[go: up one dir, main page]

WO2006066414A1 - Hydroxydihydropyridopy razine-1,8-diones et procedes d’inhibition de l’integrase du vih - Google Patents

Hydroxydihydropyridopy razine-1,8-diones et procedes d’inhibition de l’integrase du vih 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
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2005/001964
Other languages
English (en)
Inventor
Laval Chan Chun Kong
Bingcan Liu
Nghe Nguyen-Ba
Caroline Cadilhac
Nathalie Turcotte
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Virochem Pharma Inc
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/fr
Priority to EP05849193A priority patent/EP1973906A1/fr
Publication of WO2006066414A1 publication Critical patent/WO2006066414A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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 .

Landscapes

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

Abstract

Composés bi- ou tricycliques de formule (I) dans lesquels R1, R4 et R5 sont tels que définis ici, A représente une liaison simple ou double et deux R2, R2’, R3 et R3’ peuvent être groupés pour former un cycle condensé ou spiro. Ces composés et leurs sels pharmaceutiquement acceptables sont utilisés dans des combinaisons ou des compositions pharmaceutiques et sont utiles dans des procédés pour prévenir ou traiter l’infection par le virus de l’immunodéficience humaine (VIH) ou dans des procédés pour prévenir, retarder ou traiter le syndrome d’immunodéficience acquise (SIDA).
PCT/CA2005/001964 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones et procedes d’inhibition de l’integrase du vih Ceased WO2006066414A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002634499A CA2634499A1 (fr) 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones et procedes d'inhibition de l'integrase du vih
EP05849193A EP1973906A1 (fr) 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones et procedes d'inhibitation de l'integrase du vih

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 (fr) 2006-06-29

Family

ID=36601330

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2005/001964 Ceased WO2006066414A1 (fr) 2004-12-23 2005-12-22 Hydroxydihydropyridopy razine-1,8-diones et procedes d’inhibition de l’integrase du vih

Country Status (3)

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

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1725554A1 (fr) * 2004-03-09 2006-11-29 Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. Inhibiteurs de l'int grase du vih
US7211572B2 (en) 2003-08-13 2007-05-01 Japan Tobacco Inc. Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor
WO2007049675A1 (fr) * 2005-10-27 2007-05-03 Shionogi & Co., Ltd. Dérivé de carbamoylpyridone polycyclique ayant une activité d'inhibition sur l'intégrase du vih
WO2010110409A1 (fr) 2009-03-26 2010-09-30 塩野義製薬株式会社 Procédé de production de dérivés de pyrone et de pyridone
WO2010147068A1 (fr) * 2009-06-15 2010-12-23 塩野義製薬株式会社 Dérivé de carbamoylpyridone polycyclique substituée
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 (fr) * 2013-09-27 2015-04-02 Merck Sharp & Dohme Corp. Dérivés de quinolizine substitués utiles en tant qu'inhibiteurs de l'integrase du vih
WO2015095258A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Composés hétérocycliques spirocycliques utiles en tant qu'inhibiteurs de l'intégrase du vih
WO2014172188A3 (fr) * 2013-04-16 2015-10-29 Merck Sharp & Dohme Corp. Composés dérivés de 4-pyridone et leurs utilisations en tant qu'inhibiteurs de la vih intégrase
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 (fr) * 2014-07-07 2016-01-14 F. Hoffmann-La Roche Ag Composés pyridopyraziniques et leur utilisation dans le traitement, l'amélioration des symptômes ou la prévention de la grippe
US9421214B2 (en) 2013-07-12 2016-08-23 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2016154527A1 (fr) * 2015-03-26 2016-09-29 Merck Sharp & Dohme Corp. Dérivés de quinolizine substitués par un phosphate utiles en tant qu'inhibiteurs de l'intégrase du vih
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 (fr) * 2015-05-25 2016-12-01 Merck Sharp & Dohme Corp. Composés hétérocycliques tricycliques fusionnés utiles pour traiter l'infection au vih
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 (ko) 2015-04-28 2017-11-29 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체 및 그의 프로드러그
WO2018030463A1 (fr) 2016-08-10 2018-02-15 塩野義製薬株式会社 Dérivé de pyridone polycyclique substitué et composition pharmaceutique contenant un promédicament de celui-ci
US10065950B2 (en) 2010-02-26 2018-09-04 Japan Tobacco Inc. Substituted thiazoles as HIV integrase inhibitors
KR20190049916A (ko) 2015-04-28 2019-05-09 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체 및 그의 프로드러그
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 (zh) * 2020-07-03 2022-01-04 广州南鑫药业有限公司 一种吡嗪二酮衍生物及其用途
US11358711B2 (en) 2019-06-20 2022-06-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds useful as HIV integrase inhibitors
CN114835702A (zh) * 2021-01-30 2022-08-02 广州南鑫药业有限公司 一种吡嗪二酮衍生物及其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2498111A1 (fr) * 2002-09-11 2004-03-25 Merck & Co., Inc. Composes de dihydroxypyridopyrazine-1,6-diones utiles en tant qu'inhibiteurs de l'integrase du vih
WO2005087768A1 (fr) * 2004-03-09 2005-09-22 Merck & Co., Inc. Inhibiteurs de l'intégrase du vih
WO2005087766A1 (fr) * 2004-03-09 2005-09-22 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Inhibiteurs de l'intégrase du vih

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2498111A1 (fr) * 2002-09-11 2004-03-25 Merck & Co., Inc. Composes de dihydroxypyridopyrazine-1,6-diones utiles en tant qu'inhibiteurs de l'integrase du vih
WO2005087768A1 (fr) * 2004-03-09 2005-09-22 Merck & Co., Inc. Inhibiteurs de l'intégrase du vih
WO2005087767A1 (fr) * 2004-03-09 2005-09-22 Merck & Co., Inc. Inhibiteurs de vih-integrase
WO2005087766A1 (fr) * 2004-03-09 2005-09-22 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Inhibiteurs de l'intégrase du vih

Cited By (116)

* 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 (fr) * 2004-03-09 2006-11-29 Istituto di Richerche di Biologia Molecolare P. Angeletti S.p.A. Inhibiteurs de l'int grase du vih
US7858788B2 (en) * 2005-02-21 2010-12-28 Shionogi & Co., Ltd. Bicyclic carbamoylpyridone derivative 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
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
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
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
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
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
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
US8188271B2 (en) 2005-10-27 2012-05-29 Shionogi & Co., Ltd. Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
WO2007049675A1 (fr) * 2005-10-27 2007-05-03 Shionogi & Co., Ltd. Dérivé de carbamoylpyridone polycyclique ayant une activité d'inhibition sur l'intégrase du vih
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
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
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
US8940912B2 (en) 2008-07-25 2015-01-27 Viiv Healthcare Company 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid
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
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
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
US8754214B2 (en) 2008-12-11 2014-06-17 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
US8669362B2 (en) 2008-12-11 2014-03-11 Shiongi & Co., Ltd. Processes and Intermediates for carbamoylpyridone HIV integrase inhibitors
US8624023B2 (en) 2008-12-11 2014-01-07 Shionogi & Co., Ltd. Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates
EP3109235A1 (fr) 2009-03-26 2016-12-28 Shionogi & Co., Ltd Procédé de production de dérivés et de pyridone
US8865907B2 (en) 2009-03-26 2014-10-21 Shionogi & Co., Ltd. Method of producing pyrone and pyridone derivatives
US9505783B2 (en) 2009-03-26 2016-11-29 Shionogi & Co., Ltd. Method of producing pyrone and pyridone derivatives
WO2010110409A1 (fr) 2009-03-26 2010-09-30 塩野義製薬株式会社 Procédé de production de dérivés de pyrone et de pyridone
US9260453B2 (en) 2009-03-26 2016-02-16 Shionogi & Co., Ltd. Method for producing pyrone and pyridone derivatives
KR20110132462A (ko) 2009-03-26 2011-12-07 시오노기세야쿠 가부시키가이샤 피론 및 피리돈 유도체의 제조 방법
CN102803260B (zh) * 2009-06-15 2016-02-10 盐野义制药株式会社 被取代的多环性氨基甲酰基吡啶酮衍生物
WO2010147068A1 (fr) * 2009-06-15 2010-12-23 塩野義製薬株式会社 Dérivé de carbamoylpyridone polycyclique substituée
US9815835B2 (en) 2009-06-15 2017-11-14 Shionogi & Co., Ltd. Substituted polycyclic carbamolypyridone derivative
US8927710B2 (en) 2009-06-15 2015-01-06 Shionogi & Co., Ltd. Substituted polycyclic carbamoylpyridone derivative
US9469638B2 (en) 2009-06-15 2016-10-18 Shionogi & Co., Ltd. Substituted polycyclic carbamoylpyridone derivative
CN102803260A (zh) * 2009-06-15 2012-11-28 盐野义制药株式会社 被取代的多环性氨基甲酰基吡啶酮衍生物
JPWO2010147068A1 (ja) * 2009-06-15 2012-12-06 塩野義製薬株式会社 置換された多環性カルバモイルピリドン誘導体
US10065950B2 (en) 2010-02-26 2018-09-04 Japan Tobacco Inc. Substituted thiazoles as HIV integrase inhibitors
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
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
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
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
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
US10174051B2 (en) 2010-03-23 2019-01-08 Viiv Healthcare Company Substituted pyridinones as intermediates in the preparation of polycyclic carbamoylpyridone derivatives
US8889877B2 (en) 2010-03-23 2014-11-18 Viiv Healthcare Company Processes for preparing pyridinone carboxylic acid aldehydes
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
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
US9758515B2 (en) 2010-09-24 2017-09-12 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
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
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
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
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
WO2014172188A3 (fr) * 2013-04-16 2015-10-29 Merck Sharp & Dohme Corp. Composés dérivés de 4-pyridone et leurs utilisations en tant qu'inhibiteurs de la vih intégrase
US9493479B2 (en) 2013-04-16 2016-11-15 Merck Sharp & Dohme Corp. Substituted pyrido[1,2-a]pyrazines as HIV integrase inhibitors
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
US10456395B2 (en) 2013-07-12 2019-10-29 Gilead Sciences, Inc. Substituted dipyrido[1,2-a:1′,2′-d]pyrazines for treating viral infections
US9421214B2 (en) 2013-07-12 2016-08-23 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
US10668064B2 (en) 2013-07-12 2020-06-02 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
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
EA030695B1 (ru) * 2013-09-27 2018-09-28 Мерк Шарп И Доум Корп. Замещенные производные хинолизина, которые можно использовать как ингибиторы интегразы вич
JP2017105793A (ja) * 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． Ｈｉｖインテグラーゼ阻害薬として有用な置換されたキノリジン誘導体
WO2015048363A1 (fr) * 2013-09-27 2015-04-02 Merck Sharp & Dohme Corp. Dérivés de quinolizine substitués utiles en tant qu'inhibiteurs de l'integrase du vih
US9861620B2 (en) 2013-09-27 2018-01-09 Merck Sharp & Dohme Corp. 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
US10201533B2 (en) 2013-09-27 2019-02-12 Merck Sharp & Dohme Corp. Substituted quinolizine derivatives useful as HIV integrase inhibitors
JP2016531863A (ja) * 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． Ｈｉｖインテグラーゼ阻害薬として有用な置換されたキノリジン誘導体
WO2015095258A1 (fr) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Composés hétérocycliques spirocycliques utiles en tant qu'inhibiteurs de l'intégrase du vih
US9707234B2 (en) 2013-12-20 2017-07-18 Merck Sharp & Dohme Corp. Spirocyclic hetercycle 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
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
US10975096B2 (en) 2014-06-20 2021-04-13 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
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
US10519168B2 (en) 2014-06-20 2019-12-31 Gilead Sciences, Inc. Synthesis of polycyclic-carbamoylpyridone compounds
CN107001355A (zh) * 2014-07-07 2017-08-01 萨维拉制药有限公司 吡啶并吡嗪化合物和它们在治疗、改善或预防流感中的用途
WO2016005330A1 (fr) 2014-07-07 2016-01-14 F. Hoffmann-La Roche Ag Dihydropyridopyrazine-1,8-diones et leur utilisation dans le traitement, le soulagement ou la prévention de maladies virales
WO2016005331A1 (fr) * 2014-07-07 2016-01-14 F. Hoffmann-La Roche Ag Composés pyridopyraziniques et leur utilisation dans le traitement, l'amélioration des symptômes ou la prévention de la grippe
CN107074880A (zh) * 2014-07-07 2017-08-18 萨维拉制药有限公司 二氢吡啶并吡嗪‑1,8‑二酮和它们在治疗、改善或预防病毒疾病中的用途
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
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
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
US10646486B2 (en) 2014-12-23 2020-05-12 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9795602B2 (en) 2014-12-23 2017-10-24 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
WO2016154527A1 (fr) * 2015-03-26 2016-09-29 Merck Sharp & Dohme Corp. Dérivés de quinolizine substitués par un phosphate utiles en tant qu'inhibiteurs de l'intégrase du vih
US10081647B2 (en) 2015-03-26 2018-09-25 Merck Sharp & Dohme Corp. Phosphate substituted quinolizine derivatives useful as HIV integrase inhibitors
EP3285582A4 (fr) * 2015-03-26 2018-11-21 Merck Sharp & Dohme Corp. Dérivés de quinolizine substitués par un phosphate utiles en tant qu'inhibiteurs de l'intégrase du vih
US9630978B2 (en) 2015-04-02 2017-04-25 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
KR20190049916A (ko) 2015-04-28 2019-05-09 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체 및 그의 프로드러그
EP4424314A2 (fr) 2015-04-28 2024-09-04 Shionogi & Co., Ltd Dérivé de pyridone polycyclique substitué et promédicament de celui-ci
US20180118760A1 (en) 2015-04-28 2018-05-03 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
EP3428170A1 (fr) 2015-04-28 2019-01-16 Shionogi & Co., Ltd Dérivé de pyridone polycyclique anti-grippal et promédicament de celui-ci
KR20190002742A (ko) 2015-04-28 2019-01-08 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체 및 그의 프로드러그
EP4219508A1 (fr) 2015-04-28 2023-08-02 Shionogi & Co., Ltd Dérivé de pyridone polycyclique substitué et promédicament de celui-ci
KR20170131651A (ko) 2015-04-28 2017-11-29 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체 및 그의 프로드러그
US10633397B2 (en) 2015-04-28 2020-04-28 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
US10392406B2 (en) 2015-04-28 2019-08-27 Shionogi & Co., Ltd. Substituted polycyclic pyridone derivatives and prodrugs thereof
US10233193B2 (en) 2015-05-25 2019-03-19 Merck Sharp & Dohme Corp. Fused tricyclic heterocyclic compounds useful for treating HIV infection
WO2016187788A1 (fr) * 2015-05-25 2016-12-01 Merck Sharp & Dohme Corp. Composés hétérocycliques tricycliques fusionnés utiles pour traiter l'infection au vih
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
KR20190007517A (ko) 2016-08-10 2019-01-22 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체 및 그의 프로드러그를 함유하는 의약 조성물
WO2018030463A1 (fr) 2016-08-10 2018-02-15 塩野義製薬株式会社 Dérivé de pyridone polycyclique substitué et composition pharmaceutique contenant un promédicament de celui-ci
US11306106B2 (en) 2016-08-10 2022-04-19 Shionogi & Co., Ltd. Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof
US10759814B2 (en) 2016-08-10 2020-09-01 Shionogi & Co., Ltd. Pharmaceutical compositions containing substituted polycyclic pyridone derivatives and prodrug thereof
KR20190018469A (ko) 2016-08-10 2019-02-22 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체 및 그의 프로드러그를 함유하는 의약 조성물
EP4458348A2 (fr) 2016-08-10 2024-11-06 Shionogi & Co., Ltd Compositions pharmaceutiques contenant des dérivés de pyridone polycycliques substitués et promédicament de ceux-ci
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 (zh) * 2020-07-03 2022-01-04 广州南鑫药业有限公司 一种吡嗪二酮衍生物及其用途
CN114835702A (zh) * 2021-01-30 2022-08-02 广州南鑫药业有限公司 一种吡嗪二酮衍生物及其用途

Also Published As

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

Similar Documents

Publication Publication Date Title
WO2006066414A1 (fr) Hydroxydihydropyridopy razine-1,8-diones et procedes d’inhibition de l’integrase du vih
US9896459B2 (en) Azaindoles as respiratory syncytial virus antiviral agents
US20050176767A1 (en) Pyridine carboxamide and methods for inhibiting HIV integrase
KR101700267B1 (ko) 화합물
EP2651933B1 (fr) Azabenzimidazoles en tant qu'agents antiviraux contre le virus respiratoire syncytial
US10548910B2 (en) Amido-substituted pyridotriazine derivatives useful as HIV integrase inhibitors
WO2020018975A1 (fr) Composés de sulfonimidamide en tant qu'inhibiteurs de l'activité de l'interleukine 1
EP3352781B1 (fr) Inhibiteurs nucléosidiques de la transcriptase inverse substitués en position 4' et préparations associées
KR102132574B1 (ko) 트라이사이클릭 자이라제 억제제
US9493479B2 (en) Substituted pyrido[1,2-a]pyrazines as HIV integrase inhibitors
ES2693152T3 (es) Compuesto de pirimido-diazepinona
US20120022045A1 (en) Bridged compounds as hiv integrase inhibitors
US20150218164A1 (en) Substituted naphthyridinedione derivatives as hiv integrase inhibitors
EP4450503A1 (fr) Composés hétérocycliques aromatiques, leur procédé de préparation et leurs utilisations
US20120220571A1 (en) Hiv integrase inhibitors
EP1786816A1 (fr) Composes de spirohydantoine et procedes de modulation de l'activite des recepteurs de chimiokine
HK1190711A (en) Chemical compounds as synthetic intermediates

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