one of claims 1 to 41.
51. A method of inhibiting HIV integrase in a subj ect , comprising administering to the subj ect a therapeutically effective amount of a compound according to any one of claims 1 to 41.
52. A method of preventing integration of HIV DNA into host cell DNA in a subj ect, comprising administering to the subj ect a therapeutically effective amount of a compound according to any one of claims 1 to 41.
53. A method of preventing HIV DNA strand transfer to the host cell DNA in a subject, comprising administering to the subj ect a therapeutically effective amount of a compound according to any one of claims 1 to 41.
54. Use of a compound according to any one of claims 1 to 41 for the manufacture of a medicament for preventing or treating HIV infection or preventing, delaying or treating AIDS .
55. Use of a compound according to any one of claims 1 to 41 for the manufacture of a medicament for preventing any one of HIV replication, integration of HIV DNA into host cell DNA, 3' -end processing of HIV DNA or HIV DNA strand transfer to the host cell DNA.
56. A compound according to any one of claims 1 to 41, for use in medical therapy.
57. A compound according to any one of claims 1 to 41, for use in preventing or treating HIV infection or preventing, delaying or treating AIDS .
PCT/CA2005/001964 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase WO2006066414A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002634499A CA2634499A1 (en) 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase
EP05849193A EP1973906A1 (en) 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US63818004P 2004-12-23 2004-12-23
US60/638,180 2004-12-23

Publications (1)

Publication Number Publication Date
WO2006066414A1 true WO2006066414A1 (en) 2006-06-29

Family

ID=36601330

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2005/001964 WO2006066414A1 (en) 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase

Country Status (3)

Country Link
EP (1) EP1973906A1 (en)
CA (1) CA2634499A1 (en)
WO (1) WO2006066414A1 (en)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1725554A1 (en) * 2004-03-09 2006-11-29 Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. Hiv integrase inhibitors
US7211572B2 (en) 2003-08-13 2007-05-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
WO2007049675A1 (en) * 2005-10-27 2007-05-03 Shionogi & Co., Ltd. Polycyclic carbamoylpyridone derivative having inhibitory activity on hiv integrase
WO2010110409A1 (en) 2009-03-26 2010-09-30 塩野義製薬株式会社 Process for producing pyrone and pyridone derivatives
WO2010147068A1 (en) * 2009-06-15 2010-12-23 塩野義製薬株式会社 Substituted polycyclic carbamoylpyridone derivative
US7858788B2 (en) * 2005-02-21 2010-12-28 Shionogi & Co., Ltd. Bicyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
US8129385B2 (en) 2005-04-28 2012-03-06 Shionogi & Co., Ltd. Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness
US8552187B2 (en) 2008-12-11 2013-10-08 Shionogi & Co., Ltd. Processes and intermediates for carbamoylpyridone HIV integrase inhibitors
US8580967B2 (en) 2008-07-25 2013-11-12 Shionogi & Co., Ltd. Methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate and processes for the preparation thereof
US8624023B2 (en) 2008-12-11 2014-01-07 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes
US8987441B2 (en) 2010-09-24 2015-03-24 Shionogi & Co., Ltd. Substituted polycyclic carbamoyl pyridone derivative prodrug
WO2015048363A1 (en) * 2013-09-27 2015-04-02 Merck Sharp & Dohme Corp. Substituted quinolizine derivatives useful as hiv integrase inhibitors
WO2015095258A1 (en) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Spirocyclic heterocycle compounds useful as hiv integrase inhibitors
WO2014172188A3 (en) * 2013-04-16 2015-10-29 Merck Sharp & Dohme Corp. 4-pyridone derivative compounds and uses thereof as hiv integrase inhibitors
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
US20160002227A1 (en) * 2014-07-07 2016-01-07 F. Hoffmann-La Roche Ag Cap/endo dual inhibitors and their use in the treatment, amelioration or prevention of a viral disease
WO2016005331A1 (en) * 2014-07-07 2016-01-14 F. Hoffmann-La Roche Ag Pyridopyrazine compounds and their use in the treatment, amelioration or prevention of influenza
US9421214B2 (en) 2013-07-12 2016-08-23 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2016154527A1 (en) * 2015-03-26 2016-09-29 Merck Sharp & Dohme Corp. Phosphate-substituted quinolizine derivatives useful as hiv integrase inhibitors
US9458159B2 (en) 2013-07-12 2016-10-04 Gilead Sciences, Inc. Substituted pyrido[1′,2′:4,5]pyrazino[1,2-a]azepines for treating viral infections
WO2016187788A1 (en) * 2015-05-25 2016-12-01 Merck Sharp & Dohme Corp. Fused tricyclic heterocyclic compounds useful for treating hiv infection
US9522912B2 (en) 2014-12-23 2016-12-20 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9630978B2 (en) 2015-04-02 2017-04-25 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9682084B2 (en) 2014-06-20 2017-06-20 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9,-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
KR20170131651A (en) 2015-04-28 2017-11-29 시오노기세야쿠 가부시키가이샤 Substituted polycyclic pyridone derivatives and prodrugs thereof
WO2018030463A1 (en) 2016-08-10 2018-02-15 塩野義製薬株式会社 Substituted polycyclic pyridone derivative and pharmaceutical composition containing prodrug thereof
US10065950B2 (en) 2010-02-26 2018-09-04 Japan Tobacco Inc. Substituted thiazoles as HIV integrase inhibitors
KR20190049916A (en) 2015-04-28 2019-05-09 시오노기세야쿠 가부시키가이샤 Substituted polycyclic pyridone derivative and prodrug thereof
US10385067B2 (en) 2014-06-20 2019-08-20 Gilead Sciences, Inc. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate
US10479801B2 (en) 2016-12-02 2019-11-19 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US11040048B2 (en) 2015-12-15 2021-06-22 Shionogi & Co., Ltd. Medicament for treating influenza characterized by combining a Cap-dependent endonuclease inhibitor and an anti-influenza drug
CN113880831A (en) * 2020-07-03 2022-01-04 广州南鑫药业有限公司 Pyrazine dione derivative and application thereof
US11358711B2 (en) 2019-06-20 2022-06-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
CN114835702A (en) * 2021-01-30 2022-08-02 广州南鑫药业有限公司 Pyrazine dione derivative and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2498111A1 (en) * 2002-09-11 2004-03-25 Merck & Co., Inc. Dihydroxypyridopyrazine-1,6-dione compounds useful as hiv integrase inhibitors
WO2005087766A1 (en) * 2004-03-09 2005-09-22 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Hiv integrase inhibitors
WO2005087768A1 (en) * 2004-03-09 2005-09-22 Merck & Co., Inc. Hiv integrase inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2498111A1 (en) * 2002-09-11 2004-03-25 Merck & Co., Inc. Dihydroxypyridopyrazine-1,6-dione compounds useful as hiv integrase inhibitors
WO2005087766A1 (en) * 2004-03-09 2005-09-22 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Hiv integrase inhibitors
WO2005087768A1 (en) * 2004-03-09 2005-09-22 Merck & Co., Inc. Hiv integrase inhibitors
WO2005087767A1 (en) * 2004-03-09 2005-09-22 Merck & Co., Inc. Hiv integrase inhibitors

Cited By (115)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7211572B2 (en) 2003-08-13 2007-05-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
EP1725554A1 (en) * 2004-03-09 2006-11-29 Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. Hiv integrase inhibitors
US7858788B2 (en) * 2005-02-21 2010-12-28 Shionogi & Co., Ltd. Bicyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
US8410103B2 (en) 2005-04-28 2013-04-02 Shionogi & Co., Ltd. (3S,11aR)-N-[2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide useful as anti-HIV agent
US8778943B2 (en) 2005-04-28 2014-07-15 Shionogi & Co., Ltd. Substituted 10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1h-pyrido[1,2-α]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamides
US10927129B2 (en) 2005-04-28 2021-02-23 Shinogi & Co., Ltd. N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3] oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide having HIV integrase inhibitory activity
US11267823B2 (en) 2005-04-28 2022-03-08 Shionogi & Co., Ltd. Substituted 1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidines having HIV integrase inhibitory activity
US9051337B2 (en) 2005-04-28 2015-06-09 Shionogi & Co., Ltd. Substituted 10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1h-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamides
US8129385B2 (en) 2005-04-28 2012-03-06 Shionogi & Co., Ltd. Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness
US9273065B2 (en) 2005-04-28 2016-03-01 Shionogi & Co., Ltd. Substituted pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidines as HIV integrase inhibitors
US8188271B2 (en) 2005-10-27 2012-05-29 Shionogi & Co., Ltd. Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
WO2007049675A1 (en) * 2005-10-27 2007-05-03 Shionogi & Co., Ltd. Polycyclic carbamoylpyridone derivative having inhibitory activity on hiv integrase
US9012650B2 (en) 2008-07-25 2015-04-21 Shionogi & Co., Ltd. Substituted (3S, 11aR)-N-[(2,4-difluorophenyl)methyl]-6-oxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamides of formula (I) useful as HIV agents
US8940912B2 (en) 2008-07-25 2015-01-27 Viiv Healthcare Company 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid
US8580967B2 (en) 2008-07-25 2013-11-12 Shionogi & Co., Ltd. Methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate and processes for the preparation thereof
US9707246B2 (en) 2008-07-25 2017-07-18 Shionogi & Co., Ltd. Substituted (3S,11AR)-N-[(2,4-difluorophenyl)methyl]-6-oxy-3-methyl-5,7-dioxo-2,3,5,7,11,11A-hexahydro[1,3]oxazolo[3,2-A]pyrido[1,2-D]pyrazine-8-carboxamides as HIV agents
US9133216B2 (en) 2008-07-25 2015-09-15 Shionogi & Co., Ltd. (3S,11aR)-6-[(phenylmethyl)oxy]-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-9 and/or (3S,11aR)-6-[(phenymethyl)oxy]-8-bromo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-10
US8981129B2 (en) 2008-07-25 2015-03-17 Shionogi & Co., Ltd. 2-(2-hydroxy-2-phenylethyl)-3-[(phenylmethyl)oxy]-4H-pyran-4-one of the formula P-3 and/or 2-[(E)-2-phenylethenyl]-3-[(phenylmethyl)oxy]-4H-Pyran-4-one of the formula P-4
US8765965B2 (en) 2008-07-25 2014-07-01 Shionogi & Co., Ltd. 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid of the formula P-6 and/or methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate of the formula P-7
US8624023B2 (en) 2008-12-11 2014-01-07 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US9365587B2 (en) 2008-12-11 2016-06-14 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US8754214B2 (en) 2008-12-11 2014-06-17 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US8669362B2 (en) 2008-12-11 2014-03-11 Shiongi & Co., Ltd. Processes and Intermediates for carbamoylpyridone HIV integrase inhibitors
US8552187B2 (en) 2008-12-11 2013-10-08 Shionogi & Co., Ltd. Processes and intermediates for carbamoylpyridone HIV integrase inhibitors
US9242986B2 (en) 2008-12-11 2016-01-26 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
US9505783B2 (en) 2009-03-26 2016-11-29 Shionogi & Co., Ltd. Method of producing pyrone and pyridone derivatives
US8865907B2 (en) 2009-03-26 2014-10-21 Shionogi & Co., Ltd. Method of producing pyrone and pyridone derivatives
EP3109235A1 (en) 2009-03-26 2016-12-28 Shionogi & Co., Ltd Method of producing pyridone derivatives
KR20110132462A (en) 2009-03-26 2011-12-07 시오노기세야쿠 가부시키가이샤 Process for producing pyrone and pyridone derivatives
US9260453B2 (en) 2009-03-26 2016-02-16 Shionogi & Co., Ltd. Method for producing pyrone and pyridone derivatives
WO2010110409A1 (en) 2009-03-26 2010-09-30 塩野義製薬株式会社 Process for producing pyrone and pyridone derivatives
CN102803260B (en) * 2009-06-15 2016-02-10 盐野义制药株式会社 The polycyclic carbamoylpyridone derivative be substituted
US8927710B2 (en) 2009-06-15 2015-01-06 Shionogi & Co., Ltd. Substituted polycyclic carbamoylpyridone derivative
CN102803260A (en) * 2009-06-15 2012-11-28 盐野义制药株式会社 Substituted polycyclic carbamoylpyridone derivative
JPWO2010147068A1 (en) * 2009-06-15 2012-12-06 塩野義製薬株式会社 Substituted polycyclic carbamoylpyridone derivatives
WO2010147068A1 (en) * 2009-06-15 2010-12-23 塩野義製薬株式会社 Substituted polycyclic carbamoylpyridone derivative
US9469638B2 (en) 2009-06-15 2016-10-18 Shionogi & Co., Ltd. Substituted polycyclic carbamoylpyridone derivative
JP5737691B2 (en) * 2009-06-15 2015-06-17 塩野義製薬株式会社 Substituted polycyclic carbamoylpyridone derivatives
US9815835B2 (en) 2009-06-15 2017-11-14 Shionogi & Co., Ltd. Substituted polycyclic carbamolypyridone derivative
US10065950B2 (en) 2010-02-26 2018-09-04 Japan Tobacco Inc. Substituted thiazoles as HIV integrase inhibitors
US10654871B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing (3S,11aR)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
US9643981B2 (en) 2010-03-23 2017-05-09 Viiv Healthcare Company Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12A-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
US10647728B2 (en) 2010-03-23 2020-05-12 Viiv Healthcare Company Process for preparing (3S,11aR)-6-methoxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid
US10233196B2 (en) 2010-03-23 2019-03-19 Viiv Healthcare Company Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US10654870B2 (en) 2010-03-23 2020-05-19 Viiv Healthcare Company Process for preparing substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US10174051B2 (en) 2010-03-23 2019-01-08 Viiv Healthcare Company Substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US9938296B2 (en) 2010-03-23 2018-04-10 Viiv Healthcare Company Process for preparing (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes
US9758515B2 (en) 2010-09-24 2017-09-12 Shionogi & Co., Ltd. Substituted polycyclic carbamoyl pyridone derivative prodrug
US10202379B2 (en) 2010-09-24 2019-02-12 Shionogi & Co., Ltd. Substituted polycyclic carbamoyl pyridone derivative prodrug
US8987441B2 (en) 2010-09-24 2015-03-24 Shionogi & Co., Ltd. Substituted polycyclic carbamoyl pyridone derivative prodrug
US10035809B2 (en) 2012-12-21 2018-07-31 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydro-1,5-methanopyrido[1′,2′:4,5]pyrazino[1,2-a][1,3]diazepines and methods for treating viral infections
US10689399B2 (en) 2012-12-21 2020-06-23 Gilead Sciences, Inc. Substituted 3,4,5,6,8,10,14,14a-octahydro-2h-2,6-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazocines and methods for treating viral infections
US9216996B2 (en) 2012-12-21 2015-12-22 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections
US9732092B2 (en) 2012-12-21 2017-08-15 Gilead Sciences, Inc. Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]OXAZEPINES and methods for treating viral infections
US11548901B2 (en) 2012-12-21 2023-01-10 Gilead Sciences, Inc. Substituted 1,4-methanopyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidines for treating viral infections
US9493479B2 (en) 2013-04-16 2016-11-15 Merck Sharp & Dohme Corp. Substituted pyrido[1,2-a]pyrazines as HIV integrase inhibitors
WO2014172188A3 (en) * 2013-04-16 2015-10-29 Merck Sharp & Dohme Corp. 4-pyridone derivative compounds and uses thereof as hiv integrase inhibitors
US9421214B2 (en) 2013-07-12 2016-08-23 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US10456395B2 (en) 2013-07-12 2019-10-29 Gilead Sciences, Inc. Substituted dipyrido[1,2-a:1′,2′-d]pyrazines for treating viral infections
US9700554B2 (en) 2013-07-12 2017-07-11 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US11213523B2 (en) 2013-07-12 2022-01-04 Gilead Sciences, Inc. Substituted pyrido[1,2-a]pyrrolo[1,2-d]pyrazines for treating viral infections
US11883397B2 (en) 2013-07-12 2024-01-30 Gilead Sciences, Inc. Substituted pyrido[1,2-a]pyrrolo[1,2-d]pyrazines for treating viral infections
US10668064B2 (en) 2013-07-12 2020-06-02 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9458159B2 (en) 2013-07-12 2016-10-04 Gilead Sciences, Inc. Substituted pyrido[1′,2′:4,5]pyrazino[1,2-a]azepines for treating viral infections
JP2016531863A (en) * 2013-09-27 2016-10-13 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Substituted quinolidine derivatives useful as HIV integrase inhibitors
US10201533B2 (en) 2013-09-27 2019-02-12 Merck Sharp & Dohme Corp. Substituted quinolizine derivatives useful as HIV integrase inhibitors
WO2015048363A1 (en) * 2013-09-27 2015-04-02 Merck Sharp & Dohme Corp. Substituted quinolizine derivatives useful as hiv integrase inhibitors
US9861620B2 (en) 2013-09-27 2018-01-09 Merck Sharp & Dohme Corp. Substituted quinolizine derivatives useful as HIV integrase inhibitors
EA030695B1 (en) * 2013-09-27 2018-09-28 Мерк Шарп И Доум Корп. Substituted quinolizine derivatives useful as hiv integrase inhibitors
AU2014324829B2 (en) * 2013-09-27 2017-09-07 Merck Sharp & Dohme Corp. Substituted Quinolizine Derivatives useful as HIV integrase inhibitors
JP2017105793A (en) * 2013-09-27 2017-06-15 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Substituted quinolizine derivatives useful as HIV integrase inhibitors
US9707234B2 (en) 2013-12-20 2017-07-18 Merck Sharp & Dohme Corp. Spirocyclic hetercycle compounds useful as HIV integrase inhibitors
WO2015095258A1 (en) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Spirocyclic heterocycle compounds useful as hiv integrase inhibitors
US11202780B2 (en) 2014-06-20 2021-12-21 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
US10098886B2 (en) 2014-06-20 2018-10-16 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13A- octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-B] [1,3] oxazepine-10-carboxamide
US10385067B2 (en) 2014-06-20 2019-08-20 Gilead Sciences, Inc. Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepin-8-olate
US10975096B2 (en) 2014-06-20 2021-04-13 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US9682084B2 (en) 2014-06-20 2017-06-20 Gilead Sciences, Inc. Crystalline forms of (2R,5S,13AR)-8-hydroxy-7,9,-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
US20160002227A1 (en) * 2014-07-07 2016-01-07 F. Hoffmann-La Roche Ag Cap/endo dual inhibitors and their use in the treatment, amelioration or prevention of a viral disease
WO2016005330A1 (en) 2014-07-07 2016-01-14 F. Hoffmann-La Roche Ag Dihydropyridopyrazine-1,8-diones and their use in the treatment, amelioration or prevention of viral diseases
WO2016005331A1 (en) * 2014-07-07 2016-01-14 F. Hoffmann-La Roche Ag Pyridopyrazine compounds and their use in the treatment, amelioration or prevention of influenza
US9359351B2 (en) 2014-07-07 2016-06-07 F. Hoffmann-La Roche Ag Cap/endo dual inhibitors and their use in the treatment, amelioration or prevention of a viral disease
US9827244B2 (en) * 2014-07-07 2017-11-28 F. Hoffmann-La Roche Ag Cap/endo dual inhibitors and their use in the treatment, amelioration or prevention of a viral disease
CN107001355A (en) * 2014-07-07 2017-08-01 萨维拉制药有限公司 Pyridopyrazine compound and their purposes in treating, ameliorating or preventing influenza
CN107074880A (en) * 2014-07-07 2017-08-18 萨维拉制药有限公司 The diketone of dihydro pyrido pyrazine 1,8 and their purposes in treating, ameliorating or preventing virus disease
US9795602B2 (en) 2014-12-23 2017-10-24 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US10646486B2 (en) 2014-12-23 2020-05-12 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9522912B2 (en) 2014-12-23 2016-12-20 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
EP3285582A4 (en) * 2015-03-26 2018-11-21 Merck Sharp & Dohme Corp. Phosphate-substituted quinolizine derivatives useful as hiv integrase inhibitors
WO2016154527A1 (en) * 2015-03-26 2016-09-29 Merck Sharp & Dohme Corp. Phosphate-substituted quinolizine derivatives useful as hiv integrase inhibitors
US10081647B2 (en) 2015-03-26 2018-09-25 Merck Sharp & Dohme Corp. Phosphate substituted quinolizine derivatives useful as HIV integrase inhibitors
US9630978B2 (en) 2015-04-02 2017-04-25 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
EP4219508A1 (en) 2015-04-28 2023-08-02 Shionogi & Co., Ltd Substituted polycyclic pyridone derivative and prodrug thereof
US20180118760A1 (en) 2015-04-28 2018-05-03 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
US10633397B2 (en) 2015-04-28 2020-04-28 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
KR20190002742A (en) 2015-04-28 2019-01-08 시오노기세야쿠 가부시키가이샤 Substituted polycyclic pyridone derivative and prodrug thereof
KR20190049916A (en) 2015-04-28 2019-05-09 시오노기세야쿠 가부시키가이샤 Substituted polycyclic pyridone derivative and prodrug thereof
US10392406B2 (en) 2015-04-28 2019-08-27 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
KR20170131651A (en) 2015-04-28 2017-11-29 시오노기세야쿠 가부시키가이샤 Substituted polycyclic pyridone derivatives and prodrugs thereof
EP3428170A1 (en) 2015-04-28 2019-01-16 Shionogi & Co., Ltd Anti-influenza polycyclic pyridone derivative and prodrug thereof
WO2016187788A1 (en) * 2015-05-25 2016-12-01 Merck Sharp & Dohme Corp. Fused tricyclic heterocyclic compounds useful for treating hiv infection
US10233193B2 (en) 2015-05-25 2019-03-19 Merck Sharp & Dohme Corp. Fused tricyclic heterocyclic compounds useful for treating HIV infection
US11040048B2 (en) 2015-12-15 2021-06-22 Shionogi & Co., Ltd. Medicament for treating influenza characterized by combining a Cap-dependent endonuclease inhibitor and an anti-influenza drug
US10759814B2 (en) 2016-08-10 2020-09-01 Shionogi & Co., Ltd. Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof
KR20190007517A (en) 2016-08-10 2019-01-22 시오노기세야쿠 가부시키가이샤 A pharmaceutical composition containing a substituted polycyclic pyridone derivative and a prodrug thereof
US11306106B2 (en) 2016-08-10 2022-04-19 Shionogi & Co., Ltd. Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof
WO2018030463A1 (en) 2016-08-10 2018-02-15 塩野義製薬株式会社 Substituted polycyclic pyridone derivative and pharmaceutical composition containing prodrug thereof
KR20190018469A (en) 2016-08-10 2019-02-22 시오노기세야쿠 가부시키가이샤 Substituted polycyclic pyridone derivative and pharmaceutical composition containing prodrug thereof
US10829499B2 (en) 2016-12-02 2020-11-10 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
US10479801B2 (en) 2016-12-02 2019-11-19 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
US11358711B2 (en) 2019-06-20 2022-06-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
CN113880831A (en) * 2020-07-03 2022-01-04 广州南鑫药业有限公司 Pyrazine dione derivative and application thereof
CN114835702A (en) * 2021-01-30 2022-08-02 广州南鑫药业有限公司 Pyrazine dione derivative and application thereof

Also Published As

Publication number Publication date
CA2634499A1 (en) 2006-06-29
EP1973906A1 (en) 2008-10-01

Similar Documents

Publication Publication Date Title
WO2006066414A1 (en) Hydroxydihydropyridopy razine-1,8-diones and methods for inhibiting hiv integrase
US9896459B2 (en) Azaindoles as respiratory syncytial virus antiviral agents
US20050176767A1 (en) Pyridine carboxamide and methods for inhibiting HIV integrase
US9707246B2 (en) Substituted (3S,11AR)-N-[(2,4-difluorophenyl)methyl]-6-oxy-3-methyl-5,7-dioxo-2,3,5,7,11,11A-hexahydro[1,3]oxazolo[3,2-A]pyrido[1,2-D]pyrazine-8-carboxamides as HIV agents
EP2651933B1 (en) Azabenzimidazoles as respiratory syncytial virus antiviral agents
EP3823974A1 (en) Sulfonimidamide compounds as inhibitors of interleukin-1 activity
EP3352781B1 (en) 4&#39;-substituted nucleoside reverse transcriptase inhibitors and preparations thereof
RU2350604C2 (en) Derivatives of tetrahydroquinoline showing protective action from hiv-infection
KR102132574B1 (en) Tricyclic gyrase inhibitors
AU2020308353A1 (en) Heterocyclic compounds as inhibitors of KRAS G12C
US9493479B2 (en) Substituted pyrido[1,2-a]pyrazines as HIV integrase inhibitors
US20180325927A1 (en) Amido-Substituted Pyridotriazine Derivatives Useful As HIV Integrase Inhibitors
US20150203512A1 (en) Macrocyclic compounds as hiv integrase inhibitors
ES2693152T3 (en) Pyrimido-diazepinone compound
US20150218164A1 (en) Substituted naphthyridinedione derivatives as hiv integrase inhibitors
US20120022045A1 (en) Bridged compounds as hiv integrase inhibitors
AU2011320651A1 (en) HIV integrase inhibitors
WO2005023810A1 (en) Spirohydantoin compounds and methods for the modulation of chemokine receptor activity
CN116262750A (en) Aromatic heterocyclic compound and preparation method and application thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WPC Withdrawal of priority claims after completion of the technical preparations for international publication

Ref document number: 60/638,180

Country of ref document: US

Date of ref document: 20041223

Free format text: WITHDRAWN AFTER TECHNICAL PREPARATION FINISHED

WWE Wipo information: entry into national phase

Ref document number: 2634499

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2005849193

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2005849193

Country of ref document: EP