WO2006116764A1 - Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity - Google Patents

Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity Download PDF

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Publication number
WO2006116764A1
WO2006116764A1 PCT/US2006/016604 US2006016604W WO2006116764A1 WO 2006116764 A1 WO2006116764 A1 WO 2006116764A1 US 2006016604 W US2006016604 W US 2006016604W WO 2006116764 A1 WO2006116764 A1 WO 2006116764A1
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Prior art keywords
optionally substituted
hydroxy
methyl
dioxo
compound
Prior art date
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PCT/US2006/016604
Other languages
French (fr)
Inventor
Brian Alvin Johns
Takashi Kawasuji
Teruhiko Taishi
Yoshiyuki Taoda
Original Assignee
Smithkline Beecham Corporation
Shionogi & Co., Ltd.
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Application filed by Smithkline Beecham Corporation, Shionogi & Co., Ltd. filed Critical Smithkline Beecham Corporation
Priority to SI200631703T priority Critical patent/SI1874117T1/en
Priority to DK06758843.4T priority patent/DK1874117T3/en
Priority to AU2006239177A priority patent/AU2006239177B8/en
Priority to KR1020157036007A priority patent/KR101848819B1/en
Priority to US11/919,386 priority patent/US8129385B2/en
Priority to EP06758843.4A priority patent/EP1874117B8/en
Priority to KR1020077027734A priority patent/KR101363875B1/en
Priority to ES06758843.4T priority patent/ES2437268T3/en
Priority to EP18166621.5A priority patent/EP3372281B1/en
Priority to EA200702080A priority patent/EA014162B1/en
Priority to KR1020137028203A priority patent/KR101504998B1/en
Priority to CA2606282A priority patent/CA2606282C/en
Priority to PL17195280T priority patent/PL3284520T3/en
Priority to KR1020147017235A priority patent/KR101580310B1/en
Priority to EP17156762.1A priority patent/EP3187225B1/en
Priority to PL06758843T priority patent/PL1874117T3/en
Priority to EP16154531.4A priority patent/EP3045206B2/en
Priority to JP2008509227A priority patent/JP4295353B2/en
Priority to MX2007013351A priority patent/MX302718B/en
Priority to NZ562339A priority patent/NZ562339A/en
Priority to CN200680022891.4A priority patent/CN101212903B/en
Priority to PL18166621T priority patent/PL3372281T3/en
Priority to EP17195280.7A priority patent/EP3284520B1/en
Priority to BRPI0610030A priority patent/BRPI0610030B8/en
Publication of WO2006116764A1 publication Critical patent/WO2006116764A1/en
Priority to NO20075165A priority patent/NO339525B1/en
Priority to IL186555A priority patent/IL186555A/en
Priority to HK08100942.1A priority patent/HK1107227A1/en
Priority to IL215788A priority patent/IL215788A0/en
Priority to US13/352,686 priority patent/US8410103B2/en
Priority to US13/763,174 priority patent/US8778943B2/en
Priority to IL225207A priority patent/IL225207A/en
Priority to IL225206A priority patent/IL225206A/en
Priority to US14/211,364 priority patent/US9051337B2/en
Priority to LU92446C priority patent/LU92446I2/en
Priority to FR14C0041C priority patent/FR14C0041I2/en
Priority to CY2014024C priority patent/CY2014024I2/en
Priority to NL300676C priority patent/NL300676I2/nl
Priority to HUS1400039C priority patent/HUS1400039I1/en
Priority to US14/700,679 priority patent/US9273065B2/en
Priority to US15/001,336 priority patent/US20160137666A1/en
Priority to US15/086,616 priority patent/US20160207939A1/en
Priority to NO20161315A priority patent/NO340111B1/en
Priority to US15/290,094 priority patent/US20170029438A1/en
Priority to US15/427,184 priority patent/US20170145033A1/en
Priority to NO2017010C priority patent/NO2017010I1/en
Priority to US15/482,896 priority patent/US20170209454A1/en
Priority to US15/498,684 priority patent/US20170224695A1/en
Priority to US15/498,667 priority patent/US20170224694A1/en
Priority to US15/597,343 priority patent/US20170253616A1/en
Priority to US15/598,655 priority patent/US20170260203A1/en
Priority to US15/598,671 priority patent/US20170267693A1/en
Priority to US15/697,847 priority patent/US20170369509A1/en
Priority to US16/244,441 priority patent/US20190152990A1/en
Priority to US16/400,373 priority patent/US10927129B2/en
Priority to CY20191100891T priority patent/CY1122052T1/en
Priority to US16/924,390 priority patent/US11267823B2/en
Priority to NO2021018C priority patent/NO2021018I1/en
Priority to CY20211100866T priority patent/CY1124601T1/en
Priority to US17/586,006 priority patent/US20220213121A1/en

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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to novel compounds possessing an antiviral activity, in detail polycyclic carbamoylpyridone derivatives possessing an inhibitory activity against HIV integrase and a pharmaceutical composition containing the same, especially an anti-HIV agent.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • the therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses.
  • AZT reverse transcriptase inhibitors
  • Indinavir protease inhibitors
  • Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent, however agents having the same mechanism of action often exhibit cross-resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.
  • an HIV integrase inhibitor has been focused on as an anti-HIV agent having a novel mechanism of action (Ref: Patent Documents 1 and 2 )
  • an anti-HIV agent having such a mechanism of action known are carbamoyl-substituted hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and carbamoyl-substituted hydroxypyrrolidione derivative (Ref: Patent Document 5).
  • Patent Document 6 a patent application concerning carbamoyl-substituted hydroxypyridone derivative has been filed (Ref: Patent Document 6, Example 8) .
  • Patent Document 10 Other HIV integrase inhibitors include N-containing condensed cyclic compounds (Ref: Patent Document 10).
  • Patent Document 1 WO03/0166275
  • Patent Document 2 WO2004/024693
  • Patent Document 3 WO03/035076
  • Patent Document 4 WO03/035076
  • Patent Document 5 WO2004/004657
  • Patent Document 6 JP Patent Application 2003-32772
  • Patent Document 7 JP Patent Publication 1990- 108668
  • Patent Document 8 JP Patent Publication 1990-108683
  • Patent Document 9 JP Patent Publication 1990-96506
  • Patent Document 10 WO2005/016927
  • the present inventors have intensively studied to find that a novel polycyclic carbamoylpyridone derivative possesses a potent HIV integrase inhibitory activity
  • a compound of the present invention and a pharmaceutical composition containing the same are useful as an antiviral agent, an antirotroviral agent, an anti-HIV agent, an anti-HTLV- 1 (Human T cell leukemia virus type 1) agent, an anti-FIV (Feline immunodeficiency virus) agent or an anti-SIV (Simian immunodeficiency virus) agent, especially an anti-HIV agent or anti-AIDS agent, to accomplish the present invention shown below.
  • Z i is NR 4 ;
  • R 4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, S, SO, SO 2
  • Z 2 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from O, S, SO, SO 2 , NR 5 (R 5 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic groxip, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy or optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl
  • R 1 is hydrogen or lower alkyl
  • X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom;
  • R 2 is optionally substituted aryl
  • R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino;
  • a ring is optionally substituted heterocycle
  • R 14 and R x are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO 2 , NR 5 (
  • R 1 is hydrogen or lower alkyl
  • X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and N H, 01- lower alkylene or lowor alkenylonc each may be intervened by the heteroatom group;
  • R 2 is optionally substituted aryl
  • R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycioalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino)
  • D ring is optionally substituted heterocycle
  • R 1 is hydrogen or lower alkyl
  • X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and N H , or lower alkylene or lower alkenylene each may bo intervened by the hetoroatom group;
  • R 2 is optionally substituted aryl
  • R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycioalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino)), its pharmaceutically acceptable salt, or solvate thereof.
  • R J is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino.
  • a ring is optionally substituted heterocycloJ
  • R H and R x are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted hetcrocyclo lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residxie or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S
  • R 1 is hydrogen or lower alkyl
  • X is a single bond, a heteroatom group selected from O, S, SO, SO_ and N H, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group ;
  • R 2 is optionally substituted aryL'
  • R 3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino), its pharmaceutically acceptable salt, or solvate thereof
  • a ring is an optionally substituted and optionally condensed 5- to 7- membered heterocycle containing 1 to 2 hetero atom(s); the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof;
  • R 14 and R. x are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic grovip, optionally substituted heterocycle lower alkyl, optionally substituted heterocyclooxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO 2 ,
  • R u is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted hetorocyclcoxy or optionally substituted amino), its pharmaceutically acceptable salt, or
  • R 1 is hydrogen or lower alkyli
  • R is independently selected from halogen and Substitucnt group SV,
  • n is an integer of 0 to 3, its pharmaceutically acceptable salt, or solvate thereof.
  • R 20 to R 40 are each independently a group selected from Substituent group S2, or any two groups of R a ⁇ Lo R 40 , which bonds to tho same carbon atom, Laken together with the carbon atom, may form an optionally substituted carbocyle or optionally substituted heterocycle, or each combination of (R 20 and R 22 ), (R 23 and R 2 O, (R M and R 2 O, (R" and R 2 O, (R»° and R 1J 0, (R « 2 and RJ'O, (R 35 and R ⁇ ), (R" and R ⁇ ), and (R' 3S andR 40 ), Laken together with the neighboring atom, may form an optionally substittited carbocyle or optionally substituted heterocycle.
  • Substituent group S2 hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkcnyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substittited cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted
  • a compoxmd according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1)l Z NR 26 , and R 2S and R 2 ⁇ taken together with the neighboring atom may form an optionally substituted 5- to 7-
  • a compotmd according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3); Z NR 40 , and R ; ' 9 and R 40 taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle.
  • D ring is optionally substituted hetorocycleJ
  • R 1 is hydrogen or lower alkyl
  • X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
  • R 2 is optionally substituted aryli
  • R 15 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkonyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyclooxy or optionally substituted amino), pharmaceutically acceptable salt, or solvate thereof (31)
  • acceptable salt is a sodium salt.
  • a pharmaceutical composition comprising a compound according to any one of the above (1) Lo (33), or a pharmaceutically acceptable salt, or solvate thereof.
  • R f is one or two halogonj
  • R/- is C 1-8 alkyl, Ce- i ⁇ arylC 1-8 alkyl, Cc- ⁇ aryl, or alkoxy
  • P 1 is C 6-14 arylC 1-8 alkyl
  • R ⁇ is C 1-8 alkyl, CrM.iarylC 1-8 alkyl, C ⁇ -M&ryl, or alkoxyJ to form a compound of formula (I-20a).
  • R D is one or two halogen;
  • R ⁇ is C 1-8 alkyl, C ⁇ -i-jarylC 1-8 alkyl, Co-uaryl, or alkoxy; and
  • P 1 is Cfi-t-iarylGi-aalkyL'
  • R D is one or two halogen; H 50 is C 1-8 alkyl; and P 1 is CB-i-iarylC 1-8 alkyL" with a compound of the formula
  • R u is one or two halogen; and P 1 is C ⁇ -i-jarylC 1-8 alkyl;
  • R 0 is one or two halogen; and P 1 is CG narylC 1-8 alkyl; comprising condensing a compound of the formula
  • R 0 is one or two halogen;
  • R SI) is C 1-8 alkylJ and P 1 is Ce-uarylC 1-8 alkyl; with a compound of the formula
  • E- 0 is one or two halogeni and P 1 is G ⁇ -i-iarylC 1-8 alkylJ comprising condensing" a compound of the formula
  • R 0 is one or two halogen; and P 1 is CtM-iarylC 1-8 alkyl; comprising condensing a compound of the formula
  • R D is one or two halogen; R r >° is C 1-8 alkyl.” and P 1 is CiM-iarylCi ⁇ alkyl; with a compound of the formula
  • R 0 is one or two halogen. and P 1 is Cc-uarylC 1-8 alkyl;
  • R° is one or two halogen; and P 1 is C ⁇ -HarylCi-salkyl; comprising condensing a compound of the formula
  • R° is one or two halogen
  • R G0 is C 1-8 alkyL' with a compound of the formula to form a compound of formula (I-23b)
  • R° is one or two halogen;
  • R z is Ci- ⁇ alkyl ⁇
  • R" 1 is hydrogen, Ca- ⁇ cycloalkyl, , heterocycle, or C 1-8 alkyl optionally substituted with hydroxy, Ca-ficycloalkyl, alkoxy, heterocycle, heteroaryl, Co- ⁇ . ⁇ aryl, or amino, wherein said amino may be optionally substituted with — C(O)C 1-8 alkyl or C 1-8 alkyl; and
  • P 1 is Co-uarylC 1-8 alkyL'
  • R Q is one or two halogen * ' and R 00 is C i- ⁇ alkyl; and P 1 is C ⁇ - uarylGi-salkyK with a compoimd of the formula
  • R'' is C 1-8 alkyll
  • R" 1 is hydrogen, C;w>cycloalkyl, , heterocycle, or C i- ⁇ alkyl optionally substituted with hydroxy, C 3-6 cycloalkyl, alkoxy, heterocycle, heteroaryl, C 6-14 aryl, or amino, wherein said amino may be optionally substituted with -C(O)C 1-8 alkyl or d-ealkyl; to form a compound of the formula (I-24a).
  • R 0 is one or two halogen;
  • R ⁇ is Oi-ealkyl;
  • E"- 1 is hydrogen, Cj-ocycloalkyl, , hotorocycle, or Gi- ⁇ alkyl optionally substituted with hydroxy, Ca ccycloalkyl, alkoxy, heterocycle, heteroaryl, CG i-iaryl, or amino, wherein said amino may be optionally substituted with -C(O)C 1-8 alkyl or C 1-8 alkyl; and P 1 is C ⁇ MarylC 1-8 alkyl;
  • R e is one or two halogen;
  • R 50 is C 1-8 alkylJ and P 1 is Cos- uaryld- ⁇ alkyl; with a compound of the formula
  • R/ is C 1-8 alkylJ and II' 1 is hydrogen, Cwjcycloalkyl, , hetorocycle, or C 1-8 alkyl optionally substituted with hydroxy, Ca-ecycloalkyl, alkoxy, hetorocycle, heteroaryl, Ce-waryl, or amino, wherein said amino may be optionally substituted with -C(O)C 1-8 alkyl or C 1-8 alkyl;
  • R u is one or two halogen;
  • R ⁇ l is hydrogen, C 3-6 cycloalkyl, , heterocycle, or Ci-salkyl optionally substituted with hydroxy, Cu-Gcycloalkyl, alkoxy, heterocycle, heteroaryl, C 6-14 aryl, or amino, wherein said amino may be optionally substituted with -C(O)Cb»alkyl or C 1-8 alkyli and P 1 is is Co-MarylC 1-8 alkyl;
  • .R 0 is one or two halogen; and R B0 is C 1-8 alkyl; and P 1 is Co-MarylCi-salkyl; with a racemic compound of the formula
  • R zl is hydrogen, Cu-ocycloalkyl, , hefcerocycle, or C 1-8 alkyl optionally substituted with hydroxy, Cn-ecycloalkyl, alkoxy, heterocycle, heteroaryl, C ⁇ -Maryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci-»alkyl or C 1-8 alkyl;
  • R 0 is one or two halogen;
  • R' / ⁇ is hydrogen, Ca-Gcycloalkyl, , heterocycle, or C 1-8 alkyl optionally substituted with hydroxy, Ca-ocycloalkyl, alkoxy, heterocycle, heteroaryl, Cc-waryl, or amino, wherein said amino may be optionally substituted with -C(O)C ⁇ - «alkyl or Gi- ⁇ alkyli and P 1 is Cc-i.iarylCi ⁇ alkyll comprising condensing a compound of the formula
  • R° is one or two halogen;
  • R r '° is C 1-8 alkyll and
  • P 1 is C ⁇ -MarylC 1-8 alkyl; with a racemic compound of the formula
  • R ⁇ l is hydrogen, Cu-ccycloalkyl, , heterocycle, or C 1-8 alkyl optionally substituted with hydroxy, Cs-rscycloalkyl, alkoxy, heterocycle, heteroaryl, Ce-iaaryl, or amino, wherein said amino may be optionally substituted with -C(O)C l-salkyl or C 1-8 alkyl;
  • R 0 is halogen
  • P 1 is CcH-iarylC 1-8 alkyl; comprising condensing a compound of the formula
  • the present invention further provides a pharmacetitical composition containing any of the compounds shown above, a pharmaceutically acceptable salt or a solvate thereof, especially an antrHIV agent, [Effect of the Invention] [0005]
  • the present invention compounds possess an integrasc inhibitory activity and/or a coil-growth inhibitory activity against virus, especially HIV. Accordingly, they are useful for the prevention or treatment of various diseases mediated by integrase or virus infection diseases (e g., AIDS).
  • the present invention further provides a process for preparing a diastereomer, a mixture thereof, or racemate. [Preferred Embodiment of the [nventionj [0006]
  • “Lower alkenylene” moans a straight or branched C2 to C6 alkenylene, which consists of the above “Lower alkylene” having one or more double bonds, such as vinylene, propylene, or butenylene, prefeiably a straight C2 to C3 alkenylene such as vinylene or propylene.
  • “Lower alkyl” means a straight or branched Cl to C10 alkyl such as methyl, ethyl, n-propyl, i-propyl, t-butyl, lsobutyl, sec-butyl, n-pentyl, and n-hexyl, and preferred is Cl to C3 alkyl, more preferred is methyl, ethyl or n-propyl, n-pentyl, isopentyl, ncopentyl, tert-pentyl, n-hexyl, isohexyl, n-hoptyl, n-octyl, lrnonyl, and n-dosyl, preferably Cl to C6 lower alkyl, more preferably Cl to C4 lower alkyl such as methyl, ethyl, n-propyl, isopropyl, lvbutyl, iaobut
  • Alkenyl moans a straight or branched C2 to C8 alkenyl, which consists of the above “alkyl” having one or more double bonds, such as vinyl, 1-propenyl, 2-propenyl, 1-butonyl, 2-butenyl, 3-butcnyl, 1,3-butadionyl, and 3-methyl-2-butenyl, preferably C2 to C6 alkenyl, and more preferably C2 to C4 alkenyl.
  • “Lower alkenyloxy” means oxy attached to the above lower alkenyl, such as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butonyloxy, 3-butonyloxy, 1,3-butadionyloxy, and 3-methyl-2-butenyloxy.
  • Cycloalkyl means C3 to C8 cyclic saturated hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl, preferably C3 to C6 cycloalkyl,
  • Cycloalkyl lower alkyl means lower alkyl substituted with the above cycloalkyl, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cyclohexylethyl, and preferably C3 to C6 cycloalkyl lower alkyl.
  • Aryl means monocyclic aromatic hydrocarbon (e.g., phenyl) and polycyclic hydrocarbon (e.g., l -naphthy1,2- naphUiyl, 1-anthryl, 2-anthryl, 9-anlhryl, 1-phenanlhryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl),
  • p referably phenyl or naphthyl (e.g., 1-napthyl, 2-naphlhyl).
  • Aryloxy means oxy attached to the above aryl, such as 1-naphthyloxy, 2-naphthyloxy, 1-anthryloxy, 2-anLhryloxy, 9-anthryloxy, 1-phenanthryloxy, 2-phenanthryloxy, 3-phenanthryloxy, 4-phenanthryloxy, and 9-phenanthi-yloxy, preferably phenyloxy or naphthyloxy (e.g., 1- napthyloxy, 2-naphthyloxy).
  • Heterocyclic group means "hetoro ⁇ ng" or "hetoroaryl".
  • Heteroring means a non-aromatic ring which has at least one of N, O and/or S in the ring and may be bonded at any substitutable position, preferably 5- to 7-mcmbered ring, such as 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrolidmyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, pipendino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperadinyl, 2-piporadinyl, 2-morpholinyl, 3-morpholinyl, morpholino,
  • Heteroaryl means monocyclic aromatic helero-type ring- or condensed aromatic hetero-type ring.
  • “Monocyclic aromatic hetero-typo ring” means a 5- to 8- membered aromatic ring, which contains 1 to 4 of O, S, P and/ or N and may bo bonded at any substitutable position.
  • Condensed aromatic hotero-type ring means a group wherein an aromatic ring containing 1 to 4 of O, S, P and/ or N is condensed with 1 to 4 of 5- to 8-membered aromatic ring(s) or the other 5- to 8-membored aromatic heteroring(s).
  • heteroroaryl examples include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imida ⁇ olyl (e.g., J/imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazole-1-yl, l ,2,4-triazolo-3-yl, l,2,4-triazole ⁇ l-yl), tetrazolyl (e,g,, 1-tetrazolyl, 2-totrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-ox
  • Hetorocycle means a cycle which can be lead to the above heterocyclic group.
  • Heterocyclic group lower alkyl or “Hcterocycle lower alkyl” means lower alkyl substituted with the above heterocyclic group
  • Heterocyclic group oxy or “Heterocycle oxy” means an oxy attached to the above heterocyclic group.
  • Heterocyclic group carbonyl or “Heterocyclccarbonyl” means a carbonyl attached to the above heterocyclic group
  • Lower alkoxy or “alkoxy” means an oxy attached to the above lower alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy.
  • Substituent group B examples include hydroxy, carboxy, halogen (F,C] 7 Br,I), halo lower alkyl (e.g., CFD,CH 2 CF 3 , CH 2 CCl 8 ), halo lower alkoxy (e.g., OCKi, OCH 3 CF 3 , OCH2CCI3), lower alkyl (e.g., methyl, chtyl, isopropyl, tert-butyl), lower alkenyl (e.g., vinyl), lower alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), lower alkenyloxy (e.g., vinyloxy, allyloxy), lower alkoxycarbonyl (e.g.,
  • CFs CH 2 CFa, CH 2 CCl 3
  • halo lower alkoxy e.g., OCF 3 , OCH2CF3, OCH2CCI3
  • lower alkyl e.g., methyl, ethyl, isopropyl, tert-butyl
  • lower alkoxy e.g., methoxy, ethoxy, propoxy, butoxy
  • optionallj' substituted amino e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino), oxo, or phosphoric acid residue.
  • substituents of "optionally substituted amino" or “optionally substituted carbamoyl” include mono- or di- lower alkyl, lower alkylcarbonyl, lower alkylsulfonyl, optionally substituted lower alkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g., carbamoylmethyl), mono- or di- lower alkylcarbamoyl lower alkyl (e.g., dimethylcarbamoylethyl), hydroxyl lower alkyl, heterocycle lower alkyl (e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonyl lower alkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or di- lower alkylamino lower alkyl (e.g., dimethylaminoethyl),
  • two substituents on the amino together with the neighboring N atom may form an N-containi ⁇ g heterocyclo which optionally contains S and/or O in the ring (preferably 5- to 7- membered ring or saturated ring) and is optionally substituted with oxo or hydroxy.
  • the optional S atom in the ring may be substituted with oxo.
  • the N-containing heterocycle is preferably a 5- or 6-membcred ring such as piperadinyl, piperidino, morpholino, pyrrolidino, 2-oxopiperidino, 2-oxopyrrolidino, 4-hydroxymorpholino.
  • Phosphoric acid residue moans a group shown of the formula ⁇ -PO(OH)2.
  • Optionally substituted phosphoric acid residtie means a phosphoric acid residue wherein the OH part and/or a hydrogen of the OH is optionally substituted with a phosphoric acid residue, preferably shown by the formula ⁇
  • RA and R each is independently OR c or NR 15 R 13 (wherein R c , R 15 and R 1 ' are each independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally sxibstituted aryl, optionally subst.txitcd heterocyclic g ⁇ oup, or JLl 13 and R R taken together with the neighboring N atom may form an optionally substituted heterocyclc (preferably 5- to 6- membcred ring)) or R ⁇ and R 13 taken together with the neighboring P atom may form an optionally substituted heterocyclc (preferably 5- ( o 6- memberod ring)),
  • R ⁇ and R B are bothOR 0 , or one of them is ORC and the other is NR 0 R 1 '.
  • R c , R n and R ⁇ each is preferably, independently, lower alkyl (e.g., methyl, ethyl).
  • the optionally substituted hetorocycle formed by R ⁇ and R B taken together with the neighboring P atom may be the following structure '
  • Hydroxy substituted with optionally substituted phosphoric acid residue is preferably hydroxy substituted with a phosphoric acid residue substituted with di lower alkyls, and more preferably a group of the formula-
  • Amino substituted with optionally substituted phosphoric acid residue is preferably amino substituted with a phosphoric acid residue substituted with di lower alky Is, and more preferably a group of the formula:
  • R 1 is hydrogen or lower alkyl, preferably hydrogen.
  • X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH (hereafter also referred to as "M"), or lower alkylene or lower alkcnylene each may be intervened by the heteroatom,
  • M a heteroatom group selected from O, S, SO, SO 2 and NH
  • lower alkylene or lower alkcnylene each may be intervened by the heteroatom
  • the term of "intervened by” means the following cases: 1) The heteroatom group is present between carbon atoms which constitutes the alkylene or alkcnylene.
  • the heteroatom group is attached to the N atom of the carbamoyl group neighboring to X.
  • the heteroatom group (M) may be the same or different, and one or more atoms. Examples of that lower alkylene is intervened by a heteroatom group include -M-CH 2 -, -CH 2 -M-CH 3 -, -CH 2 -M-, and -CH 2 -M-M-CH 2 -.
  • X is preferably a spacer consisting 1 to 3 joined atoms, X is more preferably lower alkylene or lower alkonylene each may be intervened by a heteroatom group, or O, X is most preferably Cl to C3 alkylene, C2 to C3 alkenylene, or O. Especially preferred is methylene or O.
  • R 2 is optionally substituted aryl, preferably phenyl.
  • a substituent on the aryl is the same or different, J to 3, preferably 1 to 2 substitucnt(s), including preferably halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, and lower alkylcarbamoyl, and Substituent group SlO optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substitutedphosphoric acid residue, hydroxyl substituted with optionally substitutedphosphoric acid residue, amino substituted with optionally substitutedphosphoric acid residue, lower alkyl substituted with optionally substitutodphosphoric acid residue (said lower alkyl may be intervened with a hetero atom group(s) selected from O, S, SO, SO 2 , NR ⁇
  • a substituent on the aryl is preferably at the 4-position
  • R 2 is more preferably phenyl or phenyl substituted with at least halogen, and most preferably 4-halogenophenyl (e.g., 4-F-phenyl),
  • R 2 is preforably phenyl optionally substituted with 1 to 3 R(s) mentioned below.
  • R each is independently a group selected from halogen and Substituent group S l.
  • n is an integer of 0 to 3, preferably 0 or 1 to 2.
  • R is preferably halogen.
  • R is more preferably the same or different group selected from halogen, lower alkyl, lower alkoxy, lower alkoxylower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylsulfonylamino, carbamoyl, and lower alkylcarbamoyl. More preferably, R is two halogens, or halogen and another group. R preferably locates at the 4-position and optional another position of the benzene ring-.
  • R' 5 can be a various substituent which does not bring a negative effect to the pharmacological activity, including hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy, and optionally substituted amino.
  • substituent of "optionally substituted” include halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl, heterocyclic group, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl, halogenated lower alkoxy, and preferably halogen, hydroxy, amino, lower alkylamino, lower alkyl, and lower alkoxy.
  • R J is more preferably hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino, and most preferably hydrogen or lower alkyl (e.g., methyl), esp. hydrogen.
  • Z 3 shows C, GH, optionally substituted lower alkylene, lower alkenylene etc , and Z 2 and R 4 of Z 1 taken together form a ring, whereby compound (I) shows a tricyclic compound (l-1) or (I- 11) shown below, or its derivative, tetracyclic compound,
  • a ring is optionally substituted hotorocycle containing at least an N atom
  • the hotorocyclo is a 5- to 7-membered ring which contains preferably ⁇ to 3, more preferably 2 to 3 atoms of O, S and/or N.
  • the heterocyclo is preferably selected from the above heterocycle,
  • the arc optionally contains 1 to 2 heteroatom(s) at any possible position.
  • One of preferable embodiments of A ring is an optionally substituted ring shown below.
  • a ring is preferably a ring of (a), (b), or (c).
  • Z is preferably O or Nil 1 ".
  • examples of R 19 include l)hydrogen, 2)optionally substituted lower alkyl (the substituent is e.g., amino optionally substituted with mono- or di- lower alkyli cycloalkyl, hydroxy; optionally substituted heterocyclic group (preferably 5- to 7-membered ring, e.g., furyl, thionyl, thiazolyl, pyridil, morpholino, imidazole; examples of the substituont include lower alkyl, halogen); optionally substituted heterocyclecarbonyl (the heterocyclo is preferably 5- to 7-membcred ring, e.g., l ⁇ iorpholinocarbonyl); optionally substituted phenyl (the substituent is e.g., lower alkyl, amino, lower alkylamino, hydroxy, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylthio, lower
  • the other substituent; on A ring may be selected from R lr > to R l fl or Substituent group S2, preferably lower alkyl.
  • Substitucnts on A ring may form a condensed ring or a spiro ring as mentioned below, whereby compoxuid (1) includes a tetracyclic compound.
  • a ring is more preferably any of the following rings:
  • R 20 to R 40 are each independently a group selected from Substituent group S2, or any two groups of R 20 to R'' ", which bonds to the same carbon atom, taken together with the carbon atom, may form a spiro ring, i.e., an optionally substituted carbocyle or optionally substituted heterocycle, or each combination of (R 20 and R 22 ), (R M and R 2 O, (R 2 ⁇ and R ⁇ ), (R" and R3 ⁇ ), (Rsci and R ⁇ ), (R" and R ; «), (R- 30 and R ⁇ ), (R 37 and R. 38 ), and (R i3fl andR ⁇ 10 ), taken together with the neighboring atom, may form an optionally substituted carbocyle or optionally substituted heterocycle,
  • Substitution group S2 hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclccarbonyl, optionally substituted heterocycle lower alkylcarbony
  • R-" Lo R 40 each is preferably hydrogen, optionally substituted lower alkyl (examples of the substituent: Oil, lower alkoxy, cycloalkyl, lower alkylthio, lower alkylsulfonyl, heterocyclic group, aryl, optionally substituted amino (examples of the substituent: lower alkyl, acyl)), cycloalkyl, optionally substituted aryl (examples of the substituont: OH, lower alkyl), and optionally substituited heterocyclic group,
  • R*o to R 2fi , R" to R s0 , and R ⁇ to R ⁇ each is preferably hydrogen, C1-C8 alkyl, C6-C1 ⁇ 1 aryl C1-C8 alkyl, C6-C14 aryl, or alkoxy.
  • R' iG , R 33 , and R 40 each is preferably hydrogen, C3-6 cycloalkyl, heterocycle, or C1 -8 alkyl optionally substituted with hydroxy, C3-6 cycloalkyl, alkoxy, heterocycle, heteroaryl, C6-14 aryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8 alkyl or C1-8 alkyl.
  • a ring is A- I
  • Z is NR 26 ' and R ⁇ e and R ⁇ taken together form hetorocycle, and the others are hydrogens; 2) Z is O or NR 36 , (R 20 and R 22 ) or (R iA and R 2 ' 1 ) taken together form cycloalkyl which is substituted with phenyl, the others are hydrogens or optionally substituted lower alkyl.
  • a ring is A-2, preferred is that l) Z is O, R 2 ' 1 or R 28 is lower alkyl, and the others are hydrogens; 2) Z is NR ' * 1 and R A0 and R 31 taken together form heterocycle and the others are hydrogens, or R 21 and R 29 taken together form cycloalkyl and the others are hydrogens I 3) Z is O, R 27 and R ao taken together form cycloalkyl which may bo condensed with phenyl, and the others are hydrogens
  • R 1 ' 1 and R ⁇ arc each independently hydrogen, optionally substitutedlower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkcnyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted hetorocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbon
  • R u and R* arc each independently, preferably, hydrogen, hydroxyl, optionally substituted lower alkyl (the substituent is preferably, e.g., amino, lower alkyl amino, hydroxy, lower alkoxy)
  • R 1 ' 1 and R x arc preferably hydrogens.
  • a broken line in the compound (J- I) represents the presence or absence of a bond, provided thai, when the broken line represents the presence of a bond, R x is not present,
  • the compound (I) includes the following compounds,
  • V ring means the same heterocycle as A ring-, preferably 5- to 7-memberod ring, and the substituents on F ring are the same as those for A ring.
  • the other symbols are as defined above. 04
  • each symbol is as defined abovei Z is O or NR 10 ;
  • R 15 to R 19 aro each independently hydrogen or a group selected from the above Substiluont group S2, or each combination of (U ⁇ and R "O, (R” and R 1 S), (R ie an d Ri ⁇ ), and (R 1 S and R 1 ") taken together with the neighboring atom(s), may form an optionally substituted carbocycle (preferably 5- to 6 ⁇ nembered ring) or an optionally substituted hetorocyle (preferably 5- to 6-membered ring ); or each combination of (R 15 and R ] (i ) and (R 17 and R 18 ) taken together may fom oxo)
  • Compound (I -3) is preferably as follows.
  • R 1 is hydrogen; R 3 is hydrogen; m is .1 or Zl R 1 ' 1 is hydrogen.
  • R is each independently halogen, halogenated lower alkyl, lower alkoxy, halogcnated lower alkoxy, lower alkoxy lower alkyl, hydroxy lower alkyl, optionally substituted amino lower alkyl (the substituont is mono- or di- lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), optionally substituted carbamoyl (the s ⁇ bstitucnt is mono- or di- lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue or sulfonylamino optionally substituted with lower alkyl l
  • R 1 is hydrogen; R' !
  • R 1 ' 1 is hydrogen, hydroxyl or lower alkyl optionally substituted with mono- or di- lower alkylamino
  • Z is O or NR 13
  • R 10 is hydrogen or lower alkyl, lower alkoxy lower alkyl, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue).
  • (3)R is each independently, -F, -CF 3 , -OMc, -OCF 3 , -CH 2 OMe, -CH 2 OH, - CH 2 N(Me) 2 , -CONHMe, -CON(Me) 2 , -CHsPO(OEt) 2 , -PO(Om) 2 , -NHSO 2 Me, or -NMoSO 2 Me
  • IR 1 is hydrogen;
  • R 3 is hydrogen;
  • m is 1 or 2;
  • R H is hydrogen, hydroxyl or -CH 2 N(Me) 2 ;
  • Z is O or NR's (Rio is hydrogen or -CH(Me) 2 , -(CHu) 2 OMe, -(CHu) 2 PO(OEt) 8 ).
  • R 15 and Rio arc hydrogens are hydrogens or taken together with the neighboring- atom form a 3- to 7- ⁇ nembored carfaocyle; and/or Z is O or NH, This case preferably also satisfys the above (2) or (3).
  • D ring means the same hetox-ocycle as A ring, preferably 5- to 7-mcmbered ring, and the substituonts on D ring are the same as those for A ring.
  • the other symbols are as defined above,
  • the structure of compound (T) has at least the following characteristics,
  • a substituted carbamoyl group (-CONR 1 XR 2 ) is attached to the position neighboring to the oxo group on the condensed hereocyclc.
  • the above structure contribxites to a remarkably potent integrase inhibitory activity and/or cell-growth inhibitory activity against virus including HlV.
  • the structures of the other parts such as Z 1 , Z-, and R 3 oach may be of variety, being optionally substituted or optionally condensed, and its condensed ring is also optionally substituted.
  • the present invention provides a pharmaceutically acceptable salt or a solvate of compound (I), All theoretically possible tautomer, geometrical isomer, optically active compound, and racomate thereof are within the scope of the invention,
  • salts of a compound of the present invention include, as basic salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts such as N, N-diben&ylethylonediamine salts; heterocyclic aromatic amine salts such as pyridin salts, picolino salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzylt ⁇ butylammonium salts, methyltrio
  • Acid salts include, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararic acid salts, malatcs, citrates salts, ascorbates, formic acid; sulfonates such as methanesulfonatcs, isethionates, benzenesulfonates, or P-toluenesulfonatesi and acidic amino acid salts such as aspartates or glutamates, Solvates of a compound of the present invention include alcholates and hydrates.
  • L 1 is a leaving group (e g,; halogen); P 1 and P 2 are a hydroxy protecting group; P a is a carboxy protecting group (e,g, : lower alkyl); R a and R b are hydrogen or a substituent on an amino group)
  • Examples of a hydroxy protecting group include acyl (e.g.: acetyl, pivaloyl, benzoyl), aralkyl (e.g.: benzyl), lower alkyl (e.g. : methyl), alkoxyalkyl (e.g. : methoxymethyl, methoxy ethyl), lower alkylsulfonyl (e.g.: methanesulfonyl), arylsulfonyl (e.g. : benzenesulfonyl, tolvicnesulfonyl), alkoxycarbonyl (e.g. : methoxycarbonyl) and the like,
  • acyl e.g.: acetyl, pivaloyl, benzoyl
  • aralkyl e.g.: benzyl
  • lower alkyl e.g. : methyl
  • alkoxyalkyl e.g. : me
  • the present step is a reaction for condensing a compound (II) and a compound (III) to synthesize a compound (IV).
  • the reaction may be performed according to the condition for a reaction of amidating carboxylic acid which is generally performed.
  • a compound (II) may be reacted as it is, or may be reacted after converted into corresponding acid chloride or active ester.
  • the reaction is performed in a suitable solvent in the presence of a condensing agent,
  • dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like may be used, If necessary, a reagent such as 1-hydroxybenzotriazole and N-hydroxysuccinimide, or a base such as triethylamine, N-methylmorpholine, and pyridine may be added.
  • a reaction temperature is 0 to 150°C, preferably room temperature to 70°C.
  • a noirprotonic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
  • a reaction time is a few minutes to a few tens hours, preferably 9 to J 7 hours.
  • the present step is a reaction for introducing a protected hydroxy group (OP 1 ) into a compound (IV) to produce a compound (V),
  • the reaction may bo performed according to the condition for an alkoxylatmg reaction which is generally performed.
  • a compound (V) in which P 1 is methyl can be synthesized by reacting a compound (IV) with metal alkoxide (e.g.: sodium methoxidc).
  • metal alkoxide e.g.: sodium methoxidc
  • a reaction temperature is 0 to 200°C, preferably 80 to 120°C.
  • reaction solvent alcohol, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 5 to 10 hours, (Third step)
  • the present stop is a reaction for protecting a hydroxy groiip of a compound (V) to produce a compound (Vl).
  • the reaction may be performed according Lo the condition for a reaction of protecting a hydroxy group which is generally performed.
  • a compound (VI) in which P 2 is alkyl can be synthesized.
  • a reaction temperature is 0 to 100°C, preferably 0°C to room temperature.
  • reaction solvent THF, toluene, dichloromethane and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably t to 3 hours.
  • the present step is a reaction of oxidizing a nitrogen atom of a compoung (Vl) to produce a compound (VII),
  • the reaction may be performed according to the condition for an oxidation reaction using an oxidizing agent which is generally performed.
  • a reaction temperature is 0 to 100°C, preferably under icccooling to room temperature
  • reaction solvent chloroform, methylene chloride, acetic acid and the like are exemplified.
  • an oxidizing agent examples include metachloroporbenzoic acid, hydrogen peroxide and the like.
  • a reaction time is a few minutes to a few tens hours, preferably 1 to 5 hoxirs.
  • the present step is a reaction for hydroxylating a methyl group of a compound (VII).
  • reaction temperature 0 to 150°C, preferably 120 to 140°C
  • this may bo hydrolyzcd (e.g.: treatment with a base (e.g. : alkali metal hydroxide)).
  • a reaction time is a few minutes to a few tens hours, preferably 0.5 to 2 hours for acetoxylation, and 0.5 to 1 hour for hydrolysis.
  • the present step is a reaction for oxidizing a hydroxy group of a compound (VIII) to synthesize a compound (IX).
  • a reaction temperature is 0 to 150°C, preferably room temperature to 70°C.
  • a reaction solvent chloroform and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 0.1 to 1 hour.
  • the present step is a reaction for oxidizing a formyl group of a compound (IX) to synthesize a compound (X).
  • a reaction temperature is 0 to _ 50°C, preferably under ice-cooling to room temperature.
  • reaction solvent an alcohol and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 0,5 Lo 3 hours.
  • the present step as a reaction for deprotecting an OP 2 part of a compound (X) to synthesize a compound (Xl),
  • the reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
  • a reaction temperature is 0 to 150°C, preferably under ice-coolmg to room temperature.
  • reaction solvent acetonitrile, methylene chloride, THF and the like arc exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours,
  • the present step is a reaction for deprotecting an OP 1 part of a compound (Xl) to synt hesize a compound (L-A),
  • the reaction may be treated preferably with a Lewis acid (e.g.: a hi mi mi m chloride),
  • a reaction temperature is 0 to 150°C, preferably 10 to 50°C.
  • reaction solvent methylene chloride, THF and the like are exemplified.
  • a reaction time is a fow minutes to a few tens hours, preferably 1 to 3 hours,
  • the present step is a reaction for deprotecting an ester part (COOP 3 ) of a compoxmd (X) to synthesize carboxylic acid (XII).
  • COOP 3 ester part
  • XII carboxylic acid
  • hydrolysis with an alkali e.g.: NaOH
  • an alkali e.g.: NaOH
  • a reaction temperature is 0 to IB0°C, preferably 10 to 50°C.
  • reaction solvent methanol, water and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably a few minutes to 2 hours,
  • Carboxylic acid (XII) can be converted into various derivatives (c,g ⁇ ; amide).
  • the present step is a reaction for reacting a compoiind (XIl) with various amines to synthesize a compound (XIlI).
  • the reaction may be performed according to the condition for a reaction of amidatmg carboxylic acid which is generally performed and, for example, the reaction may bo performed as in the first step.
  • a reaction temperature is 0 to 150°C, preferably room temperature to 70°C.
  • a noivprotonic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like arc preferable.
  • a reaction time is a few minutes to a few Lens hours, preferably a few minutes to 3 lioxirs.
  • An amide part of the resulting compound (XIIl) may be further chemically modified (e.g.: N-alkylation).
  • the present step is a reaction for cleprotecting OP 1 and OP 2 parts of a compound (XIII) to synthesize a compound (I-B).
  • the reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
  • a reaction temperature is 0 to 200°C, preferably 150 to 180 degree,
  • a reaction time is a few minutes to a few tons hours, preferably 3 to 5 minutes.
  • the present step is a reaction for doprotecting an ester part (COOP 3 ) of a compound (XI) to synthesize carboxylic acid (XIV).
  • COOP 3 ester part
  • XIV carboxylic acid
  • hydrolysis with an alkali e.g. : lithium hydroxide may be performed.
  • a reaction temperature is 0 to 150°C, preferably 10 to 50°C.
  • reaction solvent methanol, water and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably a few minutes to 3 hours.
  • the present step is a reaction for deprotecting an OP 1 part of a compound (XIV) to synthesize a compound (I-C).
  • the reaction may be treated preferably with a Lewis acid (e.g.: boron tribromide) .
  • a reaction temperature is 0 to 150°C, preferably under ice-cooling to room temperature.
  • reaction solvent c ⁇ chloromethano and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably a few mimites to 5 hours, [0014]
  • the monocyclic carbam ⁇ ylpyridone derivative obtained above is derived into a bicyclic compound by the following method.
  • R', X, R 2 , P 1 , P 3 and R 4 arc as define above, and L 2 is a leaving group such as halogen etc.
  • the present step is a reaction for reacting the compound (XI) or a compound (XD which is a tautomer thereof with an allyl compound to synthesize a compound (XV),
  • a compound (XI') can bo synthesized, for example, according to the method of Example A- I.
  • the reaction is performed preferably in the presence of a base (e.g. : cesium carbonate).
  • a base e.g. : cesium carbonate
  • a reaction temperature is 0 to T 00°C, preferably 10 to 40°C.
  • a reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours.
  • the present step is a reaction for oxidizing a compound (XV) to synthesize a compound (XVl).
  • a compound (XV) As an oxidizing agent, osmium tetraoxidc and alkali metal osmium tetraoxidc (e. ⁇ KEOSCM) are exemplified, A reaction teinpcraturwo is 0 to 100°C, preferably 10 to 40°C.
  • As a reaction solvent 1/i-dioxane, tetrahydrofuran and the like are exemplified,
  • a reaction time is a few minutes to a few tens hours, preferably 1 to 5 hours,
  • the present step is a reaction for reacting a compound (XVI) with amine (XVIl) to perform dehydration condensation to synthesize a compound (XVIII),
  • a reaction temperature is 0 to 200°C, preferably M0 to 180°C,
  • reaction solvent methylene chloride, acetonitrile and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 0.5 to 1.5 hours
  • the present step is a reaction for deprotecting a compound (XVIIl) preferably with an acid to synthesize a compound (XIX), and may be performed according to the condition for a conventional reaction of deprotecting a protected hydroxy group.
  • a reaction temperature is 0 to 200°C.
  • a reaction time is a few minutes to a few tens hours, preferably 15 minutes to 1 hour,
  • the present step is a reaction for reducing a compound (XVlIl) to synthesize a compoxind (XX).
  • a reaction tempcratuer is 0 to 100°C, preferably 10 to 30°C.
  • reaction time is a few minutes to a few tens hours, preferably 5 to 20 hours.
  • the present step is a reaction for reacting a compound (XlV) with a compound (XXI) to synthesize a compound (XXII).
  • the present reaction may be performed according to the condition for a conventional amidation reaction,
  • a reaction temperature is 0 to 100°C, preferably 0 to 50°C.
  • a reaction solvent dimethylformamide, methylene chloride, tetrahyrlrofnran and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours.
  • the present step is a reaction for reacting a compound (XXII) with an acid to perform deprotection and intramolecular ring closure, to synthesize a compound (XXlJI).
  • the present reaction may be performed according to the condition for a conventional reaction of deprotecting acetal.
  • a reaction temperature is 0 to 100°C, preferably room temperature to 80°C.
  • a reaction solvent dioxane, totrahydrofuran and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 0,5 to 1 hour.
  • hydrochloric acid As an acid, hydrochloric acid, and paratoluonesulfonic acid are exemplified,
  • the present step is a reaction for dehydrating a compound (XXIlI) to synthesize a compound (XXJV).
  • the present reaction may bo poformed according to the condition for a conventional dehydration reaction.
  • a reaction temperature is 0 to 100°C, preferably room temperature to 80°C.
  • reaction solvent acetonitrile, methylene chloride and the like are exemplified .
  • a reaction time is a few minutes to a few tens hoxirs, preferably 1 to 5 hours, 10016J (Proce ⁇ vS 3) [Chemical formula 44j
  • the present step is a reaction for reacting a compound (XVI) with amine (XXIV) to perform dehydration condensation to synthesize a compound (XXV) according to the seventeenth step or a method of synthesizing 1 a compound 17- 1.
  • a reaction catalyst an acid (e.g. ' acetic acid) is added, and a microwave reaction apparatus is used.
  • a reaction temperature is 0 to 200°C, preferably 140 to 180°C.
  • reaction solvent methylene chloride, acetonitrile and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 0,5 to 1,5 hours.
  • the present step is a reaction for deprotecting a compound (XXV) preferably with an acid to synthesize a compound (XXVI) according to the eighteenth step, and may be performed according to the condition for a conventional reaction of deprotecting a protected hydroxy group.
  • reaction tempratnre is 0 to 200°C.
  • an acid pyridine hydrochloride, trifluoroacetic acid and the like are exemplified,
  • a reaction time is a few minutes to a few tens hours, preferably 15 minutes to 1 hour.
  • the present step is a reaction for reacting a compound (XIV) with a compound (XXIV) to synthesize a compound (XXVII) according to the twentieth step,
  • the present reaction may be performed according to the condition for a conventional amidation reaction.
  • a reaction temperature is 0 to 100°C, preferably 0 to 50°C.
  • reaction solvent dimethylformamide, methylene chloride, tetrahydrofuran and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours.
  • the present step is a reaction for reacting a compound (XXVII) or a taxitomer thereof with an allyl compound to synthesize a compound (XXVIII) according to the fifteenth step.
  • a reaction is performed preferably in the presence of a base (e,g,: cesium carbonate).
  • a base e,g,: cesium carbonate
  • a reaction temperature is 0 to 100°C, preferably 10 to 40°C.
  • a reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours,
  • the present step is a reaction for oxidizing a compound (XXVIIl) to synthesize a compoxmd (XXIX) according to the sixteenth stop ,
  • osnmim tetraoxide and alkali metal osmium tetraoxide arc exemplified.
  • a reaction temperature is 0 to 100°C, preferably 30 to 40°C,
  • reaction time is a few minutes to a few tens hours, preferablky J to 5 hours.
  • the present step is a reaction for dehydration-condensing a compoxind (XXIX) to synthesize a compound (XXX) according to the seventeenth step or a method of synthesizing a compound J 7-1.
  • a reaction catalyst an acid (e.g.: acetic acid) is added, and a microwave reaction apparatus is used.
  • a reaction temperature is 0 to 200°C, preferably 140 to 180°C.
  • reaction solvent methylene chloride, acetonitrile and the like are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 0.5 to 1,5 hours,
  • the present step is a reaction for deprotecting a compoiind (XXX) preferably with an acid to synthesize a compovmd (XXXI) according to the eighteenth step, and may be peformed according to the condition for a conventional reaction of deprotecting a protected hydroxy group.
  • a reaction temperature is 0 to 200°C.
  • an acid pyridine hydrochloride, trifhioroacetic acid and the like are exemplified,
  • reaction solvent As a reaction solvent, the aforementioned acid and lrimethylsilyl iodide are exemplified.
  • a reaction time is a few minutes to a few tens hours, preferably 15 minutes to 1 hour,
  • a compound (1-3) in which Z is NR 1H can be synthesized according to the following reaction scheme, according to Process 4, [Chemical formula 46]
  • a compound (XIV- 16) is obtained by reacting a compound (XlV) with an amine reagent, according to the thirty-fifth step.
  • a compound (XlV- 17) is obtained by subjecting a compound (XIV-16) to a general acetal deprotecting reaction according to the forty-fourth step .
  • a compound (XJV-18) is obtained (D ring formation) by deprotecting a P 1 part of a compound (XTV- 14) according to the thirty-eighth step.
  • Tho present invention further provides various intermediates (I-P) shown below and a process for preparing the same, as well as a process for preparing the above mentioned compound (I) comprising the deprotection of the intermediate.
  • R e is one or two halogen
  • R z is C 1-8 alkyl, C 6-14 arylC 1-8 alkyl, C 6-14 aryl, or alkoxy
  • P 1 is C 6-14 arylC 1-8 alkyl
  • R e is one or two halogen
  • R z is C 1-8 alkyl, C 6-14 arylC 1-8 alkyl, C 6-14 aryl, or alkoxy
  • P 1 is C 6-14 arylC 1-8 alkyl
  • R e is one or two halogen; and P 1 is C 6-14 arylC 1-8 alkyl;
  • R e is one or two halogen; and P 1 is C 6-14 arylC 1-8 alkyl;
  • Re is one or two halogen; and P 1 is C 6-14 arylC 1-8 alkyl;
  • R e is one or two halogen; and P 1 is C 6-14 arylC 1-8 alkyl;
  • R e is one or two halogen; and P 1 is C 6-14 arylC 1-8 alkyl;
  • R e is one or two halogen; and P 1 is C 6-14 arylC 1-8 alkyl;
  • Ii is one or two halogen;
  • R' is Ci salkyl;
  • R' 1 is hydrogen, C3 ⁇ cycloalkyl, , hetorocycle, or C i salkyl optionally substituted with hydroxy, C j c>cycloalkyl, alkoxy, heterocycle, heteroaryl, Ct ⁇ aryl, or amino, wherein said amino may be optionally substituted with -C(O)C 1-8 alkyl or C 1-8 alkyl.
  • R 0 is one or two halogen;
  • R' is Ci salkyl,
  • R* 1 is hydrogen, Cj Gcycloalkyl, , heterocycle, or Ci salkyl optionally substituted with hydroxy, C3 t-cycloalkyl, alkoxy, heterocycle, heteroaryl, CG ⁇ aryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci ⁇ alkyl or Ci ⁇ alkyl, and
  • P 1 is Ce i iaiylCi salkyL
  • R ⁇ is one or two halogen
  • R' 1 is hydrogen, C 3 ⁇ cycloalkyl, , heterocycle, or Ci salkyl optionally substitu ted with hydroxy, C,? ⁇ cycloalkyj, alkoxy, heterocycle, heteroaryl, Cr, uaryl, or amino, wherein said amino may be op tionally substituted with -C(O)C 1-8 alkyl or C 1-8 alkylJand P 1 is Gr, ⁇ arylCi salkyl;
  • R c is one or two halogen
  • R z1 is hydrogen, C 3-6 cycloalkyl, , heterocycle, or C 1-8 alkyl optionally substituted with hydroxy, C 3-6 cycloalkyl, alk ⁇ xy, heterocycle, heteroaryl, C 6-14 aryl, or amino, wherein said amino may be optionally substituted with -C(O)C 1-8 alkyl or C 1-8 alkyl; and P 1 is C 6-14 arylC 1-8 alkyl;
  • R e is halogen
  • P 1 is C 6-14 arylC 1-8 alkyl
  • compound (I-20a), (I-20b), (I-21a), (I-21b), (I-22a), (I-22b), (I-23a), (I-23b), (I-24a), (l-24b), (I-25), (I-26), or (I-27), can be prepared by condensing a compound of the formula:
  • R e is one or two halogen; and R 50 is C 1-8 alkyl;
  • R z is C 1-8 alkyl, C 6 -14 arylC 1-8 alkyl, C 6 -14 aryl, or alkoxy; wherein R ⁇ is C 1-8 alkyl, Cn MarylC 1-8 alkyl, Co-i-iaryl, or alkoxy;
  • ⁇ / Ci ⁇ alkyl
  • K ? ⁇ 1 is hydrogen, Cg ⁇ cycloalkyl, , heterocycle, or C 1-8 alkyl optionally substituted with hydroxy, Ca Gcyoloalkyl, alkoxy, heterocyclo, heteroaryl, Cf) l ' laryl, or amino, wherein said amino may be optionally substituted with -C(O)C 1 salkyl or C 1-8 alkyl;
  • R ⁇ is Cj- ⁇ alkyl
  • JR/ 1 is hydrogen, Cj ocycloalkyl, , heterocyclo, or C 1-8 alkyl optionally substituted with hydroxy, Ca-ocycloalkyl, alkoxy, hetorocyolc, heteroaryl, Cb j-iaryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci- 8 alkyl or d- ⁇ alkyl;
  • IV is hydrogen, Cj-ccycloalkyl, , heterocycle, or C 1-8 alkyl optionally substituted with hydroxy, Ca ccycloalkyl, alkoxy, hotorocyclo, hetoroaryl, CB naryl, or amino, wherein said amino may be optionally substituted with — C(O)C 1-8 alkyl or Ci ⁇ alkyl;
  • R v ⁇ is hydrogen, C 3-6 cycloalkyl, , heterocycle, or C 1-8 alkyl optionally substituted with hydroxy, Cs ocycloalkyl, alkoxy, heterocycle, heteroaryl, Ce- ⁇ aryl, or amino, wherein said amino may bo optionally substituted with — O(O)C 1-8 alkyl or Ci salkyli
  • the condition for the above condensation is illustrated below for example,
  • the solvent include halocarbons such as dichloromethanc, dichloroethanc, and acetic acid.
  • the reaction temperature is preferably, 0 to 200 °C, more preferably, 50 to 170°C .
  • the reaction time is usually several minutes to several hours.
  • compound (T-20a), (1-20b), (1-2. a), (I-21b), (J-22a), (I-22b), (l-23a), (I-23b), ⁇ I-24a), (l-24b), (1-25), (1-26), or (1-27) can be doprotected to give each corresponding doprotected compound wherein P 1 is hydrogen, or its pharmaceutically acceptable salt, which arc encompassed within the scope of compound (I) of the present invention.
  • the present compoxmd obtained above may be further chemically modified to synthesize another compound,
  • a reactive functional group e.g. : OH, COOH, NHa
  • the group may be protected before the reaction and may be deprotectcd after the reaction, if desired.
  • the present compound is useful, for example, as a drug such as an anti-virus drug.
  • the present compound has the remarkable inhibitory action on integrase of a virtis. Therefore, the present compound can be expected to have the preventive or therapeutic effect for various diseases derived from a virus which produces at least integrase, and is grown at infection in an animal cell, and is useful as an integraso inhibiting agent for retrovirus (e.g. HlV- I, HIV-2, HTLV- I, SIV, FIV etc.), and is useful as an anti-HIV drug etc,
  • retrovirus e.g. HlV- I, HIV-2, HTLV- I, SIV, FIV etc.
  • the present compound ma ⁇ ' bo used in joint use therapy by combining an anti ⁇ IV drug having the different action methanism such as a reverse transcriptase inhibiter and/or a protease inhibiting agent, Particularly, currently, an integrase inhibiter is not marketed, and it is useful to use in joint use therapy by combining the present compound with a reverse transcriptase inhibiter and/or a protease inhibiter.
  • an anti ⁇ IV drug having the different action methanism such as a reverse transcriptase inhibiter and/or a protease inhibiting agent
  • an integrase inhibiter is not marketed, and it is useful to use in joint use therapy by combining the present compound with a reverse transcriptase inhibiter and/or a protease inhibiter.
  • inchidcs not only use as a medical mixture for anti-HIV, but also use as a joint use agent for increasing the anti-HIV activity of other anti-HIV drug such as cocktail therapy.
  • the present compound can be used in order to prevent infection with a retrovirus vector from spreading into a tissue other than an objective tissxie, iipon use of a retrovirus vector based on HIV or MLV in the field of gene therapy.
  • a retrovirus vector based on HIV or MLV in the field of gene therapy.
  • the present compound is administered in advance, extra infection can be prevented in a body.
  • the present compound can be adminitetered orally or parenterally, In the case of oral administration, the present compound can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like' an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir.
  • a solid agent such as tablets, powders, granules, capsules and the like' an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir.
  • the present compound can be used as an aqtieous or oily suspension injectable, or a nasal drop, Upon preparation of it, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsificrs, suspending agents, preservatives, stabilizers and the like may be arbitrarily used.
  • an anti-HIV-drug particularly, an oral agent is preferable.
  • a preparation of the present invention is prepared by combining (e.g. mixing) a therapeutically effective amount of the present compound with a pharmaceutically acceptable carrier or diluent.
  • a dose of the present invention is different depcniding on an administration method, an age, a weight and conditionn of a patient, and a kind of a disease and, usually, in the case of oral administraton, about 0.05mg to 3000mg, preferably about 0.lmg to 1000mg may be administered per adult a day, if necessary, by dividing the dose, In addition, in the case of parenteral administration, about 0.0lmg to 1000mg, preferably about 0.05mg to 500mg" is administered per adult a day. Examples are shown below.
  • the extract was washed with a 5% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain a mixture (I75g") of 10 and 31, the resulting mixture was dissolved in acetic acid (1050ml) and water (1050ml), and zinc (31. Ig-, 475mmol) was added, followed by- heating to reflux for 1 hour. After the reaction solution was cooled to room tempreture, a 10% aqueous potassium carbonate solution was added, followed bj' extraction with ethyl acetate.
  • the extract was washed with an aqueous saturated ammonium chloride solution, and an aqueous saturated sodrum chloride solution, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, this was washed with diethyl ether to obtain 5-benzyloxy-N- ⁇ -fluoro-benzyl) ⁇ -hydroxy- ⁇ -hydroxymethyl-nicotinic acid amide 10 (107g, 59%) as a colorless crystal.
  • reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium bicarbonate solution, a 10% aqueous citric acid solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain
  • the organic layer was washed with water, a 5% aqueous sodium hydrogen sulfite sohition and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate
  • the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-bonzyloxy-5-(4-flx ⁇ oro-benzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)- 1,4-dihydro-pyridine-2 -carboxylic acid methyl ester 16 (5.39g, 71%) as a colorless crystal.
  • NMK (CDCl 3 )S: 3.74(3H, s), 4.60(2H, d, J 5.9Hz), 4.87(2H, s), 5.27(2H, s), 6.98-7.04(21-1, m), 7.30-7.40(7H, m), 8.39(l H, s), 9.58(1H, s), 10.38(T H, s).
  • a compound 33 was synthesized using 1-aminomethylcyclopentanol hydroxyethylamme according to the method of synthesizing a compound _ 7-J .
  • a compound 33-2 was synthesized using hydroxyethylamine according to the similar method.
  • Example C-I was synthesized using a compound 33, according to the method o ⁇ synthesizing Example A- I.
  • Example C-7) 1-(2-Diethylamino-ethyl)-5-hydroxy-4,6-dioxo-2,3, 4,6,9, 9a-hexahydro- 1H- 1,3a, 8a- triaz a-cyclopentaLbJnaphthalcnc-7-carboxylic acid 4-fluoro-benzylamide melting point: 186- 187 °C
  • Example C-8) 1 -Hydroxy-2, 11-dioxo-2,5,5a,7,8,9, 10,11-octahydro-6-oxa-4a, 10a-diaza-cycloheptarb]na phihalene-3-carboxylic acid 4-fluoro-benzylamide melting point 242-244 °C
  • Example G- 15 5-Hydroxy-1-isopropyl- ⁇ j 10-dioxo-i ,2. ⁇ ,4, ⁇ ,O.Oa.10-oxtahydro-1,4a ⁇ a-triaza-anthrace ne-7-carboxylic acid-4-fluoro-benzylamide molting point: 220 °C
  • Example F-I According to the same manner as that of Example F-I , the following Example compounds F-2 to F-63 were synthesized.
  • Example F- 3 1-Cyclopropylmethyl-5-hydroxy -6,10 ⁇ 110X0- 1,2, 3, 4, 6, 9,9a, i0-octahydro-1, 4a,8a-triaza- anth.racene-7-carboxylic acid 4-fluoro-benzylamide melting- point: 182- 184 °C
  • Example F- 4 1-Cyclopentylmethyl-S-hydroxy- ⁇ , ! -dioxo- 1,2,3,4,6,9,9a, J 0-octahydro- 1,4a,8a-triaza-a nthraceno-7-carboxyhc acid 4-fluorcrbenzylamide melting point: 184-185 0 CC
  • Example F- 6 1 -(5-Chloro- 1,3-dimethyl- 1H-pyrazol-4-ylmethyl)-5-hydroxy-6, 10-dioxo-1, 2,3, d, 6,9,9a, 1 0-octahydro-1,4a,8a-
  • Example F- 7 5-Hydx'oxy-1-(S-methoxybenzyl)-6.10-dioxo- 1,2jS,4. ⁇ .S ⁇ a, J 0-octahydro- 1,4a,8a-triazaa nthraceno-7-carboxylic acid 4-fh ⁇ Obonzylamide
  • Example F- I 0) 5-Hydroxy-1-isobutyl-S.S-dimethyl-e.10-dioxo- 1,2,3,4,0,9,9a, 10-octahydro- 1,4a,8a-tria zaanthvacene-7-ca3*boxylic acid 4-fluorobonzylamide
  • Kxaraplc F- 13 1-(3-Dimethylcarbamoylpropyl)-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a, ⁇ a-triazaanthracenG-Y-carboxylic acid 4-fltiorobenzylamide
  • Example F-20 l -Cyclohexylmethyl-S-hj'droxy- ⁇ j 10-dioxo-1,2.S,4,6.Q.Oa, 10-octahydro-1,4a,8a-t ⁇ azaan lhracene-7-carboxylic acid 4-fluorobenzylarrnde melting point: 201-202°C
  • Example F-22 1-(2-Ethyl-bulyl)-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a ⁇ a-tnazaanthr acene-7-carboxyhc acid 4-fluorobenzylamide melting point: 137- 140°C
  • Example F-24 1-Hydroxy-6-methyl-2, 11-0110X0-2,53,6,7,8,9, 10,11-octahydro-5H-4a,6, 10a-triaza-cycloh epta[blnaphthalene-3-carboxylic acid 4-fhiorobenzylamide melting point: 255°C
  • Example F-27 1-Furan-2-ylmethyl-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, J 0-octahydro-1,4a. ⁇ a-tnaza-a nthraoene-7-carboxylic acid 4-fluorobenzylamide melting point: 193- 197°C
  • Example F-28 1-(4-Dimethylamino-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a, .0-octahydro-1,4a,8a- triaza-anUiracene-7-carboxylic acid 4-fluorobenzylamide melting point: 221-223 D C
  • Example F-31) 1-(2-Chloro-6-fluoro-benzyl)-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro- 1,4a,8a- triaza-anthracene-7-carboxylic acid 4-fluorobenzylamide melting- point: 213-215°C
  • Example V -33) 1- (3,5-Bis-trifluoromethyl-benzyl)-5-hydroxy-6,10-dioxo- 1,2, 3,4,6,9,9a, 10-octahydro- 1,
  • Example F-34) 1-(4-DieLhylamino-benzyl)-5-hydroxy-6, 10-dioxo-1,2,3,4,6,9,9a, 10-oclahydro-1,4a,8a-lr iaza-anthraceno-7-carboxyhc acid 4-fluorobonzylam ⁇ de melting point: 182°C
  • Example F-36 1-(3-Dimethylamino-2-methyl-propyl)-5-hydr ⁇ xy-6, 10-dioxo-1,2,3,4,6,9,9a, 10-octahydr o-1,4a,8a-(.riaza-antliracene-7-carboxylic acid 4-fh ⁇ oro-bonzylamide
  • Example F- 37 1-(3,3-Dimethyl-butyl)-5-hydroxy-6,10-dioxo-1, 2,3, 4,6,9,9a, 10-ocLahydro- J ,4a,8a-triaza
  • Example F-38 1 -Ethyl-5-hydx*oxy-6, 10-dioxo-1,2,3,4,6,9,9a, 10-oelahydro-1.-la. ⁇ a-triaza-anihracene-?- carboxylic acid 4-fl ⁇ oro-benzylamide melting point: 221 °C
  • Example F 1-Cyclopropylmethyl-5-hydroxy- ⁇ , 10-dioxo- 1,2.G,4. ⁇ .O ⁇ a, 10-octahydro-1/ia. ⁇ a-triaza- anthracene-7-carboxyhc acid 3-chloro-2-fluoro-benzylamide molting point: 189-192°C
  • Example F 1-Furan-2-ylmethyl-5-hydroxy-6,10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a,8a-triaza-a nthraccno-7-carboxylic acid S-chloro-2-fluoro-benzylamide melting point: 190- 192°C
  • Example F- 48 1-Cyclopropj'lmethyl-5-hydroxy-6j10-dioxo-1.E.S,4.G. ⁇ a ⁇ 0-octahydro-1,4a. ⁇ a-triaza- anthvacencr7-carboxylic acid 2,4-d ⁇ luoro-benzylamide melting point: 169-171°C
  • Example F-49 1-F ⁇ van-2-ylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-a nthraccno-7-carboxylic acid 2,4-difluorcrbenzylar ⁇ idc melting point: 186- 188°C

Abstract

The present invention is to provide a novel compound (I), having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. Compound (I) wherein Z1 is NR4; R1 is hydrogen or lower alkyl; X is a single bond, a hetero atom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene in which the hetero atom group may intervene; R2 is optionally substituted aryl; R3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R4 and Z2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

Description

SPECIFICATION Polycyclic Carbamoylpyridone Derivative Having HIV Integrase Inhibitory Activity
[Technical Field] [0001]
The present invention relates to novel compounds possessing an antiviral activity, in detail polycyclic carbamoylpyridone derivatives possessing an inhibitory activity against HIV integrase and a pharmaceutical composition containing the same, especially an anti-HIV agent. [Background Art] [0002]
Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired,
On the other hand, a combination therapy is reported to be efficient in treatment for AIDS because of the frequent emergence of the resistant mutant. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent, however agents having the same mechanism of action often exhibit cross-resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.
Under the circumstances above, an HIV integrase inhibitor has been focused on as an anti-HIV agent having a novel mechanism of action (Ref: Patent Documents 1 and 2 ) As an anti-HIV agent having such a mechanism of action, known are carbamoyl-substituted hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and carbamoyl-substituted hydroxypyrrolidione derivative (Ref: Patent Document 5). Further, a patent application concerning carbamoyl-substituted hydroxypyridone derivative has been filed (Ref: Patent Document 6, Example 8) .
Other known carbamoylpyridone derivatives include
5-alkoxypyridine-3-carboxamide derivatives and T -pyrone-3-carboxamide derivatives, which are a plant growth inhibitor or herbicide (Ref: Patent Documents 7-9).
Other HIV integrase inhibitors include N-containing condensed cyclic compounds (Ref: Patent Document 10). [Patent Document 1]WO03/0166275 [Patent Document 2]WO2004/024693 [Patent Document 3]WO03/035076 [Patent Document 4]WO03/035076 [Patent Document 5]WO2004/004657 [Patent Document 6] JP Patent Application 2003-32772 [Patent Document 7] JP Patent Publication 1990- 108668 [Patent Document 8]JP Patent Publication 1990-108683 [Patent Document 9]JP Patent Publication 1990-96506 [Patent Document 10]WO2005/016927
[Disclosure of Invention]
[Problem to be Solved by the Invention]
[0003]
The development of a novel integrase inhibitor has been desired. [Means to Solve the Problem] [0004]
The present inventors have intensively studied to find that a novel polycyclic carbamoylpyridone derivative possesses a potent HIV integrase inhibitory activity
Moreover, the present inventors have discovered that a compound of the present invention and a pharmaceutical composition containing the same are useful as an antiviral agent, an antirotroviral agent, an anti-HIV agent, an anti-HTLV- 1 (Human T cell leukemia virus type 1) agent, an anti-FIV (Feline immunodeficiency virus) agent or an anti-SIV (Simian immunodeficiency virus) agent, especially an anti-HIV agent or anti-AIDS agent, to accomplish the present invention shown below.
(1)A compound of the formula :
Figure imgf000004_0001
(wherein,
Z i is NR4; R4 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, S, SO, SO2, NRa (Ra is hydrogen or lower alkyl), -N= and =N-)), O or CH2.
Z2 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from O, S, SO, SO2, NR 5 (R5 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic groxip, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy or optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom gx-oup selected from CO, O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group as R4), -N= and =N-)), -N= or =N-
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom;
R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino;
R4 and Z2 part taken together forms a ring, where bhe compound (I) is represented by the following formula (I-1), or (I-11):
Figure imgf000006_0001
(wherein,
A ring is optionally substituted heterocycle)
R14 and Rx are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group as R4), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyl; a broken line represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, Rx is not present;
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and N H, 01- lower alkylene or lowor alkenylonc each may be intervened by the heteroatom group;
R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycioalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino)
Figure imgf000007_0001
(wherein,
D ring is optionally substituted heterocycle;
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and N H , or lower alkylene or lower alkenylene each may bo intervened by the hetoroatom group;
R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycioalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino)), its pharmaceutically acceptable salt, or solvate thereof.
(2) A compound according to the above (1), pharmaceutically accep table salt, or solvate thereof, wherein R1 is hydrogen,
(3) A compound according to the above (1), pharmaceutically acceptable salt, or solvate thereof, wherein X is lower alkylenei R2 is phenyl or phenyl substituted with at least halogen.
(4) A compound according to the above (1), pharmaceutically acceptable salt, or solvate thereof, wherein RJ is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino.
(5) A compound according to the above Q), pharmaceutically acceptable salt, or solvate thereof, wherein R'! is hydrogen.
(6) A compound according to the above (1), pharmaceutically acceptable salt, or solvate thereof, wherein JR,1 is hydrogen or lower alkyli X is lower alkyleneJ R2 is phenyl or phenyl substituted with at least halogen; Ri! is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino.
(7) A compound of the formula-
Figure imgf000008_0001
(wherein,
A ring is optionally substituted heterocycloJ
RH and Rx are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted hetcrocyclo lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residxie or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NR0 (R5 is selected independently from the same substituent group as R4), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl cax'bonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl) optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyL" a broken line represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, ,RX is not present;
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SO_ and N H, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group ;
R2 is optionally substituted aryL'
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino), its pharmaceutically acceptable salt, or solvate thereof
(8) A compound according to the above (7), pharmacetitically acceptable salt, or solvate thereof, wherein R1 is hydrogen or lower alkyl; X is lower alkyleneJ R2 is phenyl or phenyl substituted with at least halogen; R3 is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino,
(9) A compound according to the above (7), pharmaceutically acceptable salt, or solvate thereof, wherein a broken line represents the absence of a bond.
(10) A compound according to the above (7), pharmaceutically acceptable salt, or solvate thereof, wherein Rx is hydrogen; R1'1 is hydrogen or optionally substituted lower alkyl. (11) A compound according to the above (7), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is an optionally substituted and optionally condensed 5- to 7- membered heterocycle containing- 1 to 2 hetero atom(s).
(12) A compound of the formula :
Figure imgf000010_0001
(wherein,
A ring is an optionally substituted and optionally condensed 5- to 7- membered heterocycle containing 1 to 2 hetero atom(s); the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof;
R14 and R.x are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic grovip, optionally substituted heterocycle lower alkyl, optionally substituted heterocyclooxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NR5 (Rβ is selected independently from the same substituent group as R'O, -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted hetcrocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aininocarbonyl;
Ru is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted hetorocyclcoxy or optionally substituted amino), its pharmaceutically acceptable salt, or
R1 is hydrogen or lower alkyli
R is independently selected from halogen and Substitucnt group SV,
Substituent group SlO optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue) amino substituted wilh optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (wherein the lower alkyl may be intervened with a heteroatom group(s) selected from CO, O, O, S, SO, SO2, NRa (R-* is hydrogen or lower alkyl), -N= and =N-), lower alkoxy lower alkyl, amino lower alkyl optionally substituted with mono- or di- lower alkyl, halogcnated lower alkyl, lower alkoxy, carbamoyl optionally substituted with mono- or di- lower alkyl, optionally substituted lower alkyl sulfonyl amino, halogenated lower alkoxy, hydroxy lower alkyl)
m is an integer of 0 to 3, its pharmaceutically acceptable salt, or solvate thereof.
(13) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein Rx and R1'' are independently hydrogen or optionally substituted lower.
(14) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein Rx and R1'1 are hydrogens.
(15) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein R3 is hydrogen. (16) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein m is 0, or 1 to 3 and at least one of R is halogen.
(17) A compound according to the above (7) or (12), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is any one of the following:
Figure imgf000012_0001
(wherein, R20 to R40 are each independently a group selected from Substituent group S2, or any two groups of Raϋ Lo R40, which bonds to tho same carbon atom, Laken together with the carbon atom, may form an optionally substituted carbocyle or optionally substituted heterocycle, or each combination of (R20 and R22), (R23 and R2O, (RM and R2O, (R" and R2O, (R»° and R1J0, (R«2 and RJ'O, (R35 and R^), (R" and R^), and (R'3SandR40), Laken together with the neighboring atom, may form an optionally substittited carbocyle or optionally substituted heterocycle.
Substituent group S2: hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkcnyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substittited cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocyclooxycarbonyl, optionally substituted aminocarbonyl, op tionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residxie, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residtie, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened with a heteroatom group(s) selected from CO, O, S, SO, SO2, NRC (R6 is independently selected from the same Substituent group as R'O, -N= and =N0
the stereochemistry of an asymmetric carbon represented by A' shows R- or S- configuration, or a mixture thereof)
(18) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein R20 to R'J0 are each independently hydrogen or substituted lower alkyl, or any two groups of R20 to R40, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted 3- to 7- membered carbocyle or optionally substituted 3- to 7- membered heterocyclc, or each combination of (R20 and R22), (R2J and R2O, (R23 and R^), (R5" and R2<->), (R^ and R31), (R32 and R-"), (R''5 and R36), (R37 and RJs), and (R^andR'i"), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered hetcrocycle.
(19) A compound according to the above (37), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A- I) I one of R20 to R2r> is optionally substituted lower alkyl and the others are hydrogens.
(20) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-I); one of (R20 and R22), (R2l! and R2O, and (R25 and R2G), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered hctorocycle.
(21) A compoxmd according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1)l Z=NR26, and R2S and R2ύ taken together with the neighboring atom may form an optionally substituted 5- to 7-
U membered heterocycle.
(22) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring' is a ring represented by (A-2)>' one of R27 to Rao is optionally substituted lower alkyl and the others are hydrogens.
(23) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); one of (R27and R29) and (R30 and R''1), taken together with the neighboring atom, may form an optionally substituted 5- to 7- memberod carbocyle or optionally substituted 5- to 7- membered heterocycle.
(24) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, whcroin A ring is a ring represented by (A-2); Z=NR31, and R'M and R!i l taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle.
(25) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A- 3); one of R32 to R;iS is optionally substituted lower alkyl and the others are hydrogens.
(26) A compound according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3)> one of (R32andR^0,(R8r'andR3«),(R:!7andR38),and(R39andR'i"), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle.
(27) A compotmd according to the above (17), pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3); Z=NR40, and R;'9 and R40 taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle.
(28) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein Rx is hydrogen; R1'1 is hydx-ogen or optionally substituted lower; R3 is hydrogen; m is 1 to 3 and at least one of Rs is halogen; A ring is a ring described in Claim 17,
(29) A compound according to the above (12), pharmaceutically acceptable salt, or solvate thereof, wherein Rx is hydrogen; R1'1 is hydrogen; R3 is hydrogen; m is 0, or 1 to 3 and at least one of Rs is halogen; A ring is a ring described in Claim 17; R2t> to Rl|ϋ are each independently hydrogen or substituted lower alkyl, or any two groups of R20 to R40, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted 3- to 7- mcmbcred carbocyle or optionally substituted 3- to 7- membered heterocycle, or each combination of (R20 and R22), (R23 and R2O, (R2C and Rso), (R^ and Rss), (R30 and RJ'), (R32 and W-1), (R" and R™), (R!" and Rl!s), and (R!19andR40), taken together with the neighboring carbon atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- mombered heterocycle.
(30) A compound of the formula^
)
Figure imgf000015_0001
(wherein,
D ring is optionally substituted hetorocycleJ
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group;
R2 is optionally substituted aryli
R15 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkonyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyclooxy or optionally substituted amino), pharmaceutically acceptable salt, or solvate thereof (31) A compound selected from the group consisting of:
(3R, J laS)-N-[(2,4-Difliiorophenyl)methyl]-6-hydroxy-3-methyl-5, 7^10X0-2,3,5,7, 11, 11a
-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyyrazinew8-carboxamide;
(4aR, 13a»S>-N-[(2,4-Difluorophenyl)methyl]- 10-hydroxy-9, 11-dioxo-2,3,4a,5,9, 11, 13, 13a
-octahydro-1^-pyrido[1, 2-ajpyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide;
(3a,9, 13a,fil-N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo- 1,2,3,3a,4,5,7,9, 13, 33a
-decahydropyrido[1',2':4,5]py razino[1,2-a]pyrrolo[1,2-dpyrimidine- 10-carboxamide;
(4a»5', 13aR)-N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9, 11,13, 13a
-octahydro-1H1pyr do[1,2-a]ppyyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide;
(4aS, 13aR)-N-[(4-Fluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2, 3^,5,9,J 1, 33, 1Sa-OCt
ahydro-1H-pyrido[1,2-a]pyrrolo[ll,2':3,4]imidazo[1,2-d]pyrazino-8-cax*boxarαido;
(3*5r,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,
7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3aS, 13aSl-N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo- 1,2,3,3a,4,5,7,9, 13, 13a-de
cahydropyrido[1',2':4,5]pyrazine[1,2-a]pyrrolo[1,2-6|lpyrimidine-10-carboxamide; (3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[( 1S)- 1-methylpropyl]-5,7-dioxo
-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11 a
-hexahydro[1, 3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11, 11a-he
xahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-5,7-dioxo-2
,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,
7, 11, 11a-hexahydro [1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3,5,7, 11, 11a
-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7-dioxo-2,3,
5,7,11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(2S,3R)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2,3,5,7
,11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide; (3R,11aS)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,
7, 11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3R,11aS)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,7-dioxo-2,3,
5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(5aR,14aR)-N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,
14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo[1,2-d]pyrazine-9-carboxamide;
(2S,3S-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(methyloxy)methyl]-5,7-dioxo-2-p
henyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(3S,11aR)-3-(Cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,
3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,
7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(5aR,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-5a,6a,7,11,13,14a-
hexahydro-5H-indeno[1',2':4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-10-carboxamid e; (2S,3R, 11aS)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7,
11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(2S,3R, 11aR)-N-[(2,4-difluorophenyl)methyl] -6-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7,
11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3R, 11aS)-N-[(2,4-Difluorophenyl)methyl] -6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,
7, 11,11a-hexahydro[1, 3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethyl]-5,7-dioxo-
2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S;11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3- [2-(methylsulfonyl)ethyl]-5,7-di
oxo-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1H-indol-3-ylmethyl)-5,7-dioxo
-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(4R, 12aR)-N-[(4-fluorophenyl)methyl] -7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-diox
o- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazine[1,2-a]pyrimidine-9-carboxamid e; (4R,12a/i;)-N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(i-methylethyl)-6,8-cUox
o-1,2,3,4,6,8,12,12a-oct;ahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-c,'irboxamid
e>
(4S,12aS)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyM-(2-methylpropyl)-6,8-
dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyϊazino[1,2-a]pyrimicline-9-carboxa
mide;
(4.S, 12aS)-1-(Cyclopropylmethyl)-N-f(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6
,8-dioxo-1,2,3,4,6,8,12,12a-ociahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carbo
xamide;
(4ώ;12a,5)-iV'-[(2,4-Difhiorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8
-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2v;Jpyrimidine-9-carbox
amide;
(4S,12aS)-N-[(2,4-I)iflιιorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-fchiazol-
2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-c
arboxamide;
(4aR,6aR,l4a»S)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-31,13-dioxo- J, 3,4^,5^,
7,11,13,14a-decahydro-2H;pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benz;oxazino-10-carboxa
midej (4aie,6aR,14aS)-N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11
, 13, 14a-decahydro-2//-pyrido[1',2':4,5]pyrazino[1,2-a] [3, l]benzoxazine- 10-carboxamide
(3S,4aR,6aR,14aSViN-[(2,4-Difl\ιorophenyl)methyl]-12-hydroxy-11,13-dioxo-3-phenyl-1
,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-'pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazine
-10-carboxamide;
(4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-methylpropyl)-11,13-d
ioxo-1,2,3,4,4a,5,6,6a,7,11,i3,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoli
ne- 10-carboxamide;
(6aR,7aS, 11aS)-N- t(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7, 7a,8,9, 10,
L1,11a,13-decahydro-θH-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazole^-carboxamide)
(6aS,7aS,11aS)-N-[(2,4-Difluorophenyl)methyl]-1-hydtOxy-2,13-dioxo-2,6a,7,7a,8,9,L0,
11,11a, 13-decahydro-βH-pyrido[1',2':4,5]pyrazino[i,2-a]benzimidazolo-3-carboxamide;
(5aS,14aS)-N-[(2,4-Oifluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,
14,14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo[1,2-d]pyrazine-9-carboxamide;
(4aK,14aR)-N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14, 14a-decahydro- 1H-pyridoIl,2 -clpyridoLl',2'i4,5lpyra'/ino[1, 2-a]pyrimidine- 11-carboxam
ide;
(4R, 12aR)-ΛA[(2,-l-Difluorophenyl)methyl]-7-hydroxy-4-methyM-(3-methylbutyl)-6,8-d
ioxo-1,2,3,4,G,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxa
naide;
(4S, 12aS)-iV'- [(2,4-Difluorophenyl)methyl] -7-hydroxy-4-methyl-1-(1-meihyleLhyl)-6,8-di
oxo-1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazinoCl, 2- a]pyrimidine-9-carboxam
ide;
US.12aS> N- t(2,4-Difluorophenyl)methyl]-7-hydroxy-4-mGtiiyl-1-(3-methylbutyl)-6,8-d
ioxo- 1,2,3,4,6,8, 12, 12a-octahyd) opyrido[1',2':4,5]pyrazino[1,2-alpyrimidinG-9-carboxa
mide;
(4S, 12aS)-Λ/"-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(3-pyridinyl
methyl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidino-9-carbo
xamide;
(4S^ 12aS)-1-Cyclopropyl-N-f(2,4-difhtorophenyl)methyl]-7-hydroxy-4-methyl-6|8-dioxo-
1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidmo-9-carboxamtdo;
(4S, 12aS)-iV'-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-rnctb.yl-1- [2-(methyloxy)ethyl] - 6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carb
oxamide;
(3aS,5aS,13aS)-N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-5-(2-methylpropyl)-10,12-d
ioxo-2,3,3a,4,6,5a,6,10,12,13a-decahydro-1H-cyclopentale]pyrido[1',2':4,5]pyrazino[1,2
-a]pyrimidine-9-carboxamide;
(3R.11aS)-N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-h
exahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4-morpholinyl)ethyl]-
11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]q
uinazoline-10-carboxamide;
(3aR,5aR,13aS)-N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,3a,4,5a,
6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carbo
xamide;
(4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-methyl-11,13-dioxo-1,2,3
,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-car
boxamide;
(4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(methyloxy)ethyl]-11, 13-dioxo-1,2,3,4,4a,5,6,6a,7, 11, 13, 14a-dodecahych>opyrido[1',2':4,5]pyrazino[1,2-a)quhτι
azoline-10-carboxamidel
(4aS,6aS,14aS)-6-l2-(Acetylaraino)ethyl]-N-[(2,4-difluorophenyl)methyl]- 12-hydroxy-1
1,13-dioxo- 1,2,3,4,4a, 5, 6, 6a,7, 11, l 3, 14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]q\ιi
nazoline- 10-carboxamideI
(3Sf, 11ai2)-N-[(2,4-Difluoj-ophenyl)methyl)-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7, 11, 11a-h
exahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxatnide;
(SS, 11aR)-3-Butyl-N- [(2,4-diiluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7, 11, 1 la-h cxahydro[1, 3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)mcfchyl]-6-b.ychOxy-3- [(4-hydroXyphenyl)mcfhyl]-5,7-
dioxo-2.S,5,7,11j 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide
(4S,12aS)-1- Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1
,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;
(4S, 12aS)-Λ'1 [(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-
2iy-thiopyran-4-yl)- 1,2,3,4,6,8, 12, 12a-octahydropy).ido[1',2':4,5]pyrazino[1,2-a]pyrimid
ine-9-carboxamidθ) (4S,12aS)-N-[(2,4-Diflxιorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo
-1,2,3,4,6,8,12,12a-octahycUOpyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-caj.'boxamide;
(4aS,6aS,14aS)-N-[(2,4-I)ifluorophenyl)methyl]-12-hydroxy-6-(2-hydroxyethyl)-11,13-d
ioxo- 1,2, 3, 4,4a, 6, 6, 6a, 7, J.i,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoli
ne- 10-caχ-boxamide;
(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-di£luorophenyl)methyl]-12-hydroxy-11,13-dioxo-
1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[l,2-a]quinazoline-1
0-carboxamide;
(4aS,6aS,14aS)-N-[(2,4-.Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-6-[2-(1-pynOli
dinyl)ethyl]-.L,2,3,4,4a,5,6,6a,7,l1,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1.,2-a]q
uinazoline-10-carboxamide;
(4aS,14aS)-N-[(2,4-Difluorophenyl)raethyn-9-hydroxy-8 ,10-dioxo-2,3, 4^^,5,6,8, 10, 14,1
4a-decahydro-1H-pyrido[1,2-clpyrido[1',2r:4,5]pyrazino[1,2-a]pyi1imidine-11-cax-boxami
del
(4S,J.2aS)-N-[(4-Fluorophenyl)mebhyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)ethyl]-6,8-
dioxo-1,2,3,4,6,8,12,12a-octahydt1opyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxa
midej (4S, 12aS)-1-Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3
,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;
(4S, 12aS)-N-U4-Fluorophenyl)methyl]-7-hydroxy-4-methyl- ) -(2-methylpropyl)-6,8-diox
o-1,2,3,4,6,8, 12,12a-octahydropy:'ido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamid
(4S, 12aS)-N- [(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo- 1,2,3,4,6,8, 12
, 12a-θctahydropyrido[1',2':4,5]pyrazino[1,2-a]pyriinidine-9-carboxamide)
(4 S, 12a/S)-N-[(4-Fluorophenyl)methyl] -7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2i7
-thiopyran-4-yl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-ijJpyrimidine
-9-carboxamide>'
(4S,12aS!)-N- [(2,4-Difluorophenyl)methyl]-7-hydroxy- 1,4-dimethyl-6,8-dioxo- 1,2,3,4,6,8
, 12, 12a-octahydχ-opyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;
(4SU2aS)-iV'- [(4-Fluovophenyl)methyl1-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo
- 1,2,3,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyra'/ino[1,2-a]pyrimidine-9-carboxamide;
(4S, 12aS)-N- [(4-Fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo- 1,2
,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyra^ino[1,2-a]pyriinidine-9-carboxamide; enantiomers thereof; diastereomors thereof; mixtures of enantiomers thereof;
mixtures of diastoreomers thereof; mixtures of enantiomers and diastereomors
thereof; and pharmaceutically acceptable salts thereof.
(32) A compound selected from the group consisting of:
(4aS"r, 13aR)-N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9, i1-dioxo-2,3,4a,5,9, 11, 13, 13a
-octahydro^ H-pyrido[j ,2-,dpyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamxdc;
(4aS, 13aR)-N-[(4-Fluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9, 11, 13, 13a-oct
ahych'o- J H-pyilido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide;
(3Λ5, 11aif)--N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(i S>1-methylpropyl]-5,7-dioxo
%3,5,7, 1141a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyra2une-8-carboxamide;
(3S, lJ aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11, l1a
-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyra'/ine-8-carboxamide;
(3S, 11aR)-N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, l l , π a-he
xahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;'
(4λ$; 12aS)-7N-[(2,4-Difluorophenyl)methyn-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-
dioxo- 1,2,3,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-caz-boxa mided
(4S,12aS)α-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6
,8-dioxo-i,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyt'azino[1,2-a]pyrimidine-9-carbo
xamide;
(4aR,6aR,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy- 11, 13^10x0-1,3,4/ ,6, 6a,
7,11,13,14a-decahydro-2i7-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]bonzoxazine-10-cat'boxa
mide;
(4aR,6aR,14aS)-N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,31
,13,14a-decahydro-2H'-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazxne-10-carboxamide
4S,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,
δa-diaza-anthraceno-T-carboxylic acid 2,4,-difluoro-bonylamide;
4R,9aS)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,
8a -diaza- anthracene - 7 -carboxj'lic acid 2,4,-difk\oro-benylamidG;
2R,9aS)-5-Hydroxy-2-methyl-6,l 0-dioxo-B,4.β.9.ga, 10-hexahydro-2H-1-oxa-4a,
8a-diaza-anthracene-7-carboxylic acid 4-fluoro-benylamide; enantiomers thereof; diastoreomers thereof; mixtures of enantiomers thereof;
mixtures of diasteroomers thereof; mixtures of enantiomers and diastereomers
thereof; and pharmaceutically acceptable salts thereof.
(33) A compound according to the above (31) or (32) wherein the pharmaceutically
acceptable salt is a sodium salt.
(34) A pharmaceutical composition comprising a compound according to any one of the above (1) Lo (33), or a pharmaceutically acceptable salt, or solvate thereof.
(35) A pharmaceutical composition according to the above (34), which is an anti-HlV agent,
(36) A process for the preparation of a compound of formula (I-20a)
Figure imgf000029_0001
wherein Rf is one or two halogonj R/- is C1-8alkyl, Ce- iαarylC1-8alkyl, Cc-πaryl, or alkoxy; and P1 is C6-14arylC1-8alkyl;
comprising condensing a compound of the formula
Figure imgf000029_0002
wherein Ru is one or two halogen; Rβ0 is C1-8alkylJ and P1 is C6-14arylC1-8alkyl; with a compound of the formula
Figure imgf000030_0003
wherein Rκ is C1-8alkyl, CrM.iarylC1-8alkyl, Cβ-M&ryl, or alkoxyJ to form a compound of formula (I-20a).
(87) A process for the preparation of a compound of formula (I-20b)
Figure imgf000030_0001
whorein RD is one or two halogen; Rκ is C1-8alkyl, Cα-i-jarylC1-8alkyl, Co-uaryl, or alkoxy; and P1 is Cfi-t-iarylGi-aalkyL'
comprising condensing a compound of the formula
Figure imgf000030_0002
wherein RD is one or two halogen; H50 is C1-8alkyl; and P1 is CB-i-iarylC1-8alkyL" with a compound of the formula
Figure imgf000030_0004
wherein .Rz is C1-8alkyl, Cπ-i«iarylC1-8alkyl, Cc-i.iaryl, or alkoxy." to form a compound of formula (I-20b), (38) A process for the preparation of a compound of formula (I-21a)
Figure imgf000031_0001
wherein Ru is one or two halogen; and P1 is Cα-i-jarylC1-8alkyl;
comprising condensing a compound of the formula
Figure imgf000031_0002
wherein R° is one or two halogen; Rβ0 is C1-8alkylJ and P1 is Gc i-iarylC1-8alkyl." with a compound of the formula
Figure imgf000031_0003
to form, a compound of formula (1-2Ia).
(39) A process for the preparation of a compound of formula (1-2 Ib)
Figure imgf000031_0004
wherein R0 is one or two halogen; and P1 is CG narylC1-8alkyl; comprising condensing a compound of the formula
Figure imgf000032_0001
wherein R0 is one or two halogen; RSI) is C1-8alkylJ and P1 is Ce-uarylC1-8alkyl; with a compound of the formula
Figure imgf000032_0004
to form a compound of formula (I-21b).
(40) A process for the preparation of a compound of formula (I-22a)
Figure imgf000032_0002
wherein E-0 is one or two halogeni and P1 is Gπ-i-iarylC1-8alkylJ comprising condensing" a compound of the formula
Figure imgf000032_0003
wherein R0 is one or two halogen; Rs0 is C1-8alkyl; and P1 is Cβ-πarylC1-8alkyl; with a compound of the formula
Figure imgf000033_0001
to form a compound of formula (I-22a).
(41) A process for the preparation of a compoxind of formula (I-22b)
Figure imgf000033_0002
wherein R0 is one or two halogen; and P1 is CtM-iarylC1-8alkyl; comprising condensing a compound of the formula
Figure imgf000033_0003
wherein RD is one or two halogen; Rr>° is C1-8alkyl." and P1 is CiM-iarylCi^alkyl; with a compound of the formula
Figure imgf000033_0004
to form a compound of formula (I-22b).
(42) A process for the preparation of a compound of formula (I-23a)
Figure imgf000033_0005
wherein R0 is one or two halogen." and P 1 is Cc-uarylC1-8alkyl;
3.1 comprising condensing a compound of the formula
Figure imgf000034_0001
wherein R0 is one or two halogen; R00 is Ci-ualkyl; and P 1 is Cβ-uarylC1-8alkyl; with a compound of the formula
Figure imgf000034_0002
to form a compound of formula (I-23a).
(43) A process for the preparation of a compound of formula (l'-23b)
Figure imgf000034_0003
wherein R° is one or two halogen; and P1 is Cβ-HarylCi-salkyl; comprising condensing a compound of the formula
Figure imgf000034_0004
wherein R° is one or two halogen; RG0 is C1-8alkyL' with a compound of the formula
Figure imgf000035_0001
to form a compound of formula (I-23b),
(44) A process for the preparation of a compound of formula (I-24a)
Figure imgf000035_0002
wherein ,R° is one or two halogen; Rz is Ci-βalkyl∑ R"1 is hydrogen, Ca-βcycloalkyl, , heterocycle, or C1-8alkyl optionally substituted with hydroxy, Ca-ficycloalkyl, alkoxy, heterocycle, heteroaryl, Co- ι.ιaryl, or amino, wherein said amino may be optionally substituted with — C(O)C1-8alkyl or C1-8alkyl; and P1 is Co-uarylC1-8alkyL'
comprising condensing a compound of the formula
Figure imgf000035_0003
wherein RQ is one or two halogen*' and R00 is C i-βalkyl; and P1 is Cβ- uarylGi-salkyK with a compoimd of the formula
Figure imgf000035_0004
wherein "R'' is C1-8alkyll R"1 is hydrogen, C;w>cycloalkyl, , heterocycle, or C i-βalkyl optionally substituted with hydroxy, C3-6cycloalkyl, alkoxy, heterocycle, heteroaryl, C6-14aryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8alkyl or d-ealkyl; to form a compound of the formula (I-24a).
(45) A process for the preparation of a compound of formxύa (P24b)
Figure imgf000036_0001
wherein R0 is one or two halogen; Rκ is Oi-ealkyl; E"-1 is hydrogen, Cj-ocycloalkyl, , hotorocycle, or Gi-βalkyl optionally substituted with hydroxy, Ca ccycloalkyl, alkoxy, heterocycle, heteroaryl, CG i-iaryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8alkyl or C1-8alkyl; and P1 is Cβ MarylC1-8alkyl;
comprising condensing a compound of the formula
Figure imgf000036_0002
wherein Re is one or two halogen; R50 is C1-8alkylJ and P1 is Cos- uaryld-βalkyl; with a compound of the formula
Figure imgf000036_0003
wherein R/ is C1-8alkylJ and II'1 is hydrogen, Cwjcycloalkyl, , hetorocycle, or C1-8alkyl optionally substituted with hydroxy, Ca-ecycloalkyl, alkoxy, hetorocycle, heteroaryl, Ce-waryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8alkyl or C1-8alkyl;
to form a compound of the formula (P24b). (46) A process for the preparation of a racemic compound of formula (1-25)
Figure imgf000037_0001
wherein Ru is one or two halogen; Rκl is hydrogen, C3-6cycloalkyl, , heterocycle, or Ci-salkyl optionally substituted with hydroxy, Cu-Gcycloalkyl, alkoxy, heterocycle, heteroaryl, C6-14aryl, or amino, wherein said amino may be optionally substituted with -C(O)Cb»alkyl or C1-8alkyli and P1 is is Co-MarylC1-8alkyl;
comprising condensing a compound of the formula
Figure imgf000037_0002
wherein .R0 is one or two halogen; and RB0 is C1-8alkyl; and P1 is Co-MarylCi-salkyl; with a racemic compound of the formula
Figure imgf000037_0003
wherein Rzl is hydrogen, Cu-ocycloalkyl, , hefcerocycle, or C1-8alkyl optionally substituted with hydroxy, Cn-ecycloalkyl, alkoxy, heterocycle, heteroaryl, Cα-Maryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci-»alkyl or C1-8alkyl;
to form a racemic compound of the formula (1-25).
(47) A process for the preparation of a racemic compound of formula (P26)
Figure imgf000038_0001
wherein R0 is one or two halogen; R'/Λ is hydrogen, Ca-Gcycloalkyl, , heterocycle, or C1-8alkyl optionally substituted with hydroxy, Ca-ocycloalkyl, alkoxy, heterocycle, heteroaryl, Cc-waryl, or amino, wherein said amino may be optionally substituted with -C(O)Cι-«alkyl or Gi-βalkyli and P1 is Cc-i.iarylCi^alkyll comprising condensing a compound of the formula
Figure imgf000038_0002
wherein R° is one or two halogen; Rr'° is C1-8alkyll and P 1 is Cβ-MarylC1-8alkyl; with a racemic compound of the formula
Figure imgf000038_0003
wherein Rκl is hydrogen, Cu-ccycloalkyl, , heterocycle, or C1-8alkyl optionally substituted with hydroxy, Cs-rscycloalkyl, alkoxy, heterocycle, heteroaryl, Ce-iaaryl, or amino, wherein said amino may be optionally substituted with -C(O)C l-salkyl or C1-8alkyl;
to form a racemic compound of formula (1-26).
(48) A process for the preparation of a racemic compound of formula (I-27)
86
Figure imgf000039_0001
wherein R0 is halogen; and P 1 is CcH-iarylC1-8alkyl; comprising condensing a compound of the formula
Figure imgf000039_0002
wherein Ra is one or two halogen; R00 is C1-8alkyl; and P 1 is Co-uarylC i salkyl; with a facemic compound of the formula
Figure imgf000039_0003
to form a racemic compound of formula (1-27).
(49). A compound of formula (I-20a) described in above (36). formula (1-20h) described m above (37), formula (1*2 Ia) described in above (38), formula (1-23 b) described in above (89), formula (I-22a) described in above (40), formula (I-22b) described in above (41), formula (I-23a) described m above (42), formula (I- 23b) described in above (43), formula (l-24a) described in above (44), formula (I- 24b) described in above (45), formula (1-25) described in abovo (46), formula (1-26) described in above (47), or formula (1-27) described in above (48), or a pharmaceutically acceptable salt thereof.
(50) A compound of formula (I-20a) described in above (36), formula (I-20b) described in above (37), formula (I-21a) described in above (38), formula (1-2 I b) described in above (39), formula (P22a) described in above (40), formula (J-22b) described in above (41), formula (I-23a) described in abovo (42), formula (I-23b) described in above (43), formula (I-24a) described in above (44), formula (I-24b) described in above (45), formula (1-25) described in above (46), formula (T- 26) described in above (47), or formula (1-27) described in above (48), or a pharmaceutically acceptable salt thereof, wherein each P1 is hydrogen.
The present invention further provides a pharmacetitical composition containing any of the compounds shown above, a pharmaceutically acceptable salt or a solvate thereof, especially an antrHIV agent, [Effect of the Invention] [0005]
The present invention compounds possess an integrasc inhibitory activity and/or a coil-growth inhibitory activity against virus, especially HIV. Accordingly, they are useful for the prevention or treatment of various diseases mediated by integrase or virus infection diseases (e g., AIDS). The present invention further provides a process for preparing a diastereomer, a mixture thereof, or racemate. [Preferred Embodiment of the [nventionj [0006]
The terms used herein arc explained below. Each term, alone or in combination with another tem, means as follows
"Lower alkylenc" moans a straight or branched Cl to C6 alkylene such as methylene, ethylene, trimethyleno, n-propyleno, tetramethylone, ethylethylenc, pentamethylene, or hexamethylone, preferably Cl to C4 straight alkylcne such as methylene, ethylene, trimethylene, and tetramethylene, more preferably methylene or ethylene,
"Lower alkenylene" moans a straight or branched C2 to C6 alkenylene, which consists of the above "Lower alkylene" having one or more double bonds, such as vinylene, propylene, or butenylene, prefeiably a straight C2 to C3 alkenylene such as vinylene or propylene.
"Lower alkyl" means a straight or branched Cl to C10 alkyl such as methyl, ethyl, n-propyl, i-propyl, t-butyl, lsobutyl, sec-butyl, n-pentyl, and n-hexyl, and preferred is Cl to C3 alkyl, more preferred is methyl, ethyl or n-propyl, n-pentyl, isopentyl, ncopentyl, tert-pentyl, n-hexyl, isohexyl, n-hoptyl, n-octyl, lrnonyl, and n-dosyl, preferably Cl to C6 lower alkyl, more preferably Cl to C4 lower alkyl such as methyl, ethyl, n-propyl, isopropyl, lvbutyl, iaobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, ncopentyl, tert-pentyl, n-hexyl, and isohexyl, When lower alkyl is intervened with "-N=" or "=N-", the lower alkyl may have a double bond to form -
Figure imgf000041_0001
-CH=N-CHa etc.
"Alkenyl" moans a straight or branched C2 to C8 alkenyl, which consists of the above "alkyl" having one or more double bonds, such as vinyl, 1-propenyl, 2-propenyl, 1-butonyl, 2-butenyl, 3-butcnyl, 1,3-butadionyl, and 3-methyl-2-butenyl, preferably C2 to C6 alkenyl, and more preferably C2 to C4 alkenyl.
"Lower alkenyloxy" means oxy attached to the above lower alkenyl, such as vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butonyloxy, 3-butonyloxy, 1,3-butadionyloxy, and 3-methyl-2-butenyloxy.
"Cycloalkyl" means C3 to C8 cyclic saturated hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl, preferably C3 to C6 cycloalkyl,
"Cycloalkyl lower alkyl" means lower alkyl substituted with the above cycloalkyl, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cyclohexylethyl, and preferably C3 to C6 cycloalkyl lower alkyl. "Aryl" means monocyclic aromatic hydrocarbon (e.g., phenyl) and polycyclic hydrocarbon (e.g., l -naphthy1,2- naphUiyl, 1-anthryl, 2-anthryl, 9-anlhryl, 1-phenanlhryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl), p referably phenyl or naphthyl (e.g., 1-napthyl, 2-naphlhyl).
"Aralkyl" or "aryl lower alkyl" moans the above lower alkyl substituted with 1 fco 3 of the above aryl, such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, J - nap thylmethyl, 2- napthylmethyl, preferably benzyl.
"Aryloxy" means oxy attached to the above aryl, such as 1-naphthyloxy, 2-naphthyloxy, 1-anthryloxy, 2-anLhryloxy, 9-anthryloxy, 1-phenanthryloxy, 2-phenanthryloxy, 3-phenanthryloxy, 4-phenanthryloxy, and 9-phenanthi-yloxy, preferably phenyloxy or naphthyloxy (e.g., 1- napthyloxy, 2-naphthyloxy). "Heterocyclic group" means "hetoroπng" or "hetoroaryl".
"Heteroring" means a non-aromatic ring which has at least one of N, O and/or S in the ring and may be bonded at any substitutable position, preferably 5- to 7-mcmbered ring, such as 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrolidmyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, pipendino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperadinyl, 2-piporadinyl, 2-morpholinyl, 3-morpholinyl, morpholino, and tetrahydropyranyl. The non-aromatic ring is a saturated or unsaturated ring,
"Heteroaryl" means monocyclic aromatic helero-type ring- or condensed aromatic hetero-type ring.
"Monocyclic aromatic hetero-typo ring" means a 5- to 8- membered aromatic ring, which contains 1 to 4 of O, S, P and/ or N and may bo bonded at any substitutable position.
"Condensed aromatic hotero-type ring" means a group wherein an aromatic ring containing 1 to 4 of O, S, P and/ or N is condensed with 1 to 4 of 5- to 8-membered aromatic ring(s) or the other 5- to 8-membored aromatic heteroring(s).
Examples of "hetoroaryl" include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imida^olyl (e.g., J/imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazole-1-yl, l ,2,4-triazolo-3-yl, l,2,4-triazole^l-yl), tetrazolyl (e,g,, 1-tetrazolyl, 2-totrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazoiyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiacliazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridiKe.g., 2-pyridil, 3-pyridil, 4-pyridil), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g., 2-pyrazinyl), oxadiazolyl (e.g., L,3,4-oxadiazole-2-yl), benzofuryl (e.g., 2-benzo[blfuryl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzotbJfuryl, 7-benzo[b]f\ιryl), benzothienyKe.g., 2-benzotbJthicnyl, 3-benzolbjthienyl, 4-benzoLb]thionyl,
5-benzo[b|thienyl, 6-benzolbJthicnyl, 7-benzoLbJthienyl), benzoimidazolyl (e.g., 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzooxazolyl, quinoxalinyl (e.g., 2-quinoxalinyl, 5-qtύnoxalinyl, 6-quinoxalinyl), cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolinyl (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazohnyl, 6 -quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinolyl(e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-qvύnolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl), isoquinolyl (e.g., lύsoquinolyl, 3-isoqtιinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), purinyl, pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g., 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9- acridinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, βύndolyl, 7-indolyl), isoindolyl, phenandinyl (e.g., 1- phenandinyl, 2- phenandinyl) or phenothiadinyl (e.g., 1- phenothiadinyl, 2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl).
"Hetorocycle" means a cycle which can be lead to the above heterocyclic group.
"Heterocyclic group lower alkyl" or "Hcterocycle lower alkyl" means lower alkyl substituted with the above heterocyclic group,
"Heterocyclic group oxy" or "Heterocycle oxy" means an oxy attached to the above heterocyclic group.
".Heterocyclic group carbonyl" or "Heterocyclccarbonyl" means a carbonyl attached to the above heterocyclic group
"Lower alkoxy" or "alkoxy" means an oxy attached to the above lower alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy.
"Lower alkylcarbonyl", "cycloalkylcarbonyl", "cycloalkyl lower alkylcarbonyl", "lower alkoxycarbonyl", "arylcarbonyl", "aryl lower alkylcarbonyl", "aryloxycarbonyl", "heterocyclecarbonyl", "heterocycle lower alkylcarbonyl", and "heterocycle oxycarbonyl", each means a carbonyl attached to the above "lower alkyl", "cycloalkyl", "cycloalkyl lower alkyl", "lower alkoxy", "aryl", "aryl lower alkyl", "aryloxy", "heterocycle", "heterocycle lower alkyl", and "heterocycleoxy", respectively. [0007]
When a substituent(s) is/are present on "optionally substituted lower alkyl", "optionally substituted cycloalkyl", "optionally substituted cycloalkyl lower alkyl", "optionally substituted lower alkenyl", "optionally substituted lower alkoxy", "optionally substituted aryl", "optionally substituted aryl lower alkyl", "optionally substituted aryloxy", "optionally substituted aryloxy lower alkyl", "optionally substituted hetorocyle, "optionally substituted heterocyclic group", "optionally substituted heterocycle lower alkyl", "optionally substituted heterocycleoxy", "optionally substituted lower alkenyloxy", "optionally substituted lower alkylcarbonyl", "optionally substituted cycloalkylcarbonyl", "optionally substituted cycloalkyl lower alkylcarbonyl", "optionally substituted lower alkoxycarbonyl", "optionally substituted arylcarbonyl", "optionally substituted aryl lower alkylcarbonyl", "optionally substituted aryloxycarbonyl", "optionally substituted heterocyclecarbonyl", "optionally substituted heterocycle lower alkylcarbonyl", "optionally substituted heterocycleoxycarbonyl", "op tionally substituted lower alkylone", "optionally substituted lower alkenylene", "optionally substituted phosphoric acid residue", "optionally substituted carbocycle" or "optionally substituted heterocycle", each may be substituted with the same or different, 1 to 4 group(s) selected from Substituont group 13 at any position.
Examples of Substituent group B include hydroxy, carboxy, halogen (F,C]7Br,I), halo lower alkyl (e.g., CFD,CH2CF3, CH2CCl8), halo lower alkoxy (e.g., OCKi, OCH3CF3, OCH2CCI3), lower alkyl (e.g., methyl, chtyl, isopropyl, tert-butyl), lower alkenyl (e.g., vinyl), lower alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), lower alkenyloxy (e.g., vinyloxy, allyloxy), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), nitro, nitroso, optionally substituted amino (e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino), acylamino (e.g., acetylamino, benzoylamino), aralkylamino (e.g., bonzylamino, trithylamino), hydroxyamino), azido, aryl (e.g., phenyl), aralkyl (e.g., benzyl), cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, mercapt, alkylthio (e.g., methylthio), alkylsulfonyl (e.g., methansulfonyl, cthansulfonyl), optionally substituted alkylsulfonylamino (e.g., methanesulfonylamino, ethansulfonylamino, N-methylsulfonyl-N'-methylamino), optionally substiUited carbamoyl (e.g., alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl)), sulfamoyl, acyl (e.g., formyl, acetyl), formyloxy, halσformyl, oxal, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, snlfoamino, hydrazino, azido, ureido, amizino, quanidino, phthalimide, oxo, phosphoric acid residue, lower alkyl which is substituted with a phosphoric acid residue and may be intervened with a heteroatom group(s), aryl substituted with a phosphoric acid residue, aralkyl substituted with a phosphoric acid residtie, hydroxyl lower alkyl, preferably hydroxy, carboxy, halogen(F,Cl,Br,I), halo lower alkyl (e. g., CFs,CH2CFa, CH2CCl3), halo lower alkoxy (e.g., OCF3, OCH2CF3, OCH2CCI3), lower alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), optionallj' substituted amino (e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino), oxo, or phosphoric acid residue.
Examples of a substituent of "optionally substituted amino" or "optionally substituted carbamoyl" include mono- or di- lower alkyl, lower alkylcarbonyl, lower alkylsulfonyl, optionally substituted lower alkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g., carbamoylmethyl), mono- or di- lower alkylcarbamoyl lower alkyl (e.g., dimethylcarbamoylethyl), hydroxyl lower alkyl, heterocycle lower alkyl (e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonyl lower alkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- or di- lower alkylamino lower alkyl (e.g., dimethylaminoethyl)), lower alkoxy lower alkyl (e.g., methoxyethyl, ethoxymethyl, ethoxyethyl, isopropoxyethyl), acyl (e.g., formyl, optionally substituted lower alkylcarbonyl (e.g., acetyl, propionyl, butylyl, isobπtylyl, valeryl, isovaJeryl, pivaroyl, hexanoyl, octanoyl, methoxyethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl), lower alkoxy lower alkylcarbonyl (e.g., methoxyethylcarbonyl), lower alkylcarbamoyl lower alkylcarbonyl (e.g., methylcarbamoylehtylcarbonyl), alkoxycarbonylacetyl), optionally substituted arylcarbonyl (e.g., benzoyl, toloyl), optionally substituted aralkyl (e.g., benzyl, 4-fluorobenzyl), hydroxy, optionally substituted lower alkylsulfonyl (e.g., meth anesulfonyl, ethanesulfonyl, isopropylsulfonyl, 2,2,2-trifluoroothanesulfonyl, benzylsulfonyl, methoxj'ethylsulfonyl), lower alkyl, or arylsulfonyl optionally substituted with halogen (e.g., benzenesulfonyl, toluenesulfonyl,
4-fluorobenzenesulfonyl, fluorobenzenesulfonyl), cycloalkyl (e.g., cyclopropyl), aryl optionally substituted with lower alkyl (e.g., phenyl, trithyl), lower alkylaminosulfonyl (e.g., methylaminosulfonyl, dimethylaminosulfonyl), lower alkylaminocarbonyl (e.g., dimethylaminocarbonyl), lower alkoxycarbonyl (e.g., ethoxycarbonyl), cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclohexylcarbonyl), optionally substituted sulfamoyl (e.g., sulfamoyl, methylsulfamoyl, dimethylsulfamoyl), lower alkylcarbonylamino (e.g., methylcarbonylamino), heterocycle (e.g., morpholino, tetrahydropyranyl), optionally substituted amino (e.g., mono- or dralkylamino (e.g., dimethylamino), formylamino).
As to amino of "optionally substituted amino", "optionally substituted carbamoyl", or "optionally substituted carbamoylcarbonyl", two substituents on the amino together with the neighboring N atom may form an N-containiπg heterocyclo which optionally contains S and/or O in the ring (preferably 5- to 7- membered ring or saturated ring) and is optionally substituted with oxo or hydroxy. The optional S atom in the ring may be substituted with oxo. The N-containing heterocycle is preferably a 5- or 6-membcred ring such as piperadinyl, piperidino, morpholino, pyrrolidino, 2-oxopiperidino, 2-oxopyrrolidino, 4-hydroxymorpholino.
"Phosphoric acid residue" moans a group shown of the formula^ -PO(OH)2. "Optionally substituted phosphoric acid residtie" means a phosphoric acid residue wherein the OH part and/or a hydrogen of the OH is optionally substituted with a phosphoric acid residue, preferably shown by the formula^
Figure imgf000046_0002
(whorein, RA and R" each is independently ORc or NR15R13 (wherein Rc, R15 and R1 ' are each independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally sxibstituted aryl, optionally subst.txitcd heterocyclic gϊoup, or JLl13 and RR taken together with the neighboring N atom may form an optionally substituted heterocyclc (preferably 5- to 6- membcred ring)) or RΛ and R13 taken together with the neighboring P atom may form an optionally substituted heterocyclc (preferably 5- ( o 6- memberod ring)),
Preferably, RΛ and RB are bothOR0, or one of them is ORC and the other is NR0R1'.
Rc, Rn and Rκ each is preferably, independently, lower alkyl (e.g., methyl, ethyl).
The optionally substituted hetorocycle formed by RΛ and RB taken together with the neighboring P atom may be the following structure '
Figure imgf000046_0003
(wherein, the broken line means a part of the ring)
Hydroxy substituted with optionally substituted phosphoric acid residue is preferably hydroxy substituted with a phosphoric acid residue substituted with di lower alkyls, and more preferably a group of the formula-
Figure imgf000046_0001
Amino substituted with optionally substituted phosphoric acid residue is preferably amino substituted with a phosphoric acid residue substituted with di lower alky Is, and more preferably a group of the formula:
Figure imgf000047_0001
[0008] (More preferable embodiments)
R1 is hydrogen or lower alkyl, preferably hydrogen.
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH (hereafter also referred to as "M"), or lower alkylene or lower alkcnylene each may be intervened by the heteroatom, The term of "intervened by" means the following cases: 1) The heteroatom group is present between carbon atoms which constitutes the alkylene or alkcnylene.
2) The heteroatom group is attached to the N atom of the carbamoyl group neighboring to X.
3) The heteroatom group is attached to R2 neighboring to X,
The heteroatom group (M) may be the same or different, and one or more atoms. Examples of that lower alkylene is intervened by a heteroatom group include -M-CH2-, -CH2-M-CH3-, -CH2-M-, and -CH2-M-M-CH2-.
X is preferably a spacer consisting 1 to 3 joined atoms, X is more preferably lower alkylene or lower alkonylene each may be intervened by a heteroatom group, or O, X is most preferably Cl to C3 alkylene, C2 to C3 alkenylene, or O. Especially preferred is methylene or O.
R2 is optionally substituted aryl, preferably phenyl. A substituent on the aryl is the same or different, J to 3, preferably 1 to 2 substitucnt(s), including preferably halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, and lower alkylcarbamoyl, and Substituent group SlO optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substitutedphosphoric acid residue, hydroxyl substituted with optionally substitutedphosphoric acid residue, amino substituted with optionally substitutedphosphoric acid residue, lower alkyl substituted with optionally substitutodphosphoric acid residue (said lower alkyl may be intervened with a hetero atom group(s) selected from O, S, SO, SO2, NRβ (R0 is independently selected from the same substituent group for R'O, -N= and =N-), lower alkoxy lower alkyl, amino lower alkyl optionally substituted with mono- or di-lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl optionally substituted with mono- or di-lower alkyl, optionally substituted lower alkylsulfonylamino, halogenated lower alkoxy, hydroxyl lower alkyl), more preferably halogen, hydroxy,amino,cyano, lower alkyl, lower alkoxy or Substituent group Sl, and most preferred is halogen (e.g., F) and/or a group selected from Substituent group S l. A substituent on the aryl is preferably at the 4-position, R2 is more preferably phenyl or phenyl substituted with at least halogen, and most preferably 4-halogenophenyl (e.g., 4-F-phenyl), In another embodiment, R2 is preforably phenyl optionally substituted with 1 to 3 R(s) mentioned below.
In all compounds of the present invention, the structure of "-X-R2" is preferably shown by the formula below :
Figure imgf000048_0001
R each is independently a group selected from halogen and Substituent group S l.
Sxibstituent group S l! optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxyl substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, lower alkyl substituted with optionally substituted phosphoric acid residue (said lower alkyl may be intervened by a heteroatom groιιp(s) selected from CO, O, S, SO, SO2, NR" (R" is hydrogen or lower alkyl), -N= and =N-), lower alkoxy lower alkyl, optionally substituted amino lower alkyl (the substituent: mono- or di- lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), halogenated lower alkyl, lower alkoxy, optionally substituted carbamoyl (the substituent: mono- or di- lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), optionally substituted lower alkylsulfonylamino, halogenated lower alkoxy, and hydroxyl lower alkyl. m is an integer of 0 to 3, preferably 0 or 1 to 2. when m is 1, R is preferably halogen. When m is 2, R is more preferably the same or different group selected from halogen, lower alkyl, lower alkoxy, lower alkoxylower alkyl, halogenated lower alkyl, halogenated lower alkoxy, lower alkylsulfonylamino, carbamoyl, and lower alkylcarbamoyl. More preferably, R is two halogens, or halogen and another group. R preferably locates at the 4-position and optional another position of the benzene ring-.
R'5 can be a various substituent which does not bring a negative effect to the pharmacological activity, including hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy, and optionally substituted amino. Examples of substituent of "optionally substituted" include halogen, hydroxy, amino, lower alkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio, carbamoyl, lower alkylcarbamoyl, aryl, heterocyclic group, lower alkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, halogenated lower alkyl, halogenated lower alkoxy, and preferably halogen, hydroxy, amino, lower alkylamino, lower alkyl, and lower alkoxy. RJ is more preferably hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino, and most preferably hydrogen or lower alkyl (e.g., methyl), esp. hydrogen.
Z3 shows C, GH, optionally substituted lower alkylene, lower alkenylene etc , and Z2 and R4 of Z1 taken together form a ring, whereby compound (I) shows a tricyclic compound (l-1) or (I- 11) shown below, or its derivative, tetracyclic compound,
Figure imgf000049_0001
A ring is optionally substituted hotorocycle containing at least an N atom, The hotorocyclo is a 5- to 7-membered ring which contains preferably \ to 3, more preferably 2 to 3 atoms of O, S and/or N. The heterocyclo is preferably selected from the above heterocycle, The arc optionally contains 1 to 2 heteroatom(s) at any possible position. One of preferable embodiments of A ring is an optionally substituted ring shown below.
Figure imgf000050_0001
(Z is CH2, O, S, SO, SO2 or NRi')) A ring is preferably a ring of (a), (b), or (c).
Z is preferably O or Nil1".
When Z is NR19, examples of R19 include l)hydrogen, 2)optionally substituted lower alkyl (the substituent is e.g., amino optionally substituted with mono- or di- lower alkyli cycloalkyl, hydroxy; optionally substituted heterocyclic group (preferably 5- to 7-membered ring, e.g., furyl, thionyl, thiazolyl, pyridil, morpholino, imidazole; examples of the substituont include lower alkyl, halogen); optionally substituted heterocyclecarbonyl (the heterocyclo is preferably 5- to 7-membcred ring, e.g., lϊiorpholinocarbonyl); optionally substituted phenyl (the substituent is e.g., lower alkyl, amino, lower alkylamino, hydroxy, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylthio, lower alkylsulfonyl), acetylamino, carbamoyl, carbamoyl substiUitcd with mono- or di- lower alkyl, lower alkylsulfonylamino, lower alkoxy, carbonyl, halogen, thiol, lower alkylthio), 3) lower alkenyl, 4) acyl (e.g., lower alkylcarbonyl), 5) lower alkylsulfonyl, R10 may be selected from Substituent group S2 shown below.
The other substituent; on A ring may be selected from Rlr> to Rl fl or Substituent group S2, preferably lower alkyl. Substitucnts on A ring may form a condensed ring or a spiro ring as mentioned below, whereby compoxuid (1) includes a tetracyclic compound.
A ring is more preferably any of the following rings:
Figure imgf000051_0001
(wherein, R20 to R40 are each independently a group selected from Substituent group S2, or any two groups of R20 to R'' ", which bonds to the same carbon atom, taken together with the carbon atom, may form a spiro ring, i.e., an optionally substituted carbocyle or optionally substituted heterocycle, or each combination of (R20 and R22), (RM and R2O, (R2β and R^), (R" and R3β), (Rsci and R^), (R" and R;«), (R-30 and R^), (R37 and R.38), and (Ri3flandR<10), taken together with the neighboring atom, may form an optionally substituted carbocyle or optionally substituted heterocycle,
Substitution group S2: hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclccarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocydeoxycarbonyl, optionally substitutcd aminocarbonyl, optionally svibstitxited phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened with a heteroatom gτoup(s) selected from CO, O, S, SO, SO2, NR5 (R5 is independently selected from the same substitution group as R''), -N= and =N-)
The stereochemistry of an asymmetric carbon represented by * shows the R- or S- configuration, or a mixture thereof)
In one embodiment, R-" Lo R40 each is preferably hydrogen, optionally substituted lower alkyl (examples of the substituent: Oil, lower alkoxy, cycloalkyl, lower alkylthio, lower alkylsulfonyl, heterocyclic group, aryl, optionally substituted amino (examples of the substituent: lower alkyl, acyl)), cycloalkyl, optionally substituted aryl (examples of the substituont: OH, lower alkyl), and optionally substituited heterocyclic group,
In one embodiment, R*o to R2fi , R" to Rs0, and R^ to R^, each is preferably hydrogen, C1-C8 alkyl, C6-C1<1 aryl C1-C8 alkyl, C6-C14 aryl, or alkoxy.
In one embodiment, R'iG, R33, and R40, each is preferably hydrogen, C3-6 cycloalkyl, heterocycle, or C1 -8 alkyl optionally substituted with hydroxy, C3-6 cycloalkyl, alkoxy, heterocycle, heteroaryl, C6-14 aryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8 alkyl or C1-8 alkyl.
More Preferred embodiments are shown below for example
I) When A ring is A- I, preferred is that 1) Z is NR26' and R^e and R^ taken together form hetorocycle, and the others are hydrogens; 2) Z is O or NR36, (R20 and R22) or (RiA and R2'1) taken together form cycloalkyl which is substituted with phenyl, the others are hydrogens or optionally substituted lower alkyl.
W When A ring is A-2, preferred is that l) Z is O, R2' 1 or R28 is lower alkyl, and the others are hydrogens; 2) Z is NR'*1 and RA0 and R31 taken together form heterocycle and the others are hydrogens, or R21 and R29 taken together form cycloalkyl and the others are hydrogens I 3) Z is O, R27 and Rao taken together form cycloalkyl which may bo condensed with phenyl, and the others are hydrogens
R1'1 and Rχ arc each independently hydrogen, optionally substitutedlower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkcnyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted hetorocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocyclooxycarbonyl, optionally substituted aminocarbonyl, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy optionally substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened with a heterotom group(s) selected from O, S, SO, SO2, NRa (R'1 is hydrogen or lower alkyl), -N= and =N-).
Ru and R* arc each independently, preferably, hydrogen, hydroxyl, optionally substituted lower alkyl (the substituent is preferably, e.g., amino, lower alkyl amino, hydroxy, lower alkoxy) R1'1 and Rx arc preferably hydrogens.
A broken line in the compound (J- I) represents the presence or absence of a bond, provided thai, when the broken line represents the presence of a bond, Rx is not present,
[0009]
The compound (I) includes the following compounds,
Figure imgf000054_0001
(wherein each symbol is as defined above)
)
Figure imgf000054_0002
V ring means the same heterocycle as A ring-, preferably 5- to 7-memberod ring, and the substituents on F ring are the same as those for A ring. The other symbols are as defined above. 04
Figure imgf000055_0001
)
(wherein each symbol is as defined abovei Z is O or NR10; R15 to R19 aro each independently hydrogen or a group selected from the above Substiluont group S2, or each combination of (U^ and R "O, (R" and R1S), (R ie and Riβ), and (R1S and R1") taken together with the neighboring atom(s), may form an optionally substituted carbocycle (preferably 5- to 6τnembered ring) or an optionally substituted hetorocyle (preferably 5- to 6-membered ring ); or each combination of (R15 and R] (i) and (R17 and R18) taken together may fom oxo)
Compound (I -3) is preferably as follows.
(1) R1 is hydrogen; R3 is hydrogen; m is .1 or Zl R1'1 is hydrogen.
(2) m is 1 or 2, R is each independently halogen, halogenated lower alkyl, lower alkoxy, halogcnated lower alkoxy, lower alkoxy lower alkyl, hydroxy lower alkyl, optionally substituted amino lower alkyl (the substituont is mono- or di- lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), optionally substituted carbamoyl (the sυbstitucnt is mono- or di- lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl), phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue or sulfonylamino optionally substituted with lower alkyl l R1 is hydrogen; R'! is hydrogen; R1'1 is hydrogen, hydroxyl or lower alkyl optionally substituted with mono- or di- lower alkylamino; Z is O or NR13 (R10 is hydrogen or lower alkyl, lower alkoxy lower alkyl, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue). (3)R is each independently, -F, -CF3, -OMc, -OCF3, -CH2OMe, -CH2OH, - CH2N(Me)2, -CONHMe, -CON(Me)2, -CHsPO(OEt)2, -PO(Om)2, -NHSO2Me, or -NMoSO2Me IR1 is hydrogen; R3 is hydrogen; m is 1 or 2; RH is hydrogen, hydroxyl or -CH2N(Me)2; Z is O or NR's (Rio is hydrogen or -CH(Me)2, -(CHu)2OMe, -(CHu)2PO(OEt)8).
(4)R15 and Rio arc hydrogens; R17 and R18 are hydrogens or taken together with the neighboring- atom form a 3- to 7-χnembored carfaocyle; and/or Z is O or NH, This case preferably also satisfys the above (2) or (3).
)
Figure imgf000056_0001
D ring means the same hetox-ocycle as A ring, preferably 5- to 7-mcmbered ring, and the substituonts on D ring are the same as those for A ring. The other symbols are as defined above,
The structure of compound (T) has at least the following characteristics,
(1) The main structure, condensed heterocycle, is substituted with oxo (=O), hydroxy 1 (OH) and oxo.
(2) A substituted carbamoyl group (-CONR1XR2) is attached to the position neighboring to the oxo group on the condensed hereocyclc.
The above structure contribxites to a remarkably potent integrase inhibitory activity and/or cell-growth inhibitory activity against virus including HlV. In contrast, the structures of the other parts such as Z1, Z-, and R3 oach may be of variety, being optionally substituted or optionally condensed, and its condensed ring is also optionally substituted.
The present invention provides a pharmaceutically acceptable salt or a solvate of compound (I), All theoretically possible tautomer, geometrical isomer, optically active compound, and racomate thereof are within the scope of the invention,
Pharmaceutically acceptable salts of a compound of the present invention include, as basic salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine or procaine salts; aralkyl amine salts such as N, N-diben&ylethylonediamine salts; heterocyclic aromatic amine salts such as pyridin salts, picolino salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltπbutylammonium salts, methyltrioctylammonium salts or
(ctrabutylammonium salts; and basic amino acid salts such as arginine salts or lysine salts, Acid salts include, for example, mineral acid salts such as hydrochloride, sulfates salts, nitrate salts, phosphates salts, carbonates salts, hydrogencarbonates or perchlorate; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tararic acid salts, malatcs, citrates salts, ascorbates, formic acid; sulfonates such as methanesulfonatcs, isethionates, benzenesulfonates, or P-toluenesulfonatesi and acidic amino acid salts such as aspartates or glutamates, Solvates of a compound of the present invention include alcholates and hydrates.
L0012]
A general process for producing the present compound will be exemplified below.
(Method of preparing raw material) [Chemical formula 41]
ϋϋ
Figure imgf000058_0001
(wherein L1 is a leaving group (e g,; halogen); P 1 and P2 are a hydroxy protecting group; Pa is a carboxy protecting group (e,g, : lower alkyl); Ra and Rb are hydrogen or a substituent on an amino group)
Examples of a hydroxy protecting group (P1, P2) include acyl (e.g.: acetyl, pivaloyl, benzoyl), aralkyl (e.g.: benzyl), lower alkyl (e.g. : methyl), alkoxyalkyl (e.g. : methoxymethyl, methoxy ethyl), lower alkylsulfonyl (e.g.: methanesulfonyl), arylsulfonyl (e.g. : benzenesulfonyl, tolvicnesulfonyl), alkoxycarbonyl (e.g. : methoxycarbonyl) and the like,
As a carboxy protecting group (PJ), lower alkyl (e.g.; methyl, ethyl), and aralkyl (e.g.: benzyl) are exemplified, [0013] (First step)
The present step is a reaction for condensing a compound (II) and a compound (III) to synthesize a compound (IV). The reaction may be performed according to the condition for a reaction of amidating carboxylic acid which is generally performed. A compound (II) may be reacted as it is, or may be reacted after converted into corresponding acid chloride or active ester. Preferably, the reaction is performed in a suitable solvent in the presence of a condensing agent,
As a condensing agent, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the like may be used, If necessary, a reagent such as 1-hydroxybenzotriazole and N-hydroxysuccinimide, or a base such as triethylamine, N-methylmorpholine, and pyridine may be added.
A reaction temperature is 0 to 150°C, preferably room temperature to 70°C.
As a reaction solvent, a noirprotonic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like are preferable.
A reaction time is a few minutes to a few tens hours, preferably 9 to J 7 hours.
(Second step)
The present step is a reaction for introducing a protected hydroxy group (OP1) into a compound (IV) to produce a compound (V), The reaction may bo performed according to the condition for an alkoxylatmg reaction which is generally performed.
For example, a compound (V) in which P1 is methyl can be synthesized by reacting a compound (IV) with metal alkoxide (e.g.: sodium methoxidc).
A reaction temperature is 0 to 200°C, preferably 80 to 120°C.
As a reaction solvent, alcohol, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 5 to 10 hours, (Third step)
The present stop is a reaction for protecting a hydroxy groiip of a compound (V) to produce a compound (Vl). The reaction may be performed according Lo the condition for a reaction of protecting a hydroxy group which is generally performed. Fox example, by using diisopropyl azodicarboxylate or diethyl azodicarboxylate together with an alcohol and various phosphinos, a compound (VI) in which P2 is alkyl can be synthesized. A reaction temperature is 0 to 100°C, preferably 0°C to room temperature.
As a reaction solvent, THF, toluene, dichloromethane and the like are exemplified. A reaction time is a few minutes to a few tens hours, preferably t to 3 hours.
(Fourth step)
The present step is a reaction of oxidizing a nitrogen atom of a compoung (Vl) to produce a compound (VII), The reaction may be performed according to the condition for an oxidation reaction using an oxidizing agent which is generally performed.
A reaction temperature is 0 to 100°C, preferably under icccooling to room temperature,
As a reaction solvent, chloroform, methylene chloride, acetic acid and the like are exemplified.
Examples of an oxidizing agent include metachloroporbenzoic acid, hydrogen peroxide and the like. A reaction time is a few minutes to a few tens hours, preferably 1 to 5 hoxirs.
(Fifth step)
The present step is a reaction for hydroxylating a methyl group of a compound (VII). Preferably, after acetoxylation by a reaction with acetic anhydride (reaction temperature^ 0 to 150°C, preferably 120 to 140°C), this may bo hydrolyzcd (e.g.: treatment with a base (e.g. : alkali metal hydroxide)).
A reaction time is a few minutes to a few tens hours, preferably 0.5 to 2 hours for acetoxylation, and 0.5 to 1 hour for hydrolysis.
(Sixth stop)
The present step is a reaction for oxidizing a hydroxy group of a compound (VIII) to synthesize a compound (IX).
A reaction temperature is 0 to 150°C, preferably room temperature to 70°C. As a reaction solvent, chloroform and the like are exemplified.
As an oxidizing agent, dimethyl sulfoxide and the like are exemplified,
A reaction time is a few minutes to a few tens hours, preferably 0.1 to 1 hour.
(Seventh step)
The present step is a reaction for oxidizing a formyl group of a compound (IX) to synthesize a compound (X). A reaction temperature is 0 to _ 50°C, preferably under ice-cooling to room temperature.
As a reaction solvent, an alcohol and the like are exemplified.
As an oxidizing agent, potassium hydroxide and iodine are exemplified. A reaction time is a few minutes to a few tens hours, preferably 0,5 Lo 3 hours.
(Eighth step)
The present step as a reaction for deprotecting an OP2 part of a compound (X) to synthesize a compound (Xl), The reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
A reaction temperature is 0 to 150°C, preferably under ice-coolmg to room temperature.
As a reaction solvent, acetonitrile, methylene chloride, THF and the like arc exemplified.
A reaction time is a few minutes to a few tens hours, preferably 1 to 3 hours,
(Ninth step)
The present step is a reaction for deprotecting an OP1 part of a compound (Xl) to synt hesize a compound (L-A), The reaction may be treated preferably with a Lewis acid (e.g.: a hi mi mi m chloride),
A reaction temperature is 0 to 150°C, preferably 10 to 50°C.
As a reaction solvent, methylene chloride, THF and the like are exemplified.
A reaction time, is a fow minutes to a few tens hours, preferably 1 to 3 hours,
(Tenth step)
The present step is a reaction for deprotecting an ester part (COOP3) of a compoxmd (X) to synthesize carboxylic acid (XII). Preferably, hydrolysis with an alkali (e.g.: NaOH) may be performed.
A reaction temperature is 0 to IB0°C, preferably 10 to 50°C.
As a reaction solvent, methanol, water and the like are exemplified, A reaction time is a few minutes to a few tens hours, preferably a few minutes to 2 hours,
Carboxylic acid (XII) can be converted into various derivatives (c,g\; amide).
(Eleventh step)
The present step is a reaction for reacting a compoiind (XIl) with various amines to synthesize a compound (XIlI). The reaction may be performed according to the condition for a reaction of amidatmg carboxylic acid which is generally performed and, for example, the reaction may bo performed as in the first step. A reaction temperature is 0 to 150°C, preferably room temperature to 70°C.
As a reaction solvent, a noivprotonic solvent can be broadly used, and tetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylene chloride, chloroform and the like arc preferable.
A reaction time is a few minutes to a few Lens hours, preferably a few minutes to 3 lioxirs.
An amide part of the resulting compound (XIIl) may be further chemically modified (e.g.: N-alkylation).
(Twelfth step)
The present step is a reaction for cleprotecting OP1 and OP2 parts of a compound (XIII) to synthesize a compound (I-B). The reaction may be performed according to the condition for a reaction of deprotecting a hydroxy protecting group which is generally performed.
For example, when pyridine hydrochloride is used, a reaction temperature is 0 to 200°C, preferably 150 to 180 degree,
A reaction time is a few minutes to a few tons hours, preferably 3 to 5 minutes. '
(Thirteenth step)
The present step is a reaction for doprotecting an ester part (COOP3) of a compound (XI) to synthesize carboxylic acid (XIV). Preferably, hydrolysis with an alkali (e.g. : lithium hydroxide) may be performed.
A reaction temperature is 0 to 150°C, preferably 10 to 50°C.
As a reaction solvent, methanol, water and the like are exemplified.
A reaction time is a few minutes to a few tens hours, preferably a few minutes to 3 hours.
(Fcαirteenth step)
The present step is a reaction for deprotecting an OP1 part of a compound (XIV) to synthesize a compound (I-C). The reaction may be treated preferably with a Lewis acid (e.g.: boron tribromide) .
A reaction temperature is 0 to 150°C, preferably under ice-cooling to room temperature.
As a reaction solvent, cϋchloromethano and the like are exemplified. A reaction time is a few minutes to a few tens hours, preferably a few mimites to 5 hours, [0014]
The monocyclic carbamαylpyridone derivative obtained above is derived into a bicyclic compound by the following method.
(Process 1) [Chemical formula 42]
Figure imgf000064_0001
(wherein R', X, R2, P1, P3 and R4 arc as define above, and L2 is a leaving group such as halogen etc.)
(Fifteenth step)
The present step is a reaction for reacting the compound (XI) or a compound (XD which is a tautomer thereof with an allyl compound to synthesize a compound (XV), A compound (XI') can bo synthesized, for example, according to the method of Example A- I.
The reaction is performed preferably in the presence of a base (e.g. : cesium carbonate).
A reaction temperature is 0 to T 00°C, preferably 10 to 40°C.
As a reaction solvent, dimethylformamide and the like are exemplified, A reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours. (Sixteenth step)
The present step is a reaction for oxidizing a compound (XV) to synthesize a compound (XVl). As an oxidizing agent, osmium tetraoxidc and alkali metal osmium tetraoxidc (e. ^KEOSCM) are exemplified, A reaction teinpcraturwo is 0 to 100°C, preferably 10 to 40°C. As a reaction solvent, 1/i-dioxane, tetrahydrofuran and the like are exemplified,
A reaction time is a few minutes to a few tens hours, preferably 1 to 5 hours,
(Seventeenth step)
The present step is a reaction for reacting a compound (XVI) with amine (XVIl) to perform dehydration condensation to synthesize a compound (XVIII),
A reaction temperature is 0 to 200°C, preferably M0 to 180°C,
As a reaction solvent, methylene chloride, acetonitrile and the like are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 0.5 to 1.5 hours,
(Eighteenth stop)
The present step is a reaction for deprotecting a compound (XVIIl) preferably with an acid to synthesize a compound (XIX), and may be performed according to the condition for a conventional reaction of deprotecting a protected hydroxy group. A reaction temperature is 0 to 200°C.
As an acid, pyridine hydrochloride, trifluoroacetic acid and the like are exemplified.
As a reaction solvent, the acid and trimethylsilyl iodide are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 15 minutes to 1 hour,
(Nineteenth step)
The present step is a reaction for reducing a compound (XVlIl) to synthesize a compoxind (XX).
As a reducing agent, Hs/Pd - C and the like are exemplified,
A reaction tempcratuer is 0 to 100°C, preferably 10 to 30°C.
As a reaction sovelnt, dimethylformamide, methanol, tetrahydrofuran and the like arc exemplified, A reaction time is a few minutes to a few tens hours, preferably 5 to 20 hours. 10015] (Process 2) The intermediate (XVIII) may be also synthesized by a method shown below.
[Chemical formula 43j
Figure imgf000066_0001
(Twentieth step)
The present step is a reaction for reacting a compound (XlV) with a compound (XXI) to synthesize a compound (XXII). The present reaction may be performed according to the condition for a conventional amidation reaction,
A reaction temperature is 0 to 100°C, preferably 0 to 50°C. As a reaction solvent, dimethylformamide, methylene chloride, tetrahyrlrofnran and the like are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours.
(Twenty -first step)
The present step is a reaction for reacting a compound (XXII) with an acid to perform deprotection and intramolecular ring closure, to synthesize a compound (XXlJI). The present reaction may be performed according to the condition for a conventional reaction of deprotecting acetal.
A reaction temperature is 0 to 100°C, preferably room temperature to 80°C. As a reaction solvent, dioxane, totrahydrofuran and the like are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 0,5 to 1 hour.
As an acid, hydrochloric acid, and paratoluonesulfonic acid are exemplified,
(Twenty-second step)
The present step is a reaction for dehydrating a compound (XXIlI) to synthesize a compound (XXJV). The present reaction may bo poformed according to the condition for a conventional dehydration reaction. A reaction temperature is 0 to 100°C, preferably room temperature to 80°C.
As a reaction solvent, acetonitrile, methylene chloride and the like are exemplified ,
A reaction time is a few minutes to a few tens hoxirs, preferably 1 to 5 hours, 10016J (ProceβvS 3) [Chemical formula 44j
Figure imgf000067_0001
(Twenty-third step)
The present step is a reaction for reacting a compound (XVI) with amine (XXIV) to perform dehydration condensation to synthesize a compound (XXV) according to the seventeenth step or a method of synthesizing1 a compound 17- 1. Preferably, as a reaction catalyst, an acid (e.g. ' acetic acid) is added, and a microwave reaction apparatus is used. A reaction temperature is 0 to 200°C, preferably 140 to 180°C.
As a reaction solvent, methylene chloride, acetonitrile and the like are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 0,5 to 1,5 hours.
(Twenty-fourth step) The present step is a reaction for deprotecting a compound (XXV) preferably with an acid to synthesize a compound (XXVI) according to the eighteenth step, and may be performed according to the condition for a conventional reaction of deprotecting a protected hydroxy group.
A reaction tempratnre is 0 to 200°C. As an acid, pyridine hydrochloride, trifluoroacetic acid and the like are exemplified,
As a reaction solvent, the aforementioned acid and trimethylsilyl iodide are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 15 minutes to 1 hour. [0017] (Process 4) [Chemical formula 45]
Figure imgf000069_0001
(Twenty-fifth step)
The present step is a reaction for reacting a compound (XIV) with a compound (XXIV) to synthesize a compound (XXVII) according to the twentieth step, The present reaction may be performed according to the condition for a conventional amidation reaction. A reaction temperature is 0 to 100°C, preferably 0 to 50°C.
As a reaction solvent, dimethylformamide, methylene chloride, tetrahydrofuran and the like are exemplified. A reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours.
(Twenty-sixth step)
The present step is a reaction for reacting a compound (XXVII) or a taxitomer thereof with an allyl compound to synthesize a compound (XXVIII) according to the fifteenth step.
A reaction is performed preferably in the presence of a base (e,g,: cesium carbonate).
A reaction temperature is 0 to 100°C, preferably 10 to 40°C.
As a reaction solvent, dimethylformamide and the like arc exemplified.
A reaction time is a few minutes to a few tens hours, preferably 1 to 10 hours,
(Twenty-seventh step)
The present step is a reaction for oxidizing a compound (XXVIIl) to synthesize a compoxmd (XXIX) according to the sixteenth stop ,
As an oxidizing agent, osnmim tetraoxide and alkali metal osmium tetraoxide (e.g.: K2θsθd) arc exemplified.
A reaction temperature is 0 to 100°C, preferably 30 to 40°C,
As a reaction solvent 1,4-dioxane, tetrahydrofuran and the like are exemplified.
A reaction time is a few minutes to a few tens hours, preferablky J to 5 hours.
(Twenty-eighth step)
The present step is a reaction for dehydration-condensing a compoxind (XXIX) to synthesize a compound (XXX) according to the seventeenth step or a method of synthesizing a compound J 7-1. Preferably, as a reaction catalyst, an acid (e.g.: acetic acid) is added, and a microwave reaction apparatus is used.
A reaction temperature is 0 to 200°C, preferably 140 to 180°C.
As a reaction solvent, methylene chloride, acetonitrile and the like are exemplified.
A reaction time is a few minutes to a few tens hours, preferably 0.5 to 1,5 hours,
(Twenty- ninth step)
The present step is a reaction for deprotecting a compoiind (XXX) preferably with an acid to synthesize a compovmd (XXXI) according to the eighteenth step, and may be peformed according to the condition for a conventional reaction of deprotecting a protected hydroxy group.
A reaction temperature is 0 to 200°C. As an acid, pyridine hydrochloride, trifhioroacetic acid and the like are exemplified,
As a reaction solvent, the aforementioned acid and lrimethylsilyl iodide are exemplified. A reaction time is a few minutes to a few tens hours, preferably 15 minutes to 1 hour,
[0018] (Process 5)
A compound (1-3) in which Z is NR1H can be synthesized according to the following reaction scheme, according to Process 4, [Chemical formula 46]
Figure imgf000072_0001
[0019]
(Process 10) lCliemical formula 5lJ
Figure imgf000073_0001
(wherein respective symbols are as defined above)
(Forty-ninth step)
A compound (XIV- 16) is obtained by reacting a compound (XlV) with an amine reagent, according to the thirty-fifth step.
(Fiftieth step)
A compound (XlV- 17) is obtained by subjecting a compound (XIV-16) to a general acetal deprotecting reaction according to the forty-fourth step .
(Fifty-first stop)
A compound (XJV-18) is obtained (D ring formation) by deprotecting a P 1 part of a compound (XTV- 14) according to the thirty-eighth step.
[00201
Tho present invention further provides various intermediates (I-P) shown below and a process for preparing the same, as well as a process for preparing the above mentioned compound (I) comprising the deprotection of the intermediate.
(Intermediates) )
Figure imgf000074_0001
(P1 is a hydroxyl-protecting group; the other symbols are as defined above)
Preferred compounds are shown below. Each P1 is a hydroxyhprotccting group, such as C6-14arylC1-8alkyl (e.g., benzyl (=Bn)).
Figure imgf000074_0002
Preferably, wherein Re is one or two halogen; Rz is C1-8alkyl, C6-14arylC1-8alkyl, C6-14aryl, or alkoxy; and P1 is C6-14arylC1-8alkyl;
Figure imgf000074_0003
Preferably, wherein Re is one or two halogen; Rz is C1-8alkyl, C6-14arylC1-8alkyl, C6-14aryl, or alkoxy; and P1 is C6-14arylC1-8alkyl;
Figure imgf000074_0004
Preferably, wherein Re is one or two halogen; and P1 is C6-14arylC1-8alkyl;
Figure imgf000075_0001
Preferably, wherein Re is one or two halogen; and P1 is C6-14arylC1-8alkyl;
Figure imgf000075_0002
Preferably, wherein Re is one or two halogen; and P1 is C6-14arylC1-8alkyl;
Figure imgf000075_0003
Preferably, wherein Re is one or two halogen; and P1 is C6-14arylC1-8alkyl;
Figure imgf000075_0004
Preferably, wherein Re is one or two halogen; and P1 is C6-14arylC1-8alkyl;
Figure imgf000075_0005
Preferably, wherein Re is one or two halogen; and P1 is C6-14arylC1-8alkyl;
Figure imgf000076_0001
Preferably, wherein Ii" is one or two halogen; R' is Ci salkyl; R'1 is hydrogen, C3 δcycloalkyl, , hetorocycle, or C i salkyl optionally substituted with hydroxy, C j c>cycloalkyl, alkoxy, heterocycle, heteroaryl, Ct πaryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8alkyl or C1-8alkyl.
Figure imgf000076_0002
Preferably, wherein R0 is one or two halogen; R' is Ci salkyl, R*1 is hydrogen, Cj Gcycloalkyl, , heterocycle, or Ci salkyl optionally substituted with hydroxy, C3 t-cycloalkyl, alkoxy, heterocycle, heteroaryl, CG πaryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci βalkyl or Ci βalkyl, and P1 is Ce i iaiylCi salkyL
Figure imgf000076_0003
Preferably, wherein Rα is one or two halogen, R'1 is hydrogen, C 3 βcycloalkyl, , heterocycle, or Ci salkyl optionally substitu ted with hydroxy, C,? βcycloalkyj, alkoxy, heterocycle, heteroaryl, Cr, uaryl, or amino, wherein said amino may be op tionally substituted with -C(O)C1-8alkyl or C1-8alkylJand P1 is Gr, πarylCi salkyl;
Figure imgf000077_0001
Preferably, wherein Rc is one or two halogen; Rz1 is hydrogen, C3-6cycloalkyl, , heterocycle, or C1-8alkyl optionally substituted with hydroxy, C3-6cycloalkyl, alkσxy, heterocycle, heteroaryl, C6-14aryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8alkyl or C1-8alkyl; and P1 is C6-14arylC1-8alkyl;
Figure imgf000077_0002
Preferably, wherein Re is halogen; and P1 is C6-14arylC1-8alkyl;
The above intermediates, compound (I-20a), (I-20b), (I-21a), (I-21b), (I-22a), (I-22b), (I-23a), (I-23b), (I-24a), (l-24b), (I-25), (I-26), or (I-27), can be prepared by condensing a compound of the formula:
Figure imgf000077_0003
wherein Re is one or two halogen; and R50 is C1-8alkyl;
with each amine shown below, respectively:
Figure imgf000077_0004
wherein Rz is C1-8alkyl, C6 -14arylC1-8alkyl, C6 -14aryl, or alkoxy;
Figure imgf000078_0001
wherein Rκ is C1-8alkyl, Cn MarylC1-8alkyl, Co-i-iaryl, or alkoxy;
Figure imgf000078_0002
wherein β/ is Ci βalkyl; K?<1 is hydrogen, Cg δcycloalkyl, , heterocycle, or C1-8alkyl optionally substituted with hydroxy, Ca Gcyoloalkyl, alkoxy, heterocyclo, heteroaryl, Cf) l'laryl, or amino, wherein said amino may be optionally substituted with -C(O)C1 salkyl or C1-8alkyl;
Figure imgf000078_0003
wherein R^ is Cj-βalkyl; JR/1 is hydrogen, Cj ocycloalkyl, , heterocyclo, or C1-8alkyl optionally substituted with hydroxy, Ca-ocycloalkyl, alkoxy, hetorocyolc, heteroaryl, Cb j-iaryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci-8alkyl or d-βalkyl;
Figure imgf000078_0004
wherein IV is hydrogen, Cj-ccycloalkyl, , heterocycle, or C1-8alkyl optionally substituted with hydroxy, Ca ccycloalkyl, alkoxy, hotorocyclo, hetoroaryl, CB naryl, or amino, wherein said amino may be optionally substituted with — C(O)C1-8alkyl or Ci βalkyl;
Figure imgf000079_0001
wherein RvΛ is hydrogen, C3-6cycloalkyl, , heterocycle, or C1-8alkyl optionally substituted with hydroxy, Cs ocycloalkyl, alkoxy, heterocycle, heteroaryl, Ce-πaryl, or amino, wherein said amino may bo optionally substituted with — O(O)C1-8alkyl or Ci salkyli
Figure imgf000079_0002
The condition for the above condensation is illustrated below for example, Examples of the solvent include halocarbons such as dichloromethanc, dichloroethanc, and acetic acid.
The reaction temperature is preferably, 0 to 200 °C, more preferably, 50 to 170°C . The reaction time is usually several minutes to several hours.
The above intermediates, compound (T-20a), (1-20b), (1-2. a), (I-21b), (J-22a), (I-22b), (l-23a), (I-23b), <I-24a), (l-24b), (1-25), (1-26), or (1-27), can be doprotected to give each corresponding doprotected compound wherein P1 is hydrogen, or its pharmaceutically acceptable salt, which arc encompassed within the scope of compound (I) of the present invention.
In addition, the present compoxmd obtained above may be further chemically modified to synthesize another compound, In addition, when there is a reactive functional group (e.g. : OH, COOH, NHa) on a side chain part etc. in the above reaction, the group may be protected before the reaction and may be deprotectcd after the reaction, if desired.
The present compound is useful, for example, as a drug such as an anti-virus drug. The present compound has the remarkable inhibitory action on integrase of a virtis. Therefore, the present compound can be expected to have the preventive or therapeutic effect for various diseases derived from a virus which produces at least integrase, and is grown at infection in an animal cell, and is useful as an integraso inhibiting agent for retrovirus (e.g. HlV- I, HIV-2, HTLV- I, SIV, FIV etc.), and is useful as an anti-HIV drug etc,
In addition, the present compound ma}' bo used in joint use therapy by combining an antiΗIV drug having the different action methanism such as a reverse transcriptase inhibiter and/or a protease inhibiting agent, Particularly, currently, an integrase inhibiter is not marketed, and it is useful to use in joint use therapy by combining the present compound with a reverse transcriptase inhibiter and/or a protease inhibiter.
Further, the above use inchidcs not only use as a medical mixture for anti-HIV, but also use as a joint use agent for increasing the anti-HIV activity of other anti-HIV drug such as cocktail therapy.
In addition, the present compound can be used in order to prevent infection with a retrovirus vector from spreading into a tissue other than an objective tissxie, iipon use of a retrovirus vector based on HIV or MLV in the field of gene therapy. Particularly, when a cell is infected with a vector in vitro, and the cell is returned into a body, if the present compound is administered in advance, extra infection can be prevented in a body.
The present compound can be adminitetered orally or parenterally, In the case of oral administration, the present compound can be also used as a conventional preparation, for example, as any dosage form of a solid agent such as tablets, powders, granules, capsules and the like' an aqueous agent; an oily suspension; or a liquid agent such as syrup and elixir. In the case of parenteral administration, the present compound can be used as an aqtieous or oily suspension injectable, or a nasal drop, Upon preparation of it, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsificrs, suspending agents, preservatives, stabilizers and the like may be arbitrarily used. As an anti-HIV-drug, particularly, an oral agent is preferable. A preparation of the present invention is prepared by combining (e.g. mixing) a therapeutically effective amount of the present compound with a pharmaceutically acceptable carrier or diluent.
A dose of the present invention is different depcniding on an administration method, an age, a weight and conditionn of a patient, and a kind of a disease and, usually, in the case of oral administraton, about 0.05mg to 3000mg, preferably about 0.lmg to 1000mg may be administered per adult a day, if necessary, by dividing the dose, In addition, in the case of parenteral administration, about 0.0lmg to 1000mg, preferably about 0.05mg to 500mg" is administered per adult a day. Examples are shown below.
[0025] Example A-I)
O-Hydroxy-2-CB-methoxy-ethy^-1^-dioxo-1jS-dihydro-2 -pyridC1,2-a]pyrazine -7-carboxylic acid 4-fluoro-banzylamide Example B-1)
9-.Hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo- 1,3,4,8-tetrahydro-2H-pyrid[1,2-a]py razine-7-carboxylic acid 4-fhιoro-benzylamide
[Chemical formula 52]
Figure imgf000081_0001
Figure imgf000082_0001
1) Mantol 1 (I 89g, 1,5mol) was dissolved in dimethylformamide (1890ml), and benzyl bromide (184ml, l,5mol) was added, Aftor the solution was stirred at 80°C for 15 minutes, potassium carbonate (228g, 1.65mol) was added, and the mixture was stirred for J hour, Aftor the reaction solution was cooled I o room temperature, an inorganic salt was filtered, and the filtrate was distilled off under reduced pressure. To the again precipitated inorganic salt was added tetrahydrofuran (1000ml), this was filtered, and the filtrate was distilled off tinder reduced pressure to obtain the crude product (329g, >100%) of 3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil.
NMR (CDClβ)δ: 2.09(3H, s), 5.15(2H, s), 6.36(1PI, d, J=5.6Hz) , 7.29-7.4l(5H, m), 7,60(1H, d, J=5.61Iz) .
2) The compound 2 (162, 2g, 750mmol) was dissolved in ethanol (-187ml), and aqueous ammonia (28%, 974ml) and a 6N aqueous sodium hydroxide solution (150ml, O00mmol) were added. After the reaction solution was stirred at 90 °C for 1 hour, this was cooled to under ice-cooling, and ammonium chloride (58g, 10S0mmol) was added, To the reaction solution was added chloroform, this was extracted, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl alcohol and diethyl ether were added to the residue, and precipitated crystals were filtered to obtain 3-benzyloxy-2-methyl- 1H-pyridine-4-one 3 (69.1g, 43%) as a pale yellow crystal.
NMR (DMSO-dfi)δ: 2.05(3H, s), 5.04(2H, a), 6 14(1H, d, J=7 0Hz), 7,31-7.42(5H, m), 7 46(1H, d, J=7.2Hz), 11.29(1H, brs). 3) Tho above compound 3 (I 29g, 599mmol) was suspended in acetonitrilo (1300ml), and N-bromosuccinic acid imide (I17g, 659mmol) was added, followed by stirring at room temperature for 90 minutes, Precipitated crystals were filtered, and washed with acetonitrilc and diethyl ether to obtain
3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4(154g, 88%) as a colorless crystal. NMR. (DMSO-dβ)δ: 2.06(3H, s), 5.04(2H, s), 7.32-7.42(5H, m), 8,03(1H, d, J=5.5Hz), 11.82(1H, brs).
4) To a solution of the compound 4 (88g, 300mmol), palladium acetate (13.4g, 60mmol) and l,3-bis(diphenylphosphino)propane (30.8g, SlCmmol) in dimethylformamide (660ml) wore added methanol (264ml) and triethylamine (210ml, l.5mol) at room temperature. The interior of a reaction vessel was replaced with carbon monoxide, and the material was stirred at room temperature for 30 minutes, and stirred at 80 degree for 18 hoxirs. A vessel to which ethyl acetate (1500ml), an aqueous saturated ammonium chloride solution (1500ml) and water (1500ml) had been added was stirred tinder ice-cooling, and tho reaction solution was added thereto. Precipitates were faltered, and washed with water (300ml), ethyl acetate (300ml) and diethyl ether (300ml) to obtain 5-benzyloxy^-hydroxy-δ-methyl-nicotimc acid methyl ester 5 (44 9g, 55%) as a colorless crystal.
NMR GDMSO-d(,)δ: 2.06(3H, s), 3.72(3H, s), 5.02(2H, s), 7 33-7.42(5H, m), 8.07(1H, s).
5) After a solution of the compound 5 (19. Ig-, 70mmol) m acetic anhydride (134ml) was stirred at 130 °C for 40 minutes, the solvent was distilled off under reduced pressure to obtain 4-acetoxy-5-benzyloxy-6τnethyl-nicotinic acid methyl ester 6 (19, 9g, 90%) as a flesh colored crystal.
NMR (CDCl3)δ: 2.29(3H, s), 2,52(3H, s), 3,89(3H, s), 4,98(2H, s), 7,36-7.4 l(5H, m), 8.85(1H, s),
6) To a solution of the compound 6 (46.2g, 147mmol) in chloroform (370ml) was added metachloroperbonzoic acid (65%) (42.8g, Iβlmmol) in portions under ice-cooling, and this was stirred at room temperature for 90 minutes. To the reaction solution was added a 10% aqueous potassium carbonate solution, and this was stirred for 10 minutes, followed by extraction with chloroform. The organic layer was washed with successively with a 10% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqxieous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether to obtain 4-acetoxy-5-benzyloxy-6-methyl-1-oxy-nicotinic acid methyl ester 7 (42.6g, 87%) as a colorless crystal.
NMR (CDCl3)δ: 2.30(3H, β), 2.41(3H, s), 3.90(3H, s), 5,02(2H, β), 7.37-7.39(5H, m), 8.70(1H, s).
7) To acetic anhydride (500ml) which had been heated to stir at 130 "C was added the compound 7 (42, 6g, 129mmol) over 2 mmtuos, and this was stirred for 20 minutes. The sovent was distilled off under reduced pressure to obtain
4-acotoxy-6-acetoxymethyl-5-benzyloxy-nicotinic acid methyl ester 8 (49.6g, >100%) as a black oil.
NMR (CDCl3)δ: 2.10(3H, s), 2.28(3H, s), 3.91(31-1, s), 6.07(2H, β), 5.20(2H, s), 7.35-7.4l(5H, m), 8.94(11-1, s).
8) To a solution of the compound 8 (46.8g, 125mmol) in methanol (140ml) was added a 2N aqueous sodium hydroxide solution (376ml) under ice-cooling, and this was stirred at 50 °C for 40 minutes To the reaction solution were added diethyl ether and 2N hydrochloric acid under ice-cooling, and precipitated crystals were filtered. Resulting crystals were washed with water and diethyl ether to obtain B-benzyloxy^-hydroxy-θ-hydroxymethyJ-mcotinic acid 9 (23.3g, 68%) as a colorless crystal.
NMR (DMSO-d«)δ: 4.49(2H, a), 5.19(2H, s), 5.85(1H, brs), 7.14-7.20(2H, m), 7 33-7.43(7H, m), 8.S0(1H, s), _ 0.73(1H, t, J=5.8H'/.), 11.96(1H, brs).
9) To a solution of the compound 9 (13 I g, 475mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (219g, lH0mmol) and 1-hydroxybenzotπazole (128g, 950mmol) in dimethylformamide (1300ml) was added 4-fluorobenzylamine (109ml, 950mmol), and this was stirred at 80°C for 1.5 hours. After the reaction solution was cooled to room temperature, hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with a 5% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (I75g") of 10 and 31, the resulting mixture was dissolved in acetic acid (1050ml) and water (1050ml), and zinc (31. Ig-, 475mmol) was added, followed by- heating to reflux for 1 hour. After the reaction solution was cooled to room tempreture, a 10% aqueous potassium carbonate solution was added, followed bj' extraction with ethyl acetate. The extract was washed with an aqueous saturated ammonium chloride solution, and an aqueous saturated sodrum chloride solution, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, this was washed with diethyl ether to obtain 5-benzyloxy-N-^-fluoro-benzyl)^-hydroxy-β-hydroxymethyl-nicotinic acid amide 10 (107g, 59%) as a colorless crystal.
NMR (DMSO-de)δ: 4.45(2H, d, J=4,3Hz), 4.52(2H, d, J=5.8Hz), 5.09(2H, s), 6.0 KlH, brs), 7.36-7.43(5H, m), 8.3l(1H, s), 12.630.H, brs),
10) After manganese dioxide (49 g) was added to a suspension of the compound 10 (9.8g, 25.6mmol) in chloroform (490ml), the mixture was stirred at room temperature for 1 hour. After the reaction solution was stirred at 60 °C for 20 minutes, Celite filtration was performed, and this was washed with chloroform heated at 50 °C. The filtrate was distilled off under reduced pressure to obtain
5-benzyloxy-N-(4-fluoro-benzyl)-6-formyl-4-hydroxy-nicotinic acid amide 12 (8.2g, 84%) as a pale yellow crystal.
NMR (DMSOdβ)δ: 4.53(2H, d, J=5.8Hz), 5.38 (2H, s), 7J 5-7.2l(2H, m), 7.35-7 46(7H, m), 8.33(1H, s), 9. Q0(1H, s), 10,35(111, t, J=5,8Hz), 12.49(1H, brs).
13 ) To an aqueous solution (105ml) of sodium chlorite (7, 13g, 78.8mmol), and sulfamic acid (7.65g\ 78.8mmol) was added a solution of the compound 12 (15,0g, 39.4mmol) in tetrahydrofuran (630ml) under ice-coling, and the mixture was stirred at room temperature for 1 hour. After water (2500m]) was added to the reaction solution, precipitated crystals were filtered, Washing with diethyl ether afforded 3-benzyloxy-5-(d-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid 13 (14.0g, 90%) as a colorless crystal,
NMR (DMSO-dβ)δ: 4.52(2H, d,
Figure imgf000085_0001
5.13 (211, a), 7.M-7.19C2H, m), 7.31-7.40(5H, m), 7,47-7.49(2H, m), 8.3l(1H, d, J=4.5Hz), 10.44(1H, t, J=5.9Hz), 12.47(1H, brs).
12) A solution of the compound 13 (198mg, 0.500mmol), 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115mg, 0.δ00mmol) and 1-hydroxybenzotriazole (81mg, 0.Θ00mmol) in dimethylformamide (3ml) was shirred at room temperature for 1.5 hours. Then, methanol (3m]) and triethylamine (353ul, J .10mmol) were added, and lhe mixture was hoated to reflux for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium bicarbonate solution, a 10% aqueous citric acid solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain
3-benzyloxy-5-(4-fluoro-bonzylcarbamoyl)-4-hydroxy-pyridine-2-cai*boxylic acid methyl estor 14 (I41mg, 69%) as a colorless crystal.
NMR (DMSO-dfi)δ: 3.85(3H, s), 4.52(2H, d, J=6.0Hz), 5.15(2H, s), 7.13-7.2l(2H, m), 7.31-7.47(71-1, m), 8.33(1H, s), 10.41QH, t, J=6.0Hz), 12.59(1H, brβ).
13) After 3-bromopropene (2.15ml, 24.8mmol) was added to a solution of the compound 14 (6.79g, 16.5mmol), and cesium carbonate (8,09g, 24.8mmol) in dimethylformamide (54ml), the mixture was stirred at room temperature for 4.5 hours. To the reaction solution was added an aqueous ammonium chloride solution, and this was extracted with ethyl acetate, washed with water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residtic was washed with diethyl ether to obtain 1- allyl-3-benzyloxy-5-(4-fluoro-benzylcarbamoyl) -4-0X0-1,4-dihydro-pyridine-2-carboxy lie acid methyl ester 15 (6,15g, 83%) as a colorless crystal.
NMR (CDCl3) δ= 3.76(3H, s), 4.54(2H, d, J=6.0Hz), 4,60(2H, d, J=6.0Hz), 5.20-5.37(2H, m), 5.25(2H, s), 5.80-S.93(1H, m), 6.98-7.04(21-1, m), 7.31-7.35(7H, m), 8.45C1H, s), 10.4K1H, m).
14) To a solution of the compound 15 (7.6g, 16.9mmol) in 1,4-dioxano (228ml) was added an aqueous solution (38ml) of potassium osmate dihydrate (372mg, 1.03 mmol), and sodium metaperiodate (14.5g, 67.6mmol) was further added, followed by stirring at room temperature for 2 hours. The reaction solution was added to a vessel to which ethyl acetate (300ml) and water (300ml) had been added, while stirring. The organic layer was washed with water, a 5% aqueous sodium hydrogen sulfite sohition and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 3-bonzyloxy-5-(4-flxιoro-benzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)- 1,4-dihydro-pyridine-2 -carboxylic acid methyl ester 16 (5.39g, 71%) as a colorless crystal. NMK (CDCl3)S: 3.74(3H, s), 4.60(2H, d, J=5.9Hz), 4.87(2H, s), 5.27(2H, s), 6.98-7.04(21-1, m), 7.30-7.40(7H, m), 8.39(l H, s), 9.58(1H, s), 10.38(T H, s).
15) To a solution of the compound 16 (400mg, 0.884mmol) in methylene chloride (12ml) were added 2-methoxyethylamine (77ul, 0.884mmol) and acetic acid (18ul), and the mixture was stirred at room temperature for 5 minutes. Thereafter, the reaction was performed at 140 °C for 30 minutes in a microwave reaction apparatus. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and fractions eluting with toluene-acetone were concentrated under reduced pressure to obtain
9-benzyloxy-2-(2-methy-ethyl)-1,8" dioxo- 1,8-dihydro-2H-pyrid[l ,2-a]pyrassine-7-carbox ylic acid 4-fluoro-benzylamide 17- 1 (226mg, 54%) as a yellow solid.
NMR (CDC13)8: 3.35(3H, s), 3.65(2H, t, J=5.1Hz), 3.97(2H, t, J=4.BHz), 4.63(2H, d, J=5.7Hz), 5.28(2H, s), 6.56(2H, m), 7,0l(2H, t, J=8.7Hz), 7.38-7.30(511, m), 7,65(2H, d, J=6.6Hz), 10.63(1H, s).
16) To the compound 17- 1 (140mg, 0.293mmol) was added trifluoroacetic acid (1.4ml) under ice-cooling, and the mixture was stirred at 0 "C for 5 minutes and, then, at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and this was diluted with chloroform, and added to ice water. This was washed with an aqueous saturated sodium bicarbonate solution, a 10% aqueous citric acid solution and water, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was rccrystalhzed with methylene chloride-ethanol to obtain Example A- I (89mg, 79%) as a yellow crystal, molting point: 223-224 °C
NMR (DMSO-dδ)δ: 3.25(3H, s), 3.58(2H, t, J=5.4Hz), 3.92(2H, t, J=5.1Hz), 4.53(2H, d, J=5.7Hss), 6.87(1 H, d, 6.3Hz), 7.14(2H, t, J=9.0Hz), 7.33-7.38(2H, m), 7.470 H, d, J=6.0Hz), 8.77(1H, β), 10.56(1H, t, J=6.0Hz), 12.00(1H, brs).
.17) The compound 17- 1 (157mg, 0.329mmol) was dissolved in dimethylformami.de (18ml) and methanol (iml), 10% palladium-carbon powder (31mg) was added, and the mixture was stirred at room temperature for 20 hours under the hydrogen atmosphere. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure The residue was dissolved in chloroform, this was filtered with Celifce again, and the filtrate was concentrated under reduced pressure, The residue was rocrystallized with methylene chlorido-methanol to obtain Example B-I (66mg, 52%) as a browm crystal, molting point: 197-199 °C
NMR (DMSO-db)δ:3.27(3H, s), 3,55(2H, t, J=5.1Hz), 3.68(2H, t, J=5,1Hz), 3.79(2H, s), 4.36(2H, s), 4.51(2H, d, J=5,7Hz), 7.15(2H, t, J=8.7Hz), 7.32-7.37(2H, m), 8.38(1 H, s), 10.46(1H, t, J=5.4Hz), 12.4α(1H, s).
Example C-I [Chemical formula 55l
Figure imgf000088_0001
L) A compound 33 was synthesized using 1-aminomethylcyclopentanol hydroxyethylamme according to the method of synthesizing a compound _ 7-J . 1H-NMR (CDCIi)δ: 1.30-1,80(101-1, m), 3.47(1 H, d, J=11.4Hz), 3.61(1H, d, J=Il.4Hz), 3 80-3.95(111, m), 4.3θ(iH, dd, J=14.7, 3.0Hz), 4.60(2H, d, J=5.7Hz), 5.17-5.23(2H, m), 5,39(1H, d, J=9.9His), 6.95-7.10(2H, m), 7.20-7.40(5H, m), 7.58(2H, d, J=7.2Hz), 8.41(1H, s), 10.400 H, s).
2) A compound 33-2 was synthesized using hydroxyethylamine according to the similar method.
Compound 33-2)
5-Ben7,yloxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1-oxa-3a,8a-diaza-cyclopenta[b]naphtha lene-7-carboxylic acid 4-fluorobenzylamide 1H-NMR (DMSO-dc)δ: 3.48-3.58(1H, m), 3.73-3.86(1H, m), 3.97-4, 10(2H, m),
4.20-4.30(1H, m), 4.46-4.βθ(2H, m), 4.85(1H, dd, J=12.3, 3.5Hz), 5.40(1H, d, J=I0.2Hz), 6.18(1H, d, J=10.2Hz), 5.28(1H, del, J=l0.2, 3.2Hz), 7.10-7.20(2H, m), 7.23-7.40(5H, m), 7.50-7.73(2H, m), 8.60(1H, s), 10.22(1H, m).
3) Example C-I was synthesized using a compound 33, according to the method oϊ synthesizing Example A- I.
Melting point: >300°C 1H-NMR (DMSO-dβ)δ: 1.10- 1.60U 0H, m), 3.25(1H, d, J=Il.4Hz), 3.37(111, d,
J=11.4Hz), 3,76(1H, t, J=I0.5Hz), 4.30(2H, d, J=5.8Hz), 4.66(1H, dd, J=12.2, 3.8Hz),
5,22(1H, dd, J=3.8, 10,4Hz), 6.90-6.96(2H, m), 7J 0-7.15(2H, m), 8.25(1H, s), 10, 10(1H, brs), 11 32(1H, brs).
The following compounds wcro synthesized using the similar method. Example C-2)
5-Hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1-oxa-3a,8a-diaza-cyclopenta[b]naphthale ne-7-carboxyhc acid 4-fluorobenzylamide Molting point: 272-274 °C 1H-NMR (DMSO-d6)δ: 3.59-3.67(1H, m), 3.72-3.81(1H, m), 3.98-4.10(2H, m), 4 27-4 35(1H, m), 4 52(2H, d, J=7.2Hz), 4,92(1H, dd, J=12 3, 12 3Hz), 5.27(1H, dd, J=3.6, 9.9Hz), 7.11-7 2θ(2H, m), 7.30-7.40(2H, m), 8 49(1H, s), 10 32(1H, t, J=5.6Hz), 11.53(1H, s).
Example C-3)
5-Hydroxy-6, 10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1 -oxa-4a,8a-diaz;aantliracone-7-carb oxylic acid 4-fluorobenzylamide molting point 259 °C 1H-NMR (DMSO-de)δ: 1.60-1.67(1H, m), 1 72-1.85(1H, m), 3.25(1H, td, J=12.8, 3.5Hz),
3,86-3.93(1H, m), 4.06(1H, dd, J=Il.4, 4 2Hz), 4.44-4.57(5H, m), 5.28(1H, t, J=3.8Hz),
7 ϋ 3-7, lδ(2H, m), 7.33-7.37(2H, m), 8 51(1H, s), 10.36(1H, t, J=6.0Hz), 12.47(1H, s),
Example C-4)
5-Hydroxy-1-isopi%opyl-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-3 ,3a,8a-triaza-cyclopenta[ b]naphthalcne-7-carboxylic acid 4-fluoro-bGnzylamide melting point: 232-234°C
NMR (DMSO-d(,)δ: 1.03(3H, d, 6,6Hz), 1.14(3H, d, 6.6Hz), 2.79-3.66(5H, m), 3,82(1H, t,
10.8Hz), 4.51(3H, m), 4.90(1H, m), 7.15(2H, t, 9.0Hz), 7.34(2H, m), 8.45(111, a), 10.39(1H, t, 5,4Hz), 11.60(1H, s).
Example O5)
5-Hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro- 1H-1,3a,8a-triaza-cyclopenta[b3naphthale ne-7-carboxylic acid 4-fluoro-benzylamide melting point: 256-258 °C
NMR (DMSOcU)δ: 3.00-3.55(5H, m), 3.96(1H, t, 11.4Hz), 4.52(2H, d, 11.7Hz), 4.76(2H, m), 7.16(2H, t, 8.7Hz), 7.35(2H, m), 8.48(1H, s), 10.42(1H, t, 5.4Hz.), 11.91(3 H, a).
Example C -6)
5-Hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-ociahydro- 1,4a, 8a-triaza-anthracene-7-carboxy lie acid 4-fluoro-benzylamidc melting point: 255°C
NMR (DMSO-dβ)δ: 1.60(1H, s), 2 75-3.16(4H, m), 4.52(2H, d, 6.0Hz), 4.13-4.68(4H, m),
7.16(2H, 9.0Hz, i), 7.34(2H, m), 10.42(1H, s), 10.44(1H, 6 0Hz, 0, 12.8l(1H, s).
Example C-7) 1-(2-Diethylamino-ethyl)-5-hydroxy-4,6-dioxo-2,3, 4,6,9, 9a-hexahydro- 1H- 1,3a, 8a- triaz a-cyclopentaLbJnaphthalcnc-7-carboxylic acid 4-fluoro-benzylamide melting point: 186- 187 °C
NMR (DMSO-de)δ: 0.97(6H, t, 7.2Hz), 2.42-2.91(10H, m), 3,44-3.87(5H, m), 4.23(1H, m), 4,51(2H, d, 5.7Hz), 5.00(1H, m), 7.16(2Ii, t, 9.0Hz), 7.33-7.37(2H, m), 8.43(3 H, s),
30,39(1H, t, 5.7Hz), 31 8l(1H, s)
Example C-8) 1 -Hydroxy-2, 11-dioxo-2,5,5a,7,8,9, 10,11-octahydro-6-oxa-4a, 10a-diaza-cycloheptarb]na phihalene-3-carboxylic acid 4-fluoro-benzylamide melting point 242-244 °C
NMR (DMSO-ds)δ: 1.40-2.00(4H, m), 3.20-3.30(1H, m), 3.66-3.77(2H, m), 4, 14-4.23(1H, m), 4.38-4.41(1 H, m), 4.52(2H, d, 6.3Hz), 4.58-4.63(1H, m), 5.34(1H, brs), 7.15(21-1, t,
9.0Hz), 7,33-7.37(2H, m), 8.50(1H, s), 10.39(311, brs), 12. 14(1H, s).
Example O9)
5-Hydroxy-1-(2-hydroxy-ethyl)-6,-10-dioxo-1,2,3,4,6,9,9a, 10-octahydro- 3 ,4a,8a-triaza-a nthracene-7-carboxylic acid 4-fluoro-benzylamide NMR (DMSO-dβ)δ: 1.58-1.80(1H, m), 2.70-3.6θ(7,B, m), 4.40-4.54(6H, m), 4.77-4.82(1H, m), 7.35(21-1, t, 9.0Hz), 7.33-7.38(SH, m), 8.52(1H, s), 10.4S(1H, brs), 12.57(1H, s).
Example (M0) 1 -Hydroxy-2, 11-dioxo-2,5a,6,7,8,9, 10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta [b]na phthalene-3-carboxylic acid d-fhioro-benzylamide melting point: 256°C
NMR (DMSOdc)δ: 1,47-3.77(4H, m), 2,69-2.81(2H, m), 3.34-3.4l(1H, m), 4.08-4.12(1H, m), 4,26-4.40(2H, m), 4.52(2H, d, J=6,0Hz), 7.15(2H, t, 8.8Hz), 7.33-7.36(2H, in),
8.43(1H, s), 10.46(H-I, t, J=6.0Hsβ), 12.680 H, s).
Kxample C- I1)
5-Hydroxy-1-(2-methoxy-ethyl)-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a,8a-triaza-a nthracene-7-carboxylic acid 4-fluoro-benzylamide melting point: 147°C
NMR (DMSO-df,)δ: 1.56- 1.74(2H, m), 2.53-2.58(1H, m), 2.66-3.10(4H, m), 3.18(3H, s),
3.41-3.39(2H, m), 4.37-4.52(5Ii, m), 4.73-4.80(1H, m), 7.15(2H, I, 8.8Hz), 7.33-7 37(2H, m), 8.56(1H, s), 10.40(1H, t, J=6.0Hz), 12 62(1H, s).
Example C- 12)
5-Hydroxy-1-(2-isopropoxy-ethyl)-6, 10-dioxo-1,2,3,4,6,9,9a, 10-octahydro-1,4a,8a-triaza
-an(.hraccno-7-carboxylic acid 4-fluoro-benzylamide melting point: 151 °C
NMR (DMSO-de)δ: 1.02(6H, dd, J=4.0, 6,0Hz), 1.56- 1 ,67(2H, m), 2.63-2.58(1H, m),
2,74-3,04(4H, m), 3.18(3H, s), 3,41-3.52(3H, m), 4.41-4.59(5H, m), 4.79-4.83(1H, m),
7, 15(2H, t, 8.8Hz), 7,34-7.36(21-1, m), 8.58(1H, s), 10.40(1H, t, J=6.0Hϋ), 12.56U H, s),
Example C- 13)
5-Hydroxy-3,3-dimethyl-6, 10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-diaza-ant hracene-7-carboxylic acid 4-flυoro-bonzylamide melting- point: 275-277 °C
NMR (DMSO-dβ)δ: 2.97(3H, s), 3.01(3Ii, s), 3,00-3.18(311, m), 4.45-4.56(5PI, m),
5.16(1H, s), 7.15(2H, t, J=9Hz), 7.35(2H, dd, J=5.4Hs5. 8.711z), 8.5l(1H, s), 10.36(1H, t,
J=6.7Hz), 12.4(1H, s). Example C- 14) 1-Cyclohexyl-5-hydroxy-6, 10-dioxΘ- 1,2,3,4,6,9,9a, 10-octahydro- 1,4a,8a-triaza-anthracG ne-7-carboxylic acid-4-fluoro-benzylamide melting point: 275-277 °C
NMR (DMSO-dr,)δ: 1,22-1,7θ(2H, m), 2.50-3, 02(3H, m), 4.45(41-1, m), 4.52(2H, s),
4.78(1H, d, J=13.2Hz), 7.16(2H, t, J=8,7Hz), 7.35(2H, dd, J=5.7Hz, 8.4Hz), 8.62(1H, s), 10,52(1H, s), 12.55(1H, s).
Example G- 15) 5-Hydroxy-1-isopropyl-βj 10-dioxo-i ,2.β,4,β,O.Oa.10-oxtahydro-1,4a^a-triaza-anthrace ne-7-carboxylic acid-4-fluoro-benzylamide molting point: 220 °C
NMR (DMSO-do)δ: 0.94(6H, d, J=9.6Hz), 1,53-1.67(2H, m), 2.92-3.30(3H, m),
4.32-4,40(4H, m), 4.52(2H, d, J=5.7Hz), 4.89(3 H, d, J=14.1Hz), 7.16(2H, t, J=9.0Hz),
7.36(2H, dd, J=6,3Hz, 9.0Hz), 8.6 l(1H, s), 10.46(1H, s), 12.55(1H, s).
Example C- 16)
5-Hydroxy-3,3-dimethyl-6, 10-dioxo- 1,2,3,4,6,9,9a, .0-octahydro- 1 ,4a,8a-triaza-anthrac ene-7-carboxylic acid 4-fluoro-benzylamide melting point: 280 °C
NMR (DMSO-dβ)δ: 0.87(3H, s), 0,93(31-1, s), 2.59-3.15(6H, m), 4.09-4.57(6H, m),
7.14(2H, d, J=9.0Hz), 7.34(2H, dd, J=5.4Hz, 8,4Hz), 8,42(HT, s), 10.46(1H, s), 12.77(1H, s),
Example C-17)
5-Hydroxy-1-(2-morpholin-4-yl-2-oxo-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a, 10-octahydro-1,4 a, 8a -tπaza- anthracene -7 -carboxylic acid 4-flvιoro-bonzylamide melting point: 140 °C
NMR (OMSO-dc)δ: l.60(2H, m), 2.91-3.62(13H, m), 4,4 l(2H, m), 4.61(2H, d, J=4.8Hz),
4.80(21-1, m), 7.15(2H, L, J=8.7Hz), 7.34(2H, m), 8.44(1H, a), 10.43(1H, β), 12.64O H, s).
Example C- 18 1-(3-Acctylamino-propyl)-5-hydroxy-6,10-dioxo- 1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-tri aza-anthracene-7-carboxylic acid 4-fluoro-benzylamide melting- point: 177-178 °C NMR (DMSOd6)S: 1.74(3H, β), 1.49-2.98(0H, m), 3.60UH, s), 4.25-4.65(7H, m), 7.34(2H, t, J=8.4Hz), 7.34(2H, m), 7.7l(1H, s), 8.26(1H, s), 10.60(1H, s).
Example C- 19) 1-Dimetliycarbamoylmethyl-5-hydroxy-6, 10-dioxo- 1,2,3,4,6, 9, 9a, 10-octahydrθ-1,4a,8a- triaza-anthracenβ-7-carboxylic acid 4-fluoro-bonzylamide melting point: 190 °C
NMR (DMSOcU)S: 1.60(2H, m), 2.76(3H, s), 2.83(3H, s), 2.90-3.59(5H, β), 4,4θ(2H, m),
4.51(21-1, d, 5.7Hz), 4.80QH, d, d=l4 4Hz), 4.98(1 H, s), 7.16(2H, t, J=8.4Hz), 7.34(2H, rn), 8.54(1H, s), 10.42QH, s).
Example C-20)
5-Hydroxy-1-(3-met,hanesulfonylamino-propyl)-6, 10-dioxo-1,2,3,4,6,9,9a, 10-octahydro- l,4a.δa-triaza-anthracene^ carboxylic acid 4-fluoro-benzylamide melting point: 176 °C
NMR (DMSOdβ)δ: 3.54-1.75(4H, m), 2.80(3H, s), 2.30-3 04(811, m), 4.45(2H, m),
4.52(2H, d, J=6.6Hz), 4.75OH, d, J=13.2Hz), 6.91(1H, t, J=5.6Hz), 7.16(2H, t,
J=8.8Hz), 7.36(2H, m), 8.6l(1H, s), 10.41 (1H, t, J=5.6Hz), 12.58(1H, s).
Example O2l)
5-Hydroxy-2-methyl-6, 10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-dizazaanthra cene-7-carboxyhc acid 4-fluorobenzylamide
NMR (CDCl3)δ: 1.27(3H, d, J=6.0Hz), 1.65- 1.78(2H, m), 3Λ1(1H, td, J=12 9, 3.7Hz),
3 89-4.00(1H, m), 4.16(1H, dd, J=13.8, 3.9Hz), 4.34(1H, dd, J=13.8, 3.9Hz), 4.60(2H, d,
J=G,0Hz), 4.71(1H, ddd, J=13.5, 4^8, 1.8Hz), 5.08(1H, t, J=3.9Hz), 6,96-7.04(2H, m),
7,26-7.35(2H, m), 8.32(1H, s), 10.4 l(1H, br s), 12.4 l(1H, br s),
Example F- 1)
5-HydϊOxy- 1-isobutyl-4,6-dioxo-2,3, 4,6,9, 9a-hexahydro- 1H- 1,3a, 8a- Iriazacy clop entafb] naphthalene -7 -carboxy he acid-4-fluorobenzylamide
[Chemical formula 59]
Figure imgf000094_0001
1) According to the method of synthesizing a compound 17- 1, the crude purified product (503mg) of a compound 48 was obtained at a yie]d of 82% from a compound 16 (β00mg).
2) To a solution of a compound 48 (.l 00mg, 0,22mmo]), isobutylaldohyde (39μl, 0.432mmol) and acetic acid (25μl, 0,432mmol) in dichloromethane (4ml) was added sodium triacetoxyborohydride (92mg, 0.432mmol) under ice-cooling1, and the mixture was stirred at room temperature for 2 hours. Further, isobutylaldehydc (20μl) and sodium triacetoxyborohydride (46mg) were added, and the mixture was stirred for 30 minutes. To the reaction solution was added water, (his was extracted with chloroform, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution. After dπng, the solvent was distilled off under reduced pressure, and this was purified by silica gel column chromatography. A compound 49 (87mg) was obtained as a colorless crystal at a yield of 78%.
J H-NMR (CDCl3)S: 0.96(3H, d, J=6.6Hz), 0.97(3H, d, J=6.3Hz), 1.72- 1.86(1H, m), 2.25-2.41(2H, m), 2.47-2, 58(1H, m), 3.39-3.46(1H, m), 3.69-3.76(2H, m), 3.85-3.93(1H, m), 4.06(1H, dd, J=9.9, 2,7Hz), 4.16-4.22(1H, m), 4.57(1H, dd, J=15.3, 5.1Hz), 4.64(1H, dd, J=14.7, 5.1Hz), 5.20(111, d, J=9.9Hz), 5.38(1H, d, J=9.9Hz), 6.96-7.05(2H, m), 7.28-7.36(5H, m), 7.58-7.62(2H, m), 8.40(1H, s), 10.44(1H, br s),
3) According to the method of a step 37) of Example B-I, a compound F- I (43mg) was obtained at a yield of 64% from a compound 49 (81mg). 1H-NMR (DMSO-dc)δ: 0.90(3H, d, J=6.4Hz), 0.9 l(3H, d, J=6.0Hz), 1.75-1.84(1H, m), 2,24-2.39(1H, m), 2,39-2.54(2H, m), 3.36-3.43(1H, m), 3.52-3,60(1H, m), 3.67-3.73(1H, m), 3.81-3.88(1H, m), 4.19-4.23(1H, m), 4.52(2Ti, d, J=6.0Hz), 4,94-4.99(1H, m), 7.12-7.20(2H, m), 7.32-7.38(2H, m), 8.45(1H, s), 10.37(J H, t, J=2.0Ha), 11.74(1H, s),
According to the same manner as that of Example F-I , the following Example compounds F-2 to F-63 were synthesized.
Example F-2)
5-Hydroxy- t-isobυtyl-6, 10-dioxo- 1,2,3,4, 6, 9,9a, 10-octahydro" 1,4 a,8a-triazaanthracene-
7-carboxylic acid 4-flυorobenzylamide melting point: 146-148 "C 1H-NMR (DMSO-de)δ: 0.63(3H, d, J=6.6Hz), 0.79(3H, d, J=6,6Hz), 1.56- 1.66(2H, m), 1.67- 1,75(1H, m), 1.94-1.99(1H, m), 2,41-2.54(2H, m), 2.96-3.06(2H, m), 4.41-4.59(5H, m), 4.76-4.81(1H, m), 7.14-7,21(2H, m), 7.33-7.38(2H, m), 8.6l(1H, s), 10.40(1H, d,
J=5 8Hz), 12.56(1H, s).
Example F- 3) 1-Cyclopropylmethyl-5-hydroxy -6,10^110X0- 1,2, 3, 4, 6, 9,9a, i0-octahydro-1, 4a,8a-triaza- anth.racene-7-carboxylic acid 4-fluoro-benzylamide melting- point: 182- 184 °C
NMR (DMSO-d6)δ: 0.06(2H, m), 0.43(211, d, 8.4Hz), 0.80(1 H, m), 1.66(2H, m),
2 28-3 30(4H, m), 4.40-4.50(4H, m), 4 52(2H, d, 6.0Hz), 4.78(2H, m), 7, 15(2H, t, 8.7Hz),
7.34(2H, m), 8.55(1H, s), 10 47(1H, s), 12.55(1H, s)
Example F- 4) 1-Cyclopentylmethyl-S-hydroxy-δ, ! -dioxo- 1,2,3,4,6,9,9a, J 0-octahydro- 1,4a,8a-triaza-a nthraceno-7-carboxyhc acid 4-fluorcrbenzylamide melting point: 184-185 0CC
NMR (DMSOd6)G: 0,88-2J 0(1H, m), 2.60(2H, m), 2 95-3 28(2H, m), 4,38-4,53(6H, m),
4.82(1H, m), 7 15(2H, t, 9.0Hz), 7 34(2H, m), 8 57(1 H, s), 10.42(1H, s), 12 45(1 H, a).
Example F-5)
5-Hydroxy-1-(4-methylsulfanylbenzyl)-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,da,8a-t riazaanthracenc-7-carboxyhc acid 4-fluorobenzylamide
(DMSO-d(,)δ: 1.51- 1.56(1H, m), 1.69-1.74(1H, m), 2.42(3H, s), 2.55-2.62(1H, m),
2.80-2.84(1H, m), 3 00-3 08(111, m), 3.32-3.36(1H, m), 3 93(111, d, J=l3.6Hz),
4.45-4.53(4H, m), 4.58(111, s), 4.8S(1H, d, J=I 5.2Hz), 7 11-7.19(6H, m), 7 33-7 4θ(2H, in), 8.34(1H, s), 10.38(111, t, J=6.0Hz), 12.58(1H, s). Example F- 6) 1 -(5-Chloro- 1,3-dimethyl- 1H-pyrazol-4-ylmethyl)-5-hydroxy-6, 10-dioxo-1, 2,3, d, 6,9,9a, 1 0-octahydro-1,4a,8a-|,riazaanthracene-7-carboxylic acid d-flnσrobenzj'lamide (DMSO-dc)δ: l.5C-1.59(2H, m), 1.88(3H, s), 2.37-2.45(1H, m), 2.76-2, 80(1H, m), 3.00-3.06(2H, m), 3.64(3H, s), 3.87(1H, d, J=13.2Η.z), 4.40-4.55(5H, m), 4.97(1H, d, J=X4.4Hz), 7.13-7.19(2H, m), 7.33-7.38(2H, m), 8.66(1H, s), 10 39(1 H, t, J=6.0Hz), 12 46(1H, s).
Example F- 7) 5-Hydx'oxy-1-(S-methoxybenzyl)-6.10-dioxo- 1,2jS,4.β.S^a, J 0-octahydro- 1,4a,8a-triazaa nthraceno-7-carboxylic acid 4-fhιθϊObonzylamide
(DMSO-d6)δ: 1.52-1.67(J H, m), X.70-1.80(1H, m), 2.60-2.68(11i, m), 2.84-2.90(1H, m),
3.01-3.09(1H, m), 3.36( 1H, d, J=14.0Hz), 3.61(3H, s), 3.9 l(1H, d, J=14.0Hz),
4 45-4.52(4H, m), 4.58(1H, s), 4.76(1PI, d, J=14,8Hz), 6.68-6.73(2H, m), 6.77OH, d,
J=7.6Hz), 7.13-7, 19(3H, m), 7 33-7.38(2H, m), 8.17(1H, s), 10.38(1H, t, J=6.0Hz), 12.57(1H, s).
Example F-8)
5-Hydroxy-i -(4-methanesulfonylbenzyl)-6,10-dioxo-1,2,3/l,6,9,9a, 10-oclahydro- 1 ,4a,8a -triazaanthracone^-carboxyhc acid 4-fluorobenzylamide
(DMSO-dr,)δ: 1.54- 1.58(1H, m), 1.74- 1,80(1H, m), 2.67- 1.74(1H, m), 2.83-2,87(1H, m),
3,05-3.12(1H, m), 3.18(3H, s), 3.62(1H, d, J=14.8Hz), 4.09(1H, d, J=14.8Hz),
4.46-4.52(4H, m), 4.67(1H, s), 4.73(1H, d, J=H.8Hz), 7.12-7.18(2H, m), 7.32-7.36(2H, m), 7.46(2H, m), 7.80(2H, d, J=8.0Hz), 8.17(1H, s), 10.37(1H, t, J=5.8Hz), 12.59(1H, s),
Example F-9)
5-Iiydroxy-1-(6-methoxypyridin-3-ylmethyl)-6, 10-dioxo-3 ,2,3,4,6,9,9a, 10-octahydro- 1,4 a,8a-tx'iazaanthracene-7-carboxylio acid 4-fluorobenzylamide
(DMSO-dπ)δ: 1.51-1.56(1H, m), 1.71-1.77(1H, m), 2.58-2.66(1H, m), 2.80-2.86(1H, m), 3.01-3.09(1H, m), 3.38(XH, d, J=13,6Hz), 3.78(3H, s), 3,87(1H, d, J=X3.6Hz), d,45-4.52(4H, m), 4.60(XH, s), 4.82(1H, d, J=13.6Hz), 6.7 l(1H, d, J=8.6Hz), 7.12-7.19(2H, m), 7.33-7.38(2H, m), 7.49(1H, d, J=8.6Hz), 7.98(XH, s), 8.30(1H, s), 10.37(1H, t, J=6.0Hz), 12.58(XH, s). Example F- I 0) 5-Hydroxy-1-isobutyl-S.S-dimethyl-e.10-dioxo- 1,2,3,4,0,9,9a, 10-octahydro- 1,4a,8a-tria zaanthvacene-7-ca3*boxylic acid 4-fluorobonzylamide
(DMSO-dc)δ: 0.64(3H, d, J=6. άΗz>, 0,82(3H, d, J=6.8Hz), 0.90(3H, s), 0.9 l(3H, s), 1,59- 1.67(1H, m), 1.92- 1.97(1H, m), 2.11-2.15(1Pl, m), 2.51-2.57(1H, m), 2.67(1H, d,
J=12.0Hz), 2,77(1H, d, J=12,8T-Iz), 4.13(1H, s), 4.2l(1H, d, J=12.8Hz), 4,47-4.59(3H, s),
4.80(1H, dd, J=M.4, 2.8Hz), 7.14-7.19(2H, m), 7.34-7.38(2H, m), 8.66(1H, s), 10.41 (1H, t, J=6.0Hz), 12,44(1H, s).
Example F-Il)
5-Hydroxy- 1,3,3-trimethyl-6,10-dioxo- 1,2,3,4,6,9,9a,10-octahydro- 1,4a,8a-triazaanthra cene-7-carboxylic acid 4-fluorobenzylamide
(DMSO-de)6; 0.89(6H, s), 2.14-2.18(1H, m), 2,24(311, s), 2.54-2.580H, m), 2.74-2.78(1H, s), 3.88(1H, s), 4.21(1H, d, J=13,2Hz), 4.45-4, 53(3H, m), 4.72-4.76(1H, m),
7.13-7.19(2H, m), 7,33-7.38(2H, m), 8.64(1H, β), 10,40(1H, t, J=6.0Hz), 12.46(1H, s).
Example F- 12)
4-[7-(4-Fhιoi"obenzylcarbamoyl)-5^hydroxy-6, 10-dioxy-3,4,6,9,9a, 10-hexahydro-2H -1,4a
,8a-tπazaanthraceno-1-yl]butanoic acid ethyl ester
(CDCla)δ: 1 23(3H, t, J=7.1Hz), 1.70-1.79(1H, m), _ .86-2.00(1H, m), 2,17-2,34(2H, m),
2.46-2.57(1H, m), 2.61-2.77(2H, m), 2.85-2.92(1H, m), 3, 13-3,18(1H, m), 4.13(2H, q,
J=7.1Hz), 4.27-4,34(2H, m), 4.57-4,63(3H, m), 4,66-4,73(1H, m), 6.95-7.03(2H, m),
7 29-7.36(2H, m), 8,36(1H, s), I0,48(1H, t, J=4.8Hz), 12.50(1H, s).
Kxaraplc F- 13) 1-(3-Dimethylcarbamoylpropyl)-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a, βa-triazaanthracenG-Y-carboxylic acid 4-fltiorobenzylamide
(CDCl.?)δ:i .62-1.82(3H, an), 1.83-2.00(i H, m), 2.10-2.35(2H, m), 2.57-2.65(2H, m), 2.75-2.96(2H, m), 2.92(3H, s), 2.96(3H, s), 3.07-3.14(1H, m), 4.23-4.30(2H, m), 4.6θ(2H, d, J=6.0Hz), 4.68(1H, dd, J=13.2, 4.5Hz), 5.12(1H, d, J=12.6Hz), 6.95-7 02(2H, m), 7.28-7.35(2H, m), 8.42(1H, s), 1054(1H, t, J=5.4Hz), 12,51 (1H, s)
Example F-14)
5-Hydroxy-1-(4-morpholin-4-yl-4-oxobut,yl)-6,10-dioxo-1,2,3,4,6,9,9a, 10-octahydro-1,4a ,8a-triazaanthracone-7-carboxylic acid 4-fluorobenzylamide (CDCl3)δ: 1.61-1.83(3H, m), 1.84-2.00QH, m), 2, 12-2.23(1H, m), 2.25-2.36QH, m), 2.56-2.64(2H, m), 2.75-2.95(2H, in), 3.09-3.15(1H, m), 3.37(2H, t, J=4.8Hz), 3,61-3.66(6H, m), 4,26-4.32(211, m), 4.59(2H, d, J=5,7Hz), 4,68(1H, dd, J= L3.2, 4.5Hz), 4.95-5.01(1H, m), 6.95-7.03(2H, m), 7.28-7.35(2H, m), 8.40(1H, s), 10.52(1 H, t, J=5.7Hz), 12.51 (1H, s).
Example F- 15)
5-Hj'droxy-1-methyl-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro- 1,4a,8a-triazaanfchracene-
7-carboxyhc acid 4-fluorobenϋylamide melting point: 252-253°C
(DMSO-de)δ: 1.56- 1.75(2H, m), 2.22(3H, s), 2.50-2.55(1H, m), 2.90-3 J 0(2H, m),
4, 17(1H, brs), 4.39-4.42(2H, m), 4.52(2H, d, J=6.0Hz), 4,74-4.78(1H, m), 7.13-7.17(2H, m), 7.33-7.37(2H, m), 8,6 l(1H, s), 10.40(1H, t, J=6.0Hz), 12.54(1H, s).
Example F- 16)
S-Hydroxy-β.10-dioxo-1-lhiophen-3-ylmethyl-1.B.S,4,6^.Θa.10-octahydro-1,4a.Sa-triaz aanthracene^-carboxylic acid 4-fluorobenzylamide melting point-' 242-243°C
(DMSO-ck)δ 1.62- 1.73(2H, m), 2.5"9-2.62(1H, m), 2.87-3 03(2H, m), 3,52(1H, d, J=13 6Hz), 3.90(1H, d, J=H 4Hz), 4.40-4.56(5H, m), 4.83-4.90(1 H, m), 6.92(1H, d, J=5.2Hz), 7.13-7.17(2H, m), 7.28-7.37(3H, m), 7.42-7.44(1H, m), 8.46(1H, s), 10.39(1H, t, J=6,0Hz), 12.58(1H, s),
Example I''-17)
5-Hydroxy-6, 10-dioxo-1-thiazol-2-ylmethyl- 1,2, 3,4,6,9,9a, 10-octahydrθ-1, 4a, δa-triazaa nthracene-7-carboxylic acid 4-fluoχ-obenzylamide melting point 214-215°C
(DMSO-d6)6: 1.54-1.72(2H, m), 2.75-2.81(1H, m), 2,95-3.07(2H, m), 3.80(1H, d,
J=16.0Hz), 4.37(1H, d, J=16,4Hz), 4.44-4,5l(4H, ra), 4.69(1H, brs), 4.89-4.93(1H, m),
7.13-7.17(2H, m), 7.32-7.35(2H, m), 7 55(1PI, d, J=3.2Hz), 7.69(1H, d, J=3.2Hz),
8.37(1H, s), 10.36(1H, t, J=6.0Hz), 12.50(11-1, s).
Example F- 18)
5-Hydroxy-(3-methyls\ιlfanyl-propyl)-6, J 0-dioxo- 1,2,3,4,6,9,9a, 10-octahydro- 1, 4a,8a-tr iazaanthraccne-7-carboxylic acid 4-flυorobenzyl amide melting point: 162-164°C
(DMSOcIe)S: 1.50- 1.82(4H, m), 2.27(3H, s), 2.32-2.44(3H, m), 2.60-2.82(2H, m), 3.00-3.14(2H, m), 4.37-4.59(51-1, m), 4.7β-4.79(1H, m), 7.13-7.17(2H, m), 7.33-7.35(2H, m), 8.6O(1H, s), 1O.4θ(1H, t, J=6.0Hz), 12.57(1H, s).
Example F- 19)
5- Hydroxy-6, 10-dioxo-1-pyridin-4-ylmethyl- 1,2,3,4,6,9,9a, I0-octahydro-1,4a,8a-i,nazaa nfchracene-7-carboxylic acid 4-fluorθbenzylamide melting point: 180-183°C
(DMSO-de)δ: 1.52-1.76(2H, m), 2.62-2.80(2H, m), 3.01-3.07(1H, ra), 3.42(1H, d,
J=15.2Hz), 4.05(1H, d, J=15.2H>,), 4.49-4.5θ(4H, m), 4 64(l H, brs), 4.78-4.81O H, m),
7.12-7.2K4H, m), 7.32-7.36(2H, m), 8.33(1H, s), 8.42(2H, d, J=4.4Hz), 10.39(1H, t,
J=6.0Hz), 12,55(1H, s).
Example F-20) l -Cyclohexylmethyl-S-hj'droxy-βj 10-dioxo-1,2.S,4,6.Q.Oa, 10-octahydro-1,4a,8a-tπazaan lhracene-7-carboxylic acid 4-fluorobenzylarrnde melting point: 201-202°C
(DMSO-d<s)δ. 0.56-0.59(1H, m), 0.87-0.84(1H, m), 1.02-1.13(3H, m), J .23-1.290 H, m), 1 49- 1.70(6H, m), 1.92- 1.97(1H, in), 2.52-2.55(1H, m), 2.96-3.03(2H, m), 4.40-4.43(3H, m), 4.52(2H, d, J=6 0Hz), 4.73-4.77(1H, m), 7.12-7.16(2H, m), 7.32-7,36(2Ii, m),
8.59(1H, s), 10.40(1H, t, J=5.2Hz), 12.58(1H, &).
Example F-2l)
5-Hydroxy-6, 10-dioxo-1-pyx'idin-2-ylmethyM,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaa nthracene-7-carboxylic acid 4-fluoi"obenzylamide melting point: 216-219°C
(DMSO-do)δ: L.52-1.76(2H, m), 2.66-2.80(1H, m), 2 90-3.07(2H, m), 3.67(1H, d, J=15.2Hz), 4.01(1H, d, J=13.2Hz), 4.37-4.97(4H, m), 4.62(1H, brs), 4.85-4.88(1H, m), 7.07-7.25(41-1, m), 7.33-7.36(2H, iτi), 7.64-7.68(1H, m), 8.26(1H, s), 8.45(1H, s), 10.36(1H, t, J=6.0Hz), 12.57(J H, s)
Example F-22) 1-(2-Ethyl-bulyl)-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a^a-tnazaanthr acene-7-carboxyhc acid 4-fluorobenzylamide melting point: 137- 140°C
(DMSO-dOδ: 0.62(3H, t, J=7.2Hz), 0.77(3H, t, J=7.2Hz), 0.99- 1.30(5H, m), 1.57- 1.71(2H, m), 1.97-2.02(1H, in), 2.44-2.58(2H, m), 3.02-3.32(2H, m), 4.34-4.57(5H, m), 4.78-4,82(1H, m), 7.13-7.17(2H, m), 7.32-7.36(2H, m), 8.60(1H, s), 10.39(1H, t, J=5.2Hz), 12.64(1H, s).
Example F-23)
5-Hydroxy-1-(2-morpliolin-4-ylethyl)-6, 10-dioxo-1,2,3,4,6,9,9a, 10-octahydro- 1,4a,8a-tvi azaanthvacene-7-carboxylic acid 4-fluorobenzylamide molting point: 254-256°C
(DMSO-dβ)δ: 1,55- 1.68(2H, m), 2.28-2.39(81-1, m), 2.59-2.65(1H, xn), 2.82-3.09(3H, m),
3.33-3.58(5H, m). 4.34-4.50(3H, m), 4 52(2H, d, J=6.2Hz), 4.79-4.84(1 H, m),
7.12-7.17(2H, m), 7.32-7.36(2H, m), 8.52(1H, s), 10.45UH, t, J=5.2Hz), 12.55(1H, s).
Example F-24) 1-Hydroxy-6-methyl-2, 11-0110X0-2,53,6,7,8,9, 10,11-octahydro-5H-4a,6, 10a-triaza-cycloh epta[blnaphthalene-3-carboxylic acid 4-fhiorobenzylamide melting point: 255°C
(DMSO-dβ)δ: 1.48-1.55(11-1, m), I.67- 1.80(3H, ∞), 2.29(3H, s), 2.75-2.80(2H, m),
3.23-3.31(1H, m), 4.07-4.09(1H, m), 4.36-4,40(1H, m), 4.45-4.59(3H, m), 4.68-4.69(1H, m), 7.13-7.17(2Ii, m), 7.30-7.37(2H, m), 8.50UH, s), 30,42(1H, fc, J=6.0Hz), 12.42(1H, e).
lOxamplc F-25) 1-Hydvoxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9, 10, 11-octahydro-5H-4a,6, 10a-triaza-cyclo hep ta[b1 naphthalene- 3 -carboxylic acid 4-fhιorobenzylamide melting point: 221-223°C
DMSO-d6)δ: 0.81(31-1, d, J=6 8Hz), 0.84(3H, d, J=6.4Hz), 1.46- 1.78(6H, m), 2.36-2.54(2H, m), 2 27-2.93(2H, m), 3.17-3.23(1H, m), 4.03-4.06(1H, m), 4.32-4.56(4H, m), 4.82-4.86(1H, m), 7.13-7.17(2H, m), 7.30-7.37(21-1, m), 8.48(1H, s), 10.42(1H, t, J=6.0Hz), 12.53(1H, s).
Example F-26)
6-Cyclopropylmethyl-1-hydroxy-2, 11-dioxo-2,5a,6,7, 8,9,10, 11-octahydro-5H-4a,6, 10a-tr iaza-cycloheptalblnaphthalone-3-carboxylxc acid 4-fluorobenzylamide molting point: 213°C
DMSO-dβ)δ: 0.15-0.2G(2H, in), 0.46-0.48(2H, m), 0.86-1.06(1H, m), 1.46-1.76(4H, m), 2.45-2.65(1H, m), 2.68-2.83(1H, m), 2.91-2.98(2H, m), 3.17-3.26(1H, m), 4.08-4.14(1H, m), 4.43-4,45(2H, m), 4.54(2H, d, J=5.6Hz), 4.89-4.9 l(1H, m), 7.15-7.19(2H, m), 7.35-7.39(2H, m), 8.50(1H, s), 10.47(1H, t, J=6.0Hz), 12.52(1H, s).
Example F-27) 1-Furan-2-ylmethyl-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, J 0-octahydro-1,4a.δa-tnaza-a nthraoene-7-carboxylic acid 4-fluorobenzylamide melting point: 193- 197°C
DMSO-df,)δ: 1.67(2H, m), 2.61(1H, s), 2.93(2H7 m), 3.76(1H, d, J=14.8Hz), 3.84(1H, d,
J=I 4.8Hz), 4.34-4.47(3H, m), 4,52(2H, d, J=6.0Hz), 4.96(1H, d, J=14.8Hz), 6.36(2H, s),
7.16(2H, t, J=8 8Hz), 7.35(2H, m), 7.59(1H, s), 8.97(1H, s), 10.43(1H, s), 12.5l(1H, s),
Example F-28) 1-(4-Dimethylamino-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a, .0-octahydro-1,4a,8a- triaza-anUiracene-7-carboxylic acid 4-fluorobenzylamide melting point: 221-223DC
DMSO-d&)δ. 1.55- 1.99(2H, m), 2.87(6H, s), 2.87-3.06(4Ii, m), 3.80(1H, d, J=14.0Hz),
4.50(5H, m), 4.83(1H, d, J=14.0Hz), 6.58(2H, d, J=9.6Hz), 6.98(2H, d, J=8.8Hz),
7 15(2H, t, J=8.8Hz), 7.35(2H, m), 8.3l(1H, s), i 0.39(1H, s), 12.68(1H, s).
Example F-29)
5-Hydroxy-6, 10-dioxo-1-(4-trifluoromethyl-benzyl)-1,2,3,4,6,9,9a,10-octahydro-J ,4a,8a- triaza-anthracene-7-carboxylic acid 4-flυoχ-obenzylamide melting point: 273-277°C
DMSO-d&)δ: 1.52- 1.70(2PI, m), 2.63-8.04(3H, m), 3.50(JH, d, J=14.8Hz), 4, 10(1H, d,
J=14 8Hz), 4.54(5H, m), 4,79(1H, d, J=14.8Hz), 7.14(2H, t, J=8.8Hz), 7.33(2H, m),
7.55(2H, d, J=6.8Hz), 7.61(2H, d, J=8.0Hz), 8.220 H, s), 10.40(1H, s), 12.56(1H, s).
Example F-30)
5-Hydroxy-6, 10-dioxo-1-pyridin-3-ylmethyl- 1,2, 3,4, 6,9,9a, 10-octahydro-1,4a,8a-triaza- anthracene-7-carboxylic acid 4-fluorobenzylamide melting point: 210-212°C
DMSO-d(,)δ: 1 5I -1.76(2H, m), 2.63(1H, t, J=12.8Hz), 2.80(1H, d, J=12.0Hz), 3.07(J H, fc, J=12,8Hz), 3,44(1H, d, J=13.2Hz), 4.00(J H, d, H.0Hz), 4.47(4H, m), 4.62(J H, s), 4.84(1H, d, J=H.0Hz), 7.16(2H, t, J=8.8Hz), 7.33(2H, m), 7.58(1H, d, J=7.βHz), 8.30(1H, s), 8 45(2H, s), 10.4l(1H, s), 12.67(1H, s).
Example F-31) 1-(2-Chloro-6-fluoro-benzyl)-5-hydroxy-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro- 1,4a,8a- triaza-anthracene-7-carboxylic acid 4-fluorobenzylamide melting- point: 213-215°C
DMSO-dβ)δ:l.58(2H, 2H), 2.55-3.09(3H, m), 3.45(1H, d, J=12.4Hz), 4.16(1H, d,
J=12.4Hz), 4.40-4.58(41-1, m), 5.32(1H, d, J=M.4Hz), 7.15-7 38(7H, m), 8.66U H, s), 10,41 (1H, t, J=6.4Hz), .2.46(1H, s).
Example F-32)
5-Hydroxy-1-(4-methoxy-benzyl)-6, 10-dioxo- 1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza- anthracene-7-carboxylic acid 4-fluorobenzylamide melting point: 191-193°C
NMR (DMSO-dfl)5:i.50- 1.77(2Ii, ni), 2 58-3 06(3Ti, m), 3 68(3H, s), 3.88(1H, d,
J=13 6Hz), 4.41-4.55(4H, m), 4.80(2H, d, J=14 4H?,), 6.80(2H, d, J=8.8Hz), 7.0D(2H, d,
J=8.4Hz), 7.15(2H, t, J=S, 8Hz), 7,35(2H, m), 8.28(1H, s), 10,48(1H, s), 12,58(1H, s).
Example V -33) 1- (3,5-Bis-trifluoromethyl-benzyl)-5-hydroxy-6,10-dioxo- 1,2, 3,4,6,9,9a, 10-octahydro- 1,
4a,8a-octahydro-1,4a,8a-tπaza-anth.-acene-7-carboxylic acid 4-fluorobenzylamide melting point: 275-277°C
NMR (DMSO-ds)δ:i.58-1.88(2H, m), 2,51-3.14(3H, m), 3.33-4.10(3H, m), 4,5l(2H, m),
4.73(1H, m), 7.15(211, m), 7.34(211, m), 7.82-7.93(41-1, m), 10.3l(1H, s), 12.57(1H, s).
Example F-34) 1-(4-DieLhylamino-benzyl)-5-hydroxy-6, 10-dioxo-1,2,3,4,6,9,9a, 10-oclahydro-1,4a,8a-lr iaza-anthraceno-7-carboxyhc acid 4-fluorobonzylamιde melting point: 182°C
NMR (DMSO-dβ)δ: 1.04(6H, t, J=6.8Hz), 1 50-1.69(2H, m), 2.55-3.05(3H, in), 3.26(4H, q, J=7,2Hz), 3. S0(1H, d, J= 13.6Hz), 4.44-4.57(4H, m), 4.9l(1H, d, J=12 4Hz), 6,52(2H, d, J=8.8Hz), 6.94(2H, d, J=8.4Hz), 7.15(2H, t, J=8.4Hz), 7.35(2H, m), 8.46(1H, s), 10.410H, s), 12.600H, &). Example F- 35)
5-Hydroxy-1-((E)-2-mcfchyl-bul-2-enyl)-6,10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a,8a-t riaza -anthracene -7-carboxylic acid 4-fluoro-benzylamide melting point: 175- 177°C
NMR (DMSO-dβ)δ: 1.35(3H, s), 1.5 l(3H, d, J=6,0Hz), 1.52-1.69(3H, m), 2.60-3.15(3H, m), 4.31-4.52(5H, m), 4.67-4,76(1H, m), 5.30-5.40(J H, m), 7.15(2H, t, J=8,4Hz),
7.28-43(2H, m), 8.46(1H, s), 10,39(1H, brs), 12,60(1H, s).
Example F-36) 1-(3-Dimethylamino-2-methyl-propyl)-5-hydrθxy-6, 10-dioxo-1,2,3,4,6,9,9a, 10-octahydr o-1,4a,8a-(.riaza-antliracene-7-carboxylic acid 4-fhιoro-bonzylamide
NMR (DMSO-dβ)β: 0.63-0,68(2H, m), 1,57-1 82(3H, m), 2.11-2,49(10H, m),
2.98-3.11(2H, m), 4.41-4.54(5H, m), 4.73-4.80(1H, m), 7.14-7 18(2H, in), 7.31-7,38(2H, m), 8.58(1H, s), 10.d0OH, s), 32.57OH, s).
Example F- 37) 1-(3,3-Dimethyl-butyl)-5-hydroxy-6,10-dioxo-1, 2,3, 4,6,9,9a, 10-ocLahydro- J ,4a,8a-triaza
-anthracene-7-carboxylic acid 4-fhιorcrbenzylamide melting point: 175-! 77°C
NMR (DMSO-dβ)δ: 1.19- 1.36(2H, m), 1.57-1.70(2H, m), 2.23-2,30(J H, m), 2.51-2,69(2H, rα), 2.97-3,04(2H, m), 4.42-4.54(5H, m), 4.78(1H, d, J=14.0Hz), 7.13-7.17(2H, m),
7,33-7,36(2H, m), 8.630 H, s), 10.390 H, t, J=6.0Hz), 12.56(1H, s).
Example F-38) 1 -Ethyl-5-hydx*oxy-6, 10-dioxo-1,2,3,4,6,9,9a, 10-oelahydro-1.-la.δa-triaza-anihracene-?- carboxylic acid 4-flυoro-benzylamide melting point: 221 °C
NMR (DMSO-de)δ: 0.94(3H, t, J=6.8Hz), 1.56-1 71(2H, m), 2.45-2.50(1H, m),
2.59-2.76(2H, m), 2.96-3.03(2H, nf), 4.40-4.44(3H, m), 4.52(2H, d, J=6.0Hz),
4,77-4.82(1H, m), 7.14-7.18(2H, m), 7.34-7.38(2H, m), 8.62(Hi, s), 10.41OH, t,
J=6.0Hz), 12.69(1H, s).
Example F-39) 5-Hydroxy-6, 10-dioxo-1-(2-oxo-propyl)- 1,2,3,4,6,9,9a, 10-octahydro-1,4a,8a-triaza-anLh raccne-7-carboxylic acid 4-fluoro-bonzylamido moiling point: 244-246°C
NMR (DMSO-de)δ: 1.54-1.61(1H, m), 1.67- ..76(1H, m), 2.22(3H, s), 2.60-2.56(1H, m),
2.91-3.02(2H, m), 4.18(1H, s), 4.38-4.45(2H, m), 4.52(2H, d, J=6.0Hz), 4.76(1H, d,
J=14.4Hz), 7,13-7.18(2H, m), 7.34-7.37(2H, m), 8.61 (1H, s), 10.40(1H, t, J=G,0Hs;), 12,54(1H, s).
Example F-40)
5-Hydroxy-6, 30-dioxo-1-(4,4,4-lrifluoro-bυtyl)-1,2,3,4,6,9,9a, 10-ocfcahydro-1,4a,8a-tria za-anthracene-7-carboxylic acid 4-fluoro-bennylamide melting' point: 220°C
NMH (DMSO-dcJδ: 1.63- 1.62(2H, m), 1.67- 1.75(1H, m), 2.07-2.18(2H, m), 2.40-2.47(1H, m), 2.64-2,78(2H, m), 2.96-3.04(2H, an), 4.42-4.49(2H, m), 4.53(2PI, d, J=5.2Hz),
4.74(1H, d, J=12.8Hz), 7.13-7,17(2H, m), 7 33-7.37(2H, m), 8,61(1H, s), 10.40(Hi, t,
J=6.0Hz), 12.57(1H, s).
Example F-41)
5-Hydroxy-1-(v3-methyl-butyl)-6,10-dioxo- 1,2,3,4, 6,0, 9a, 10-oclahydro-1, 4a, 8a-tnaza-an thracene-7-carboxylic acid 4-fluorθ-benzylaαnide molting point: ISl °C
NMR (DMSO-dώδ: 0.78(6H, dd, J=7.6, 16 2Hz), 3 .2 J - 1 28(2H, m), 1.41-1.48(1H, m), 1.56- 1.7l(2H, m), 2.22-2.3l(1H, m), 2.51-2.59(1H, m), 2.66-2.73(1H, m), 2,96-3.05(2H, m), 4.41-4.55(5H, m), 4,80(1H, 01,^13,2Hz), 7.13-7.18(2H, m), 7.33-7.37(2H, m),
8,64(1H, s), 10.40(111, t, J=6,0Hz), 12.57(1H, s).
Example F-42)
5Ηydroxy-1-isobutyl-6, L0-dioxo- 1,2,3,4,6,9, 9a, 10-octahydro-1,4a,8a-triaza-anthraccne
-7-carboxylic acid 3-chloro-2-fluoro-benzylamide melting point: 180- 182°C
NMR (DMSO-do)δ: 0.62(3H, d, J=6.0Hz), 0.78(3H, d, J=6.4Hz), 1.55- 1.69(3H, m),
1.93- 1.99(1H, m), 2.97-3.08(2H, m), 4.39-4.46(3H, m), 4.59-4.64(2H, m), 4.75-4.8 l(1H, m), 7.16-7 23(1H, m), 7.27-7.34(1H, m), 7 47-7.53( LH, m), 8.59(1H, s), 10 44(1H, s),
12.57(1H, R) .
Example F -43) 1-Cyclopropylmethyl-5-hydroxy-θ, 10-dioxo- 1,2.G,4.β.O^a, 10-octahydro-1/ia.δa-triaza- anthracene-7-carboxyhc acid 3-chloro-2-fluoro-benzylamide molting point: 189-192°C
NMR (DMSO-dβ)δ: 0.00-0.10(2H, m), 0.35-0.4l(2H, m), 0.70-0, 77(1H, m), 1.57-1.69(2H, m), 2.52-2.65(1H, m), 2.67-2.85(1H, in), 2 91-2.99(1H, m), 4.30-4.<H(2H, m),
4.48-4.52(2H, m), 4.71-4.80(1H, m), 7.06-7.10(1H, m), 7.18-7.22(1H, m), 7.36-7.40(1H, m), 8.52(1H, s), 10.30(1H, s), 12.26(. H, s).
Example F -44) 1-Furan-2-ylmethyl-5-hydroxy-6,10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a,8a-triaza-a nthraccno-7-carboxylic acid S-chloro-2-fluoro-benzylamide melting point: 190- 192°C
NMR (DMSOd6)O: 1 56-1.68(2H, m), 2.54-2.63(1H, m), 2 89-2 99(2H, m), 3.8θ(2H, eld,
J=18.4, 33.2Hz), 4.37-4.5l(3H, m), 4.62(2H, d, J=6.0Hz), 4.97(1H, d, J=15,2Hz),
6.39(2H, s), 7, 18-7, 22(11-1, m), 7.31-7.34(1Ii, m), 7.48-7,51(111, m), 7.58(1H, s), 8.64(1H, s), 10.45QH, t, J=6.0Hz), 12.550 H, s).
Example F-45)
5-Hydiroxy-6,10-dioxo-1-thiazol-2-ylmethyM,2,3,4,6,9,9a, 10-octa hydro- 1,4a, 8a- triaza- anthraccne-7-carboxylic acid 3-chloro-2-fluoro-boni;ylamide melting point: 217-219°C
NMR (DMSO-d(,)δ: 1.59- 1.74(2H, m), 2.76-2.83(1H, m), 2.97-3.08(211, m), 3 90(1H, d,
J=16.0Hz), 4.360 H, d, J=16.0Hz), 4.45-4.69(5Ii, m), 4,89(1H, d, J=14.8Hz),
7.18-7.22(1H, m), 7.28-7.31 OH, m), 7.47-7.530H , m), 7.54(1H, d, J=3.2Hz), 7.68(1H, d,
J=3.2Hz), 8.34(1H, s), 10.40(1H, d, J=6.0Hz), 12.520 H, s).
Example F-46)
5-PIydroxy-6,10-dioxo-1-pyridin-2-ylmethyl -1,2, 3,4, 6, 9,9a, 10-octahydro- 1, 4a,8a -triaza - anthracene-7-carboxylic acid 3-chloro-2-fluoro-benzylamide melting- point: 190-193°C
NMR (DMSO-dβ)δ1 1.54- 1.61(J H, m), 1.69- 1 .75(1H, m), 2.66-2.74(1H, m), 2.91-3.08(211, m), 3.68(1H, d, J=14.4H/), 4.02OH, d, J=14.8Hz), 4.d0-4.67(5H, m), 4.85(1H, d,
J=12.4Hz), 7.16-7.35(3H, m), 7.46-7.52(1H, m), 7.61-7.69(1H, m), 8.2θ(1H, s),
8.43-8.470 H, m), 10.410 H, d, J=6.0Hz), 12.58OH, s) Example F-47)
5-H3'droxy-1-iaobul-yl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydi.O-1,4a,8a-triai5a-anthracone -7-carboxylic acid 2,4-difluoro-bonzylamide melting point: 194°C
NMR (DMSO-de)δ: 0.62(3H, d, J=6.4Hz), 0.78(3H, d, J=6,4Hz), 1.56-1.69(8JH, m), 1.93- 1.99(111, m), 2,97-3.08(2H, m), 4.39-4.46(3H, m), 4.50-4.69(2H, m), 4.77(1H, d, J=14.4Hz), 7.03-7.09(1H, m), 7.20-7.280 H, m), 7.36-7.43(1H, m), 8.59(l H, s), 10.39(11-1, s), 12.56Cl H, β).
Example F- 48) 1-Cyclopropj'lmethyl-5-hydroxy-6j10-dioxo-1.E.S,4.G.Θ^a^0-octahydro-1,4a.δa-triaza- anthvacencr7-carboxylic acid 2,4-dϋluoro-benzylamide melting point: 169-171°C
NMR (DMSO-dc)δ: 0.00-0.30(2H, m), 0.42-0.44(2H, m), 0.77-0.81(1H, m), 1.69- 1.74(2H, m), 2,27-2.32(1H, m), 2.62-2.72(1H, m), 3.05-3.12(11-1, m), 4.30-4.58(5H, in), 4.69(1H, d,
J=14.8Hz), 7.03-7.11(1H, m), 7.22-7.260 H, m), 7.37-7.40(3H, m), 8.62U H, s),
10 40(1H, i, J=6.0Hz), 12,57(1H, s)
Example F-49) 1-Fυvan-2-ylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-a nthraccno-7-carboxylic acid 2,4-difluorcrbenzylarαidc melting point: 186- 188°C
NMR (DMSO-dβ)δ: 1.55-1.68(2H, m), 2.55-2,64(Hi, m), 2.88-2.99(2H, m), 3.80(2H, dd, J=15.6, 34.8Hz), 4 36-4.56(5H, m), 4.97(1H, d, J=16.0Hz), 6.39(2H, s), 7.05-7.08(1H, m), 7.21-7.26(1H, m), 7.37-7.44(1H, m), 7.58(1 H, s), 8 64(1H, s), 10.38(1H, t, J=5 6Hz), 12.53(1H, s).
Example F- 50)
5-Hydroxy-6, 10-dioxo- ] -thiazol-2-ylmethyl- 3 ,2,3,4, 6, 9,9a, 10-octahydro-1,4a,8a-triaza- anthracene-7-carboxylic acid 2,4-difluoro-benzylamide melting point: 168- 170°C
NMR (DMSO-d6)δ: 1.59- 1.74(2H, m), 2 76-2.83(1H, m), 2 97-3,08(2H, m), 3.89(1H, d,
J=36,4Hz), 4,36(1H, d, J=I 6.0Hz), 4,44-4.55(4H, m), 4,G9(1H, s), 4,89(1H, d,
J=14.8H7,), 7.03-7.09(1H, m), 7.20-7.27(1H, m), 7.34-7.41(1H, m), 7.54(1H, d, J=3.2liz),
7.68(1H, d, J=3.2Hz), 8.34(1H, s), 10.35(1H, d, J=6.0Hz), 12.50(3 H, s). Example F- 51)
5-Hydroxy-6,10-dioxo-1-pyridin-2-ylmethyl- 1,2,3, 4,6, 9,9a, 10-octahydro- 1, 4a, 8a-iriaza- anthracene-7-carboxylic acid 2,4-difluoro-benzylamide molting point: 200-203°C
NMR (DMSO-du)δ: 1.54- 1.61U H, m), 1.69- 1.78(Hi, m), 2.71-2.79(1H, m), 2.91-3.09
(2H, m), 3.72(1H, d, J=14.4H-z), 4.07(1H, d, J=14.4Hz), 4.44-4.54(41-1, m), 4.70(1H , s),
4.82(1H, d, J = UAHz), 7.04-7.10(_ H, m), 7.2J -7.42(4H, m), 7,74-7.80(l H, m), 8.17(1H, s), 8.47-8,49(1H, m), 10.35(1H, d, J=6.0Hz), 12.57(1H, s).
Example F- 52) 1-Hydroxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9, 10, l 1-octahydro-5H-4a,6, 10a-tria2a-cycloh opta[bJnaphihalene-3-carboxylic acid 3-chloro-2-fluoro-benzylamidc melting point: 230-231°C
NMR (DMSO-de)δ: 1.47- 1.53(1H, m), 1 62-1.78(3H, m), 2.29(3H, s), 2.77-2.81 (2H, m),
4,05-4.10(1H, m), 4.35-4.4θ(1H, m), 4.54-4,64(3H, m), 4 70(1H, s), 7J 8-7.22(11-1, m),
7.30-7.34(1H, m), 7.47-7.52(1H, m), 8,49(1Ii, s), 10.47(Ui, d, J=6.0Hz), 12.44(1H, s).
Example F-53) 1-Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9,10,11-ocfcahydro-5H-4a,6, 10a-triaza-cyclo heptatbjnaphthaleno-3-carboxyhc acid 3-chloro-2-fluoro-benzylamide melting point: 215-216°C
NMR (DMSO-dβ)δ: 0.83(6H, dd, J=6 8, 13.6Hz), 1 45- 1.80(5H, m), 2.36-2.4K1H, m), 2,77-2.93(2H, m), 3.17-3.24(1H, m), 4.02-4.09(1H, m), 4.32-4.40(2H, m), 4 6l(2H, d, J=5.6Hz), 4.82-4,84(1H, m), 7, 18-7,22(1H, m), 7.30-7.33(1H, m), 7.48-7 5l(1H, m), 8.47(1H, s), 10.48(1H, t, J=6 0Hz), 12.56(1H, s).
Example F-54)
6-CyclopropylmethyM-hydroxy-2,11-dioxo-2,5a,6,7,8,9, 10, 11-octahydro-5H-4a,6, 10a-tr iaza-cycloheptarblnaphthalenc-3-carboxylic acid 3-chloι-o-2-fluoro-benzylamide melting point: 212PC
NMR (DMvSO-dβ)δ: 0.00-0.10(2H, m), 0.40-45(2H, m), 0.80-0.87(1H, m), 1,45-1,77(3H, m), 2,64-2.69(1H, m), 2.85-2.95(2H, m), 3.13-3.20(1H, m), 4.03-4.09(1H, ra),
4.36-4.40(2H, m), 4.59(2H, d, J=5.6Hz), 4,84-4.86(1H, m), 7.16-7.20(111, m),
7 28-7.32(1H, m), 7.46-7.50(1H, m), 8.45(1H, s), 10.46(1H, t, J=B,0Hz), 12.50(1H, s) Example F -55)
6-Furan-2-ylmethyl-1-hydroxy-2, 11-^0X0-2,68,6,7,8,9, l0,.11-ootahydro-5H-4a,6, 10a-tri aza-cycloheptarblnaphthalene-3-carboxylic acid 3-chloro-2-fluorovbonzylamide
Molting point: 189-190°C
NMR (DMSO-dβ)δ: 1.48-1.63(3H, in), l,7(M.77(1H, m), 2.79-2.83(2H, ra), 3.90(2H, dd,
J=H, 8, 39,6Hz), 4.05-4.11(1H, m), 4.40-4.5. (2H, m), 4.61(2H, d, J=5.6Hz),
4.89-4.9 K1H, m), 6.30-6.33(1H, m), 6.38-6.40(1H, ra), 7.18-7.22(1H, m), 7,30-7.34(111, m), 7.48-7.53(1H, m), 7.57(1H, s), 8.45(1H, s), 10.45(1H, t, J=6.0Hz), 12.440 H, s).
Example F-56) 1-Hydroxy-6-methyl-2, 11-dioxo-2,5a,6,7,8,9, 10,11- octahydro-5H-4a,6, 10a-triaza-cycloh eptatbJnaphthalene-3-carboxylic acid 2,4-dinuoro-benzylamide melting- point: 241°C
NMR (DMSOd6)S: 1.47-1.53(1H, m), 1,62-1.78(3H, m), 2,29(311, s), 2.77-2.81 (2H, m),
4,05-4.10(1PI, m), 4.35-4.40(1H, m), 4.53-4.61 (3H, m), 4.69(1H, s), 7.03-7.08(1H, m),
7.20-7.27(1H, m), 7.37-7.43U H, m), 8.49(1H, s), 10.42(1H, d, J=6.0Hz), 12.43(1H, s).
Example F- 57) l -Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9, 10, 11-octah.ydro-5π-4a,6,10a-triaza-cyclo hop ta[b] naphthalene -3-carboxylic acid 2,4-difluoro-benzylamide melting point: 203°C
NMR (DMSO-de)δ: 0.82(6H, dd, J=6,4, 13.2Hz), 1.45- 1.80(5H, m), 2.36-2.42(1H, m), 2.77-2.93(2PI, m), 3.15-3.23(1PI, m), 4.02-4.08(1H, m), 4.32-4.41(2H, m), 4.54(2H, d, J=5.6Hz), 4.82-4.84(1H, m), 7.02-7.09(1H, m), 7.20-7.27(1H, m), 7.36-7.48(JH, m), 8.47(1PI, s), I 0.410H, t, J=6.0Hz), 12.54(1H, s).
Example F-58)
6-Cyclopropylmethyl-1-hydroxy-2,l] -dioxo-2,5a,6,7,8,9, 10,11-octahydro-5H-4a,6, 10a-tr iaza-cyclohopta[b]naphthalene- 3-carboxylic acid 2,4-difltιoro-bonzylamide melting point: 182-183°C
NMR (DMSO-de)δ: 0.00-0.10(211, m), 0.40-45(2H, m), 0.80-0.87(1H, m), 1,43-1.77(311, m), 2.60-2.69(111, m), 2.85-2.95(2H, m), 3.11-3.19(1H, m), 4.00-4.06(1H, m), 4.36-4.40(2PI, m), 4.51 (2H, d, J=5.6PIz), 4.83-4.87(1H, m), 7.00-7.07(1PI, m), 7.16-7.23(1H, m), 7.34-7.38(111, m), 8.440 H, s), 10.39(111, t, J=6.0Hz), 12.47(1H, s). Example F-59) δ-Fiu-an-2-ylmethyl-1-hydroxy-2, 11^10X0-2^,6,7,8,9, 10, 11-octahydro-5H-4a,6, 10a-tπ aza-cyclohepta[b]naphthalene-3-carboxylic acid 2,4-diflιιoro-benz;ylamide melting- point'. 171- 173°C
NME (DMSO-ds)δ: 1,47-1.64(3H, m), 1.70- 1.77OH, m), 2,79-2.83(2H, m), 3.90(2H, dd,
J=15.6, 39.6Hz), 4.05-4.110.H, m), 4.41 -4.57(4H, m), 4.90-4.92(1H, m), 6.30-6.33(1H, m), 6.38-6.40(1H, m), 7.03-7.09(1H, m), 7.20-7.27(1H, m), 7.37-7.45(1 H , m), 7.57(1H, s), 8.44( 11-1, s), 10.4K1H, t, J=6.0H'z), 12,43(1H, s).
Example K-60)
5-Hydroxy-6,10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1 -oxa-4a,8a-diaza-anfchracene-7-car boxylic acid 3-chloro-2-fluoro-bonzylamide melting point,: 276°C
NMR (DMSO-dβ)δ: 1.60-1.68C1H, m), . .77- 1.84C1H, m), 3.85-3.93 (1H, m),
4.03-4.07(1H, m), 4.43-4.62(5H, m), 5.28(1H, s), 7.17-7.22(1H, m), 7.29-7.34(1H, m),
7,47-7.520 H, m), 8.490 H, s), 10.41 OH, d, J=6.0HSU), 12.48(1H, s).
Example F-61)
5- Hydroxy -6,10 -dioxo- 3, 4, 6, 9,9a, 10-hexahydro-2H- 1-oxa- 4a, 8a -diaza- anthracene- 7- car boxylic acid 2,4-difluoχ-o-benzylamide melting point: 258°C
NMR (DMSO-dβ)δ: 1.60- 1.69OH, m), 1.77-1.86(1H, m), 3.86-3.92 (1H, m),
4.04-4.08(1H, m), 4.43-4.55(BH, m), 5,28(1H, s), 7.03-7.09(1H, m), 7.21-7.27(1H, m),
7,36-7,43(1H, m), 8.50(1H, s), 10.35(1H, d, J=6.0Hz), 12.47( LH, s)
Example F-62)
5-Hydroxy-1-(2-methoxy-ethyl)-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-octahydro-1,4a,8a-triaza-a nthracone-7-carboxylic acid 3-chloro-2-flυoro-bonzylamide melting point: 193°C
NMR (DMSO-dft)δ: 1.63-. .73(2H, m), 2,51-2.58(1H, m), 2.71-2.78(1H, m), 2.81-2.87 (1H, m), 2,95-3.08(2H, m), 3.17(3H, s), 4.40-4.52(3H, m), 4.62(1H, d, J=5.6Hz), 4.78(1H, d, J=14.4Hz), 7.18-7.22(1H, m), 7.30-7,34( LH, m), 7.47-7.52(1H, an), 8.55(1H, s), I0,45(1H, d, J=6.0Hz), 12.59(1H, s). Example P -63)
5-Hydroxy-1-(2-methoxy-ethyl)-6, 10-dioxo- 1,2, 3,4, 6,9,9a, 10-octahydro-1,4a,8a-lriaza-a nthracene-7-carboxylic acid 2,4-difJuoro-benzylamide melting point: 166-168°C
NMR (DMSO-dc)δ: 1.55- 1.72(2H, m), 2,51-2.58(1H, m), 2.70-2.77(1H, m), 2.80-2,87
(1H, m), 2,97-3.07(21-1, m), 3.18(3H, s), 4.39-4.52(3H, m), 4. Sd(1H, d, J=β.2Hsϋ),
4.78(11-1, d, J=I 3.6Hz), 7.03-7.09(1H, m), 7.20-7.27(1H, m), 7,37-7.43(11-1, m), 8.55(1H, s), 10.dOdli, d, J=6.0H&), I 2.58(1H, s).
Example F- 64)
5-Hydroxy-1-(1H-imidazol-4 -ylmethyl)-6, 10-dioxo- 1,2, 3, 4,6,9,9a, 10-octahydro-1, 4a, 8a-t riazaanthracone-7-carboxylic acid 4-fluorobonzylamide
(DMSO-dή)δ: 1.55-1.59(1H, m), 1.64-1.7O(1H, m), 2.58-2.66(1H, m), 2,87-2,95(2H, m),
3.67(1H, d, J=15.2Hz), 3.73(1H, d, J=15.2Hz), 4.34(1H, s), 4,38-4,43(111, m),
4.47-4,54(3H, m), 5.05(1H, d, J=14.0Hz), 7,Oθ(1H, s), 7J 3-7.19(2H, m), 7.33-7.38(1H, m), 7.59(1H, s), 8.55(3 H, s), 10.41(111, t, J=6.6Hz), 11.95(1H, br s), 12.59(1H, s).
Example IM) 1 -Acetyl-5-hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triai5a-cyclopenta[b]n aphthalone-7-carboxylic acid 4-fluoro-benzylamxde
[Chemical formula 61]
Figure imgf000110_0001
l) To a solution of a compound 48 (120mg, 0.26 mmol) in methylene chloride (1,2 ml) were added triethylaraine (43 μl, 0,31 mmol), acetic anhydride (29 μl, 0.31 mmol), and 4-dimethylaminopyridine (cat.) atrroom temperature, and the mixture was stirred for 30 minutes. Further, triethylamine (18 μl, 0.13 mmol) and acetic anhydride (_ 2 pi, 0,13 mmol) were added, and the mixture was stirred for ά hours, 2N hydrochloric
. 08 acid was added, this was extracted with chloroform, and the organic layer was washed with water, dried with sodium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to crystallize the material, which was filtered to obtain 53 (112 mg) as a pale orange crystal at a yield of 86 %.
2) An Example compound H-J (71 mg) was obtained at a yield of 82 % from a compound 53 (1,06 mg), according to Ih 0 method of Example B-I 17). melting point 290°C
NM R (DMSO-dδ)δ: 2.08(3H, s), 3.44-4.2l(5H, m), 4.51(2H, d, 5.7Hz), 4.93(1H, m),
5.46-5.62(1H, m), 7.15(2H, t, 9.0Hz), 7,34(2H, m), 8.49(1H, s), 10,40(1H, t, 5.7Hz), 11.48(1H, s).
An Example compound H-2 was synthesized according to the same manner as that of Example Ii-1.
Example H-2) 1 -Acetyl-5-hydroxy-6, 10-dioxo- 1,2.S,4.B.O^a.10-octahydro- 1,4a^a-tπaza-anthracene-?
-carboxylic acid 4-fluoπrbenzylamido melting point: 290°C
NMR (DMSOdβ)δ: 1.95(2H, m), 2,14(3H, e), 2.85(2H, m), 4.45(4H, m), 4.5l(2H, d,
5.7Hz), 5.99(1H, s), 7.15(2H, t, 9.0Hz), 7,34(2H, m), 8.370 H, s), 10.46(1H, s),
J 2.28OH, s).
Example I-1)
5-Hydroxy-1-methanesiilfonj'l-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H- 1,3a,8a-triaza-cyc] op en ta [bj naphtha lone- 7 -carboxy lie acid 4-fluoro-benzylamido
LChcmical formula 62]
Figure imgf000111_0001
1) To a solution of a compound 48,»(140 mg, 0,30 mmol) in pyridine (1.4 ml) wore added methanesulfonyl chloride (28 μl, 0.36 mmol), and 4-dimethylaminopyridine (cat,) at room temperature, and the mixture was stirred for 3 hours. After 2N hydrochloric acid was added, this was extracted with ethyl acetate, and the organic layer was washed with water, dried with sodium sulfate, and concentrated under reduced pressure. Diisopropylether was added Lo crystallize the material, which was filtered to obtain 54 (127 mg) as a pale orange crystal at a yield of 78 %.
2) According' to the method of Example B-1 17), an Example compound 1-1 (21 mg) was obtained at a yield of 21 % from a compound 54 (123 mg). melting point: 260°C
NMR (DMSO-cU)δ: 3, 16(3J-I, s), 3.30-4.15(5H, m), 4,45(2H, d, 5.7Hz), 4.27(2H, m),
5,36(11-1, m), 7.14(2H, t, 8.7Hz), 7.33(2H, m), 8,22(1H, s), 10.53(1H, s).
According to the same manner as that of Example J - I, an Example compound 1-2 was synthesized.
Example 1-2)
5-Hydroxy-1 -methanesulfonyl-6, 10-dioxo- 1,2,3,4,6,9,9a, 10-oclahydro- 1,4a, 8a-triaza-an thracencr7-carboxyhc acid 4-fluoro-benzylamide molting point: 257-259°C
NMR (DMSO-d&)δ: 1.80- _ ,96(2H, m), 3.02-3.58(2H, m), 3.16(3H, s), 4,76(2H, m),
5,56(11-1, s), 7.16(2H, t, 9.0Hz), 7.35(2H, m), 8.36(1H, s), 10.39(1H, s).
Example L-I)
5,9-Dihydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-1H-2-oxa-4a,8a-diaza-anthracenc-7- carboxylic acid 4-fluoro-bonzylamide lChemical formula 65]
Figure imgf000112_0001
1) According to the method of synthesizing a compound 66, a compound 62 (278 jng, 57%) was obtained from a compound 13 (357 mg).
2) According to the method of synthesizing a compound 57, a compound 63 (202 mg, 79 %) was obtained from a compound 62 (278 mg).
3) To a solution of a compound 63 (200 mg, 0,403 mmol) in chloroform (2 ml) were added dimethyl sulfoxide (286 μl, 4,03 mmol), and triethylamine (337 μl, 2.42 mmol), the mixture was stirred for 10 minutes under ice-cooling, a sulfur trioxido-pyridine complex (321 mg, 2,02 mmol) was added, and the mixture was stirred at room temperature for 2 hours, To the reaction solution was added water (3 ml), and chloroform was distilled off under reduced pressxire, followed by extraction with ethyl acetate, The organic layer was washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Tho crystalline residue was washed with ethyl acetate to obtain a compound 64 (60 mg) at a yield of 30 %.
4) Using a compound 64, and according to the method of synthesizing Kxample A-1, an Example compound L-I was synthesized.
NMR (DMSO-dfc)δ' 2.98-3.10(1H, m), 3.38-3.60(211, m), 3.80-4.20(5H, m), 4.40-4.65(2H, m), 5,48(1H, brs), 5.85(1H, s), 7.15(2H, t, J=8.4Hz), 7.33-7 37(2H, m), 8.45(1H, s), 8.600 H, s), 10 27- 10.42(1H, m), 12.6l(1H, brs)
Example M-1)
] -Hydroxy-2, 10-dioxo-2,4b,5,6,7,8,9, 10-octahydro-4a,9a-diaza-benzo[a]azυlone-3-carbo xylic acid 4-fluoro-benzylamide
[Chemical formula 66]
Figure imgf000113_0001
3.) According to the method of synthesizing a compound 21, a compound 65 (207 mg) was obtained at a yield of 24 % from a compound 13 (250 mg),
2) According to the method of synthesizing a compound 64, a compound 66 (313 mg, 67 %) was obtained from a compound 65 (470 mg).
3) After trifluoroacetic acid (10 ml) was added to a compound 66 (100 mg, 0,020 mmol), the mixture was stirred at 75°C for 4 hours. The solvent was distilled off under reduced pressure, and this was diluted with chloroform, and added to ice water. This was washed with an aqiieous saturated sodium bicarbonate sohition, a .10 % aqueous citric acid solution, and water, and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and fractions elutod with chlorofornvanethanol were concentrated under reduced pressure, and recrystallized with ethyl acetate-diisopropyl ether to obtain an Example compound M-1 (23 mg, 16 %). melting point 281-283°C
NMR (DMSO-dβ)S: 1.43-1.52(2H, m), 1.62-1.83(3H, m), 2.04-2.18(1H, m), 2.2S-2.35(1H, m), 4.08-4.16(1H, m), 4.48-4,53(2H, m), 5,58-5,6l(1H, m), 7.11-7,2θ(2H, m), 7.30-7.38(2H, m), 8.29Q.H, s), 10.30-10.36(1H, m), 12.78(1H, brs).
Example X- 1)
(R)-6-Hydroxy-5,7-dioxo-2,3,5,7, 11,11a-hexahydro- .iH-pyrido[1,2-a]pyrrolo[1,2-d]pyraz ine-8-carboxylic acid 4*ϊluoro-ben'Λylamide [Chemical formula 67]
1.12
Figure imgf000115_0001
1) Selenium dioxide (666mg, B.0mmol) was added to the solution of compound 2 (216mg, l.0mmol) in bromobenzene (2ml). Then the mixture was heated up to 360°C, and stirred for 16h. After celite filtration the solvent was evaporate, The precipitate was purified by silicagel column chromatography, and fractions oluting with n-hexan/EtOAc were concentrated under reduced pressure to obtain compound 100 (I64mg, 71%) as a yellow oil . l lϊ-NMR (CDCl3)S1 5.52(1H, s), 6.50(1H, d, J=6.0Hz), 7.36(5H, m), 7.74(1H, d, J =6 3Hz), 9.88 (1H, s).
2) Sulfamic acid (1.50g, l5.dmmol) and NaClO2 (1.05g, 11.Gmmol) was added to the solution of compound 100 (2.54g, 11.0mmol) in acetone (20ml) and water (30ml). Then the mixture was stirred for 3h. The solvent was evaporated tinder reduced pressure to obtain compound 101 (2,18mg, 80%) as a white solid. 1H-NMR (DMSO-ds)δ: 5J l(2H, s), 6.55(1H, d, J=5.4Hz), 7.32-7.46(5H, m), 8.21(3 H, d, J=5.7Hz).
3) (R)-2-N-BOC-aminomethj'l pyrrolidine (391mg, l,95mmol) was added to the solution of compound 101 (400mg, J .62nvmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloridc (373mg, l,95mmol), and 1-hydroxybenzotriazole (219mg, 1.62mmol) in THF (6ml). After sttiring for 16h NaHCOa aqueous solution was added to the mixture, The mixture was extracted with EtOAc, which was washed with NH/jCl aqueous solution and brine, The organic phase was dried over MgSO-i, After a filtration the solvent was removed under reduced prosRurG to obtain compound 102 (694mg, 100%) as a white solid. 1H-NMR (CDCl3)δ; 1.4β(9H, s), 1.56-2.14(4H, m), 3.29(4H, m), 4.18(1H, m), 5.24( LH, s), 6.27(1H, s), 6.46(1H, d, J=5.7Hz), 7,35(5H, m), 7.69(1H, d, J=5.7HSU) .
4) The solution of compound 102 (694mg, 1.95mmol) in HCl/EtOAc (4mol/l, 8ml) was stirred for 30 min, The soluvant was removed under reduced prossur, diluted with EtOIi (16ml) then. A saturated NaHCOa aqueous solution was added to the solution to control pH at 9. The mixture was sfcrrod at 50 °C for 2h, then diluted with water The mixture was extracted with CHCb, washed with brine, and dried over MgSO-i. The solvent was removed under reduced pressure to obtain compound 103 (413mg, 68%) as a yellow solid, 1H-NMR (CDClβ)δ: 1.54-2.22(4H, m), 3.60(2H, m), 3 80(1H, t, J=12 0Hz), 4.18(1H, d, J=12.0Hz), 5.15(1H, d, J=9.9Hz), 5.35(1H, d, J=9.0Hz), 6.71(1H, d, J=5.4Hz), 7.33(3H, m), 7 50(1H, d, J=5.1Hz), 7.63(2H, d, J=7.2Hz).
5) NaOAc (11δmg, 1.44mmol) and bromine (0.234ml, 2.62mmol) were added to the solution of compound 103 (408mg, 1.31mmol) in acetic acid (8ml), stirred for 30 mm then An aqueous solution of NaOH (2M) was added to the mixture, and extracted with CH2CI2, washed with brine, and dried over NasSO-i, The solvent was removed under reduced pressure to give compound 104 (390mg, 77%) as a white solid. 1 H-NMR (CDClo)δ: 1.55-2.19(4H, m), 3.55-4.02(5H, m), 5.12(11-1, d, J=9.6Hz), 5,35(1H, d, J=9,9Hz), 7.29-7.38(3H, m), 7.6l(1H, s), 7.67(2H, d, J=6.6Hz).
6) Tetralds triphenylphosphine paradium (0) (77mg, 0.067mmol) and N.N-diisopropylethylamine (0.29ml, 1.67mmol) were added to the solution of compound 104 Q 30mg, 0,334mmol) in DMSO (2.6ml). the mixture was stirred under CO atmosphere for 2h at 80°C . The reaction mixture was diluted with a saturated NI-LiCl aqueous solution, extracted with EtOAc then, And the organic phase was washed with brine, and dried over Na.SOd. The precipitate was purified by silicagcl column chromatography, and fractions cluting with MeOH/EtOAc were concentrated under reduced pressure to obtain compound 105 (115mg, 75%) as a white oil. 1H-NMR (CDCl3)δ: 1,56-2,33(4H, m), 3.66(2H, m), 3.90(2Ii, ra), 4,19(H-I, s), 4.66(2H, m), 5.20(1 H, d, J=9.9Hz), 5.37(1H, d, J=9.9Hz), 7.00(2H, t, J=8.7Hz), 7.33(5H, m), 7.61(2Ii, m), 8.39(111, m), 10,50(1H, s).
7) A mixture of compound 105 (1. lmg, 0.241mmol) and paradium-carbon (10%, 22mg) in THF (8ml) and MeOH (2ml) was stirred under hydrogen atmosphere for 3h. After celite Alteration the solvent was removed under rcdxtced pressure to give the example X- I (57mg, 64%) as a white solid. Melting point: 274°C 1H-NMR (DMSO-dG)δ.1,56-2,25(41-1, m), 3,48-3,65(2H, m), 4.01(2H, m), 4.51(2H, d, J=5.7Hz), 4.71(1H, d, J=9.9Hz), 7.14(2H, t, J=9.0Hz), 7,33(2H, dd, J=5.7, 8,7Hz), 8,41(1H, s), 30.44(1H, t, J=6.0Hz), 12,18(1H, s).
The following compotmds were synthesized using the similar method
Example X-2)
(R) -6-Hydroxy-5,7-dioxo-2, 3,5,7, 11, 11a-hexahydro-1H-pyrido[1,2-a]pyrroloL1,2-d]pyraz ine-8-carboxylic acid 2,4-difluoro-benzylamide
Melting point: 300°C 1H-NMR'(DMSO-d6)8: 1.03-2.20(dH, m), 3.39-3.66(2H, m), 4.02(2H, m), 4,54(2H, d,
J=6,0Hz), 4,71(1H, d, J=9.9Hz), 7.06(1H, m), 7.23(1H, m), 7.38(1H, m), 8.41(1H, s), 10 43(1H, t, J=6.0Hz), 12 19(1H, s).
Example X- 3)
(R)-6-?Iydroxy-5,7-dioxo-2,3,5,7, 11, 11a-hexahydro- 1H-pyrido[1,2-a]pyrrolo[1,2-d]pyraz ine-8-carboxylic acid 3-chloro-2-ffuoro-benzylamide
Melting point: 304°C 1H-NMR (DMSO-df,)δ: 3.44-3.66(2H, m), 4.0l(2H, m), 4.61(2H, d, J=5.4Hz), 4.70(1Ii, d,
J=9.0Hz), 7.20(1H, m), 7.Sl(1H, m), 7.49(1H, m), 8.4l(1H, s), 10.49(1H, I, J=5,7Hz),
12.20(1H, s)
Example X- 4) 1-Hydroxy-2,9-dioxo-2, 5,6, 7,8,9, 10, 10a-octahydro-4a,8a-diaza-anthracene-3-carboxylic acid 4-fluoro-benzylamide Melting point: 259°C 1H-NMR (DMSO-dβ)8:i.33-1.79(6H, m), 2.51 (1H, m), 3.88(1 H, m), 4.12(1H, dd, J=0.3, 14.1Hz), 4.38(1H, d, J=12.9Hz), 4.53(3H, m), 7J 6(2H, t, J=9.0Hz), 7.34(2H, dd, J=5.7, 8.7Hz), 8.39(1H, β), I0.44(1H, t, J=6.3Hss), 12,84(1H, s).
According to the same manner as that of Example C-21, the following Example compounds Y-I to Y- 18 were synthesized.
Example Y-I)
(3S,9aS)-5-Hydroxy-3-methyl-6, 10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-diaz a-anthracαno-7-carboxylic acid 2,4-difluoro-benzylamide
Example Y- 9)
(3R,9aR)-5-Hydroxy-3-methyl-6, 10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaz a-anthraccne-7-carboxylic acid 2,4-difluoro-benzylamide
JH-NMR (CDCl8)S: 0.90(3H, d, J=6.9Hz), 2.00-2.10(1H, m), 2.70(1H, dd, J=I l .6,
13.4Hz), 3.41(111, dd, J=Il.2, .2.9Hz), 4.05-4.45(2H, m), 4.30-4.38(1H, dd, J=4.0, 14.1Hz), 4.63(2H, d, J=5.9Hz), 4.65-4.75(1H, m), 4.98(1H, t, J=3.7Hz), 6.80-6.84(2H, m), 7.32-7.40(1H, m), 8.3l(1H, s), 10.38(1H, brs), 12.37(3H, s).
Example Y- 2)
(4S,9aR)-5-Hydroxy-4-methyl-6, 10-dioxo-3, 4,6, 9,9a, 10-hexahydro-2H-1-oxa-4a,8a-diaz a-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
Example Y-3)
(4R,9aS)-5-Hydroxy-4-methyl-6, 10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-diaz a-anthracene-7-carboxyhc acid 2,4-difluoro-bonzylamide 1H-NMR (CDCl3Jδ: 1.42(3H, d, J=7,0Hz), 1.56(1H, dd, J=2.0, 14.01Iz), 2, 19-2.30(3 H, m), 4 02(3 H, d, J=2.2Hz), 4.05(1H, t, J=2.3Hz), 4.12(1H, dd, J=6.0, 13.6Hz), 4.27(1H, dd, J=4.2, 13.4Hz), 4.64(2H, d, J=5.9Hz), 4.95-5.05(1 H, m), 5.26(2H, d, J=4.1, 5 8Hz),
6.75-6.85(2Ii, m), 7.30-7.40(1H, m), 8.30(1H, s), 10.38(1H, brs), 12.45QH, s).
Example Y-4)
(2R,9aR)-5-Hydroxy-2-methoxymethyl-6, 10-dioxo-3,4,6,9,9a, 10-hexahydro-2H- l -oxa-4 a,8a-diaza-anthracone-7-cax'boxylic acid 2,4-diiTuoro-benzylamide Example Y-8) (2S,9aS)-5-Hydroxy-2-methoxymethyl-6, 10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a ,8a-diaza-anlh.raccne-7-carboxylic acid 2,4-difluoro-benzylamide 1H-NMR (CDCl3)S: 1.60-1.80(2H, m), 3.09-3.21(1H, m), 3.37(3H, s), 3.35-3.B0(2H, m),
4.00-4.11(1H, m), 4.24(1H, d, J=13.1Hz), 4.36(1H, d, J=I0.1Hz), 4.64(1H, d, J=5.9Hz),
4.70-4.80(J H, m), 5.12(1H, s), 6.75-6.85(2H, m), 7.30-7.40(1H, m), 8.30(1H, s),
10.38(1 H, brs), 12.33(1H, brs),
Example Y- 5)
(5aR,6aS, 10aR)-1-Hydroxy-2,12-dioxo-2,5,5a,7,8,9,10, 10a, 11, 12-decahydro-6aH-6-oxa- 4a,l1a-diaza-naphthaccne-3-carboxylic acid 2,4-difliioro-benzylamide [racemalel 1H-NME (DMSO-dβ)δ: 1.00- 1.85(9H, m), 2,90(1H, t, J=4.2Hz), 4.36(1H, dd, J=4 2, 12,9Hz), 4.44-4.57(4H, m), 5.32(1H, t, J=3.9Hz), 7.03-7.09(1H, m), 7.20-7.27(1 H, m), 7.35-7.43(1H, m), 8.49(1 H, s), 10.34(1H, brs).
Example Y- 6)
(2S,9aR)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-diaza- anthracene-7-carboxylic acid 2,4 -difluoro-benzylamido
Example Y-7)
(2R,9aS)-2-Ethyl-5-hydroxy-6, 10-dioxo-3, 4,6,9, 9a, 10-hexahydro-2H-1-oxa-4a, 8a-diaza- anthracene-7-carboxylic acjd 2,4-difluoro-benzylamido 1H-NMR (DMSO-dC)δ: 0.87(3H, d, J=5,4Hz), 1.40-1.51(311, m), 1.75(1H, d, J=I 0.8Hz),
3.22(1H, t, J=I0.2Hz), 3.73-3.780 H, m), 4.41-4.57(4H, m), 5.29(1H, s), 7.03-7.07(1H, m), 7.21-7.260 H, m), 7.37-7,42(1H, m), 8.50(11-1, s), 10.34(1H, brs), 12.480 H, s).
Example Y- I0)
(2S,9aS)-5-Hydroxy-6, 10-dioxo-2-phenyl-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaz a-anthracenc-7-carboxylic acid 2,4-difluoro-benzylamide 1H-NMR (CDCl3)δ: 1.70- 1.82(1H, m), 1.98(1H, d, J=9.6Hz), 3.49(1H, t, J=9.6Hz),
4.54-4.68(5H, m), 4 98(1H, d, J=8.7Hz), 5.51(1H, s), 7.04-7 08(1H, m), 7.21-7.42(7H, m), 8.50(111, s), 10.38(1H, s), 12.450 H, s).
Example Y-Il)
(2S,9aS)-5-Iiydroxy-2-isopropyl-6, 10-dioxo-3, 4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-di aza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide
Example Y-12)
(2R,9aR)-5-Hydroxy-2-isopropyl-6, 10-dioxo-3, 4,6,9, 9a, 10-hexahydro-2H-1-oxa-4a,8a-di aza-anthracone-7-carboxylic acid 2,4-difluoro-benzylamide 1H-NMR (DMSO-d6)δ: 0.86(6H, dd, J=4,8, 13.5Hz), 1.41- 1.49(1H. ra), 1.57-1.69U H, m), 1.72- 1,78(1H, m), 3.20(1H, I1 J=8.4Hss), 3.52-8.59(1H, m), 4.41-4.46(5PI, ra), 5.29(1H, s), 7.01-7,08(1H, m), 7.21-7.26(1H, m), 7.37-7.43(1H, m), 8.50(1H, s), 10,35(1H, brβ), 12.48(1H, s).
Example Y- 13)
(3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,J 0-hexahydro-2H-1-oxa-4a,8a-diaz a-anthraconc-7-oarboxylic acid 4-fluoro-benzylarαido
Example Y- 14)
(3R,9aIl)-5-Hydroxy-3-methyl-6, 10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-diaz a-anthracenc-7-carboxylic acid 4-fluorcrbenzylamide 1H-NMR (DMSO-dθ)δ: 0.8l(3H,d, J=6.6Hz), 1.84-1.93(1H, m), 2.86(1H, t, J=12.5Hz),
3.480 H, i, J=I 1.1Hz), 3 97-4.03(XH, m), 4.41-4,60(3H, m), 4.52(2H, d, J=5.9Hz),
5.20(1H, t, J=3.8Hz), 7.12-7.20(2H, m), 7.32-7.38(2H, m), 8.52(1H, s), I0.36(1H, t,
J=5.9HB), 12.45(1H, s),
Example Y-15)
(2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3, 4,6,9,9a, 10-hexahydro-2H-1-oxa-4a,8a-diaz a -anthracene- 7 -carboxyhc acid 2,4-diflxioro-benzylamide
Example Y- 16)
(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a, 10-hexahyd)O-2H-1-oxa-4a,8a-diaz a-anthraccne-7-carboxylic acid 2,4-difIuoro-bonzylamidc
XH-NMR (DMSO-dβ)δ: 1.14(3H, d, J=6.0Hz), 1.38(1H, m), 1.75(1H, d, J=13.8Hz),
3, 18-3.29(1H, m), 3.95-4.06(1H, m), 4.42-4.58(311, m), 4.54(2H, d, J=5.7Hz), 6.30U H, t,
J=S.9Hz), 7.03-7.10(1H, m), 7 20-7.29(1H, m), 7.36-7.44(1H, m), 8.50(1H, s), 10.35(1H, i, J=5.7Hz), 12.48(1H, s).
Example Y 37)
(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-211-1-oxa-4a,8a-diaz; a-anthracene-7-carboxylic acid 4-fluoro-benzylamide
Example Y- 18)
(2R,9aS)-5-Hydroxy-2-methyl-6, 10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaz a-anthracenα-7-carboxylic acid 4-fluoro-benzylamide 1H-NMR (DMSO-d6)δ: 1.15(8H, d, J=6,0Hz), J .35-1.50(1H, m), 1.75(1H, d, J=12.9Hz), 3.23(1H, td, J=13.0, 2,8Hz), 3.95-4.03(1M, m), 4.41-4.59(3H, m), 4.52(21-1, d, J=6.0Hz), 5.30(1H, I, J=3.9Hss), 7.12-7, 19(211, m), 7.32-7.38(2H, m), 8.52(1H, s), 10.36(1H, I, J=6.0Hz), 12.48(1H, s).
Corresponding amino-alcohol derivatives used in syntheses of Y- 1 to Y- 18 were prepared as optically puro version using methods similar i,o those described in the following reports.
3-Amino-2-methyl-propan-1-ol, and 4-Amino-butan-2-ol were prepared according to the method of Russell A, Barrow (J, Am. Chem, Soc, 1995, 317, 2479-2490), 3-Amhio-butair 1-ol were prepared according to the method of P. Bcsse (Tetrahedron Asymmetry 10(1999) 2213-2224). 1-Amjno-pentan-3-ol, 1-Amino-4-methyl-pentan-3-ol, 4-Amino-1-methoxy-butan-2-ol, and 3-Amino-1-phenyl-propan-1-ol wore prepared according to the method described in the following literatures, U.S. Pat. Appl. Publ., 2004133029, 08 JuI 2004, PCT Int. AppL, 2002012173, 14 Feb 2002,
All examples below consist of >95% ee and >6-l diastereomcric purity unless
indicated otherwise. The compounds shown m table ZZ consist of mixtures of
diastereomers at the depicted stereoccntcr in ratios of 1>"1 to >10-l Stereoccnters
that were formed during' the process' below have been assigned using NMR techniques
well know in the art (ID and 2D method) and/or using vibrational circular dichroism
techniques, Stereochemical assignment dcterminatons were performed on
representative examples and closely related compounds were assigned by analogy in
some cases, The schemes below are meant to be general guidance to how examples
were synthesized. It will be possible that one skilled in the art may rearrange the
order of steps or change substituents to apply the method described below and in the
examples to construct compounds of the genera] fommla. Additional methods known
to those skilled in the art or commonly present in the literature may also be applied to perform similar transformations and arriving at the same compounds of the
general formula or amino alcohol and diamine precursors.
[Chemical formula 68]
Figure imgf000122_0001
[Chemical, formula 69]
Figure imgf000122_0002
[Chemical formula 70]
Figure imgf000123_0001
[Chemical formula 71]
Figure imgf000123_0002
[Chemical formula 72]
Figure imgf000124_0001
[Chemical formula 73]
Figure imgf000124_0002
[Chemical formula 74]
. 22
Figure imgf000125_0001
[Chemical formula 74]
Figure imgf000125_0002
[Chemical formula 75]
Figure imgf000126_0001
[Chemical formula 76]
Figure imgf000126_0002
[Chemical formula 77]
Figure imgf000127_0001
[Chemical formula 78]
Figure imgf000127_0002
[Chemical formula 79]
Figure imgf000128_0001
[Chemical foπrmla 80]
Figure imgf000128_0002
[Chemical formula 81]
Figure imgf000129_0001
emical formula 82]
Figure imgf000129_0002
]27 [Chemical formula 83]
Figure imgf000130_0001
Example Z-1:
(3R,11 aS)-N-[(2,4-Diflυorophenyl)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 sodium salt.
Figure imgf000130_0002
(3R,11aS)-N-[(2,4-Diflυorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,
3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. To a solution of 16a (409 mg, 0.87 mmol) in dichloroethane (20 mL) was added (2R)-2-amino-1-propanol (0,14 mL, 1.74 mmol) and 10 drops of glacial acetic acid.
The resultant solution was heated at reflux for 2 h. Upon cooling, Celite was added
to the mixture and the solvents removed in vacuo and the material was purified via
silica gel chromatography (2% CH3OH/CH2CI2 gradient elution) to give
(3R),11aS)-N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6- [(phenylmethyl)oxy]-2,
3,5,7, 1 l , 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazinc-8-carboxamide (396
mg, 92%) as a glass, JH NMR (CDCIo) δ 10.38 (m, 1 H), 8.42 (s, 1 H), 7,54-7,53 (m, 2
H), 7,37-7.24 (m, 4 H), 6.83-6,76 (m, 2 H), 5.40 (d, J = 10.0 Hz, 1 H), 5.22 (d, J = 10,0
Hz, 1 H), 5.16 (dd, J - 9,6, 6.0 Hz, 1 H), 4,62 (m, 2 H), 4.41 (m, 1 H), 4.33-4.30 (m, 2
H), 3.84 (dd, J= 12.0, 10.0 Hz, 1 H), 3.63 (dd, J= 8,4, 7.2 Hz, 1 H), 1.37 (d, J= 6.0 Hz,
3 H); ES+ MS: 496 (M+1).
b)
(3R, 11aS)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11, 1la
-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8vcarboxamide sodium salt. To a
solution of
(37?, 11aS)-N-[(2,4-difluo]-ophenyl)methyl]-3-methyl-5,7-dioxo-6- [(phenylmethyl)oxy] -2,
3,5,7,11,11 a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396
mg, 0.80 mmol) in methanol (30 mL) was added 10% Pd/C (25 mg). Hydrogen was
bubbled through the reaction mixture via a balloon for 2 h. The resultant mixture
was filtered through Celite with methanol and dichloromethanc. The filtrate was
concentrated in vacuo to give
(3R, l] aS)-N-f(2,4-difliιorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, υ , 11a- hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide as a pink tinted
white solid (278 mg, 86%), 1H NMR (ODCU) δ 11.47 (m, 1 H), 10.29 (m, 1 H), 8,32 (s,
1 H), 7.36 (m, 1 H), 6.82 (m, 2 H), 5.31 (dd, J - 9.6, 3.6 Hz, 1 H), 4.65 (m, 2 H),
4,47-4,38 (m, 3 H), 3.93 (dd, J= 12.0, 10.0 Hz, 1 H), 3,75 (m, 1 H), 1.49 (d, J= 5.6 Hz,
3 H); BS1 MS: 406 (M+ 1). The above material (278 mg, 0,66 mmol) was taken up
m cthanol (10 mL) and treated with 1 Nsodium hydroxide (aq) (0.66 mL, 0.66 mmol).
The resulting suspension was stirred at room temperature for 30 min, Ether was
added and the liquids were collected to provide the sodium salt of the title compound
as a white powder (291 mg, 99%).' 1H NMR (OMSO- do) δ 30.68 (m, 1 H), 7,90 (s, 1 H),
7.35 (m, 1 H), 7.20 (m, 1 H), 7,01 (m, 1 H), 5,20 (m, 1 H), 4,58 (m, I H), 4.49 (m, 2 H),
4.22 (m, 2 H), 3 74 (dd, J= 11.2, 10.4 Hz, 1 H), 3.58 (m, 1 H), 1.25 (d, J=- 4.4 Hz, 3 H)
Example Z-2:
(4a.ff.13 ajg> -^V-[(2,4-Difluoroτjhenyl)methyl]- ] Q-hydroxy-9,1 ] -dioxo-2.3.4a,5,9, 11 , 13.13a
-octahydiO- ] j/-ργrido[] ,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide.
Figure imgf000132_0001
a)
(4aR, 1 SaS)-TV- [(2,4-Difluoropheny])methyl]-9, 11-dioxo- 10-[(phenylmethyl)oxy] -2,3,^a,S
,9, 11, ] 3, 13a-octahydro-1Hpyridori,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carb
oxamide. A solution of 16a (24 mg, 0.05 mmol), [(2jS)-2-pyrrolidmylmethyl]amine (0.1
mL) and 2 drops of glacial acetic acid were heated under microwave conditions at 140
] 30 °C for 10 min. Upon cooling, Celitc was added to the mixture and the solvents
removed in vacuo and the material was purified via silica gel chromatography (2%
CH3OH/CH2CI2 gradient elution) to give
(4aR, 13aS)-N-[(2,4-difluorophenyl)moi;hyl]-9, 11-dioxo- 10-[(phenylmethyl)oxyl-2,3,4a,5,
9, 11, 13, 13a-octahydro-1N-pyrido[1,2-a]pyrrolo[1',2':3,4]imida!4o[1,2- «']pyrazine-8-carbo
xamide (19 mg, 71%) as a white solid. 1Ii NMR (CDCl3) δ 10.41 (m, 1 H), 8.38 (s, I
H), 7 56 (m, 2 H), 7.38-7 24 (m, 4 H), 6.80 (m, 2 H), 5 38 (d, J= 9.6 Hz, 1 H), 5.10 (d, J
= 10 0 Hz, 1 H), 4.62 (m, 2 H), 4.40 (m, 1 H), 4.25 (dd, J= 12,0, 6.8 Bz, 1 H), 4J 0 (d, J
= 12.8 Ha, 1 H), 3.83 (m, 1 H), 3 71 (m, 1 H), 3 14-3.04 (m, 2 H), 2,78 (m, 1 H),
2,11- 1.58 (m, 4 H); ES+ MS' 521 (M+l).
b)
(4aR, 33aιS)-N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9, 11, 13, 13a
-octahydro- 1 /-/-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyra!'.ine-8-oarboxamide
To a solution of
(4aR, l3a«5)-N-[(2,4-difluorophenyl)methyl]-9, n -dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,
9,11, 13, 13a-octahydro-1i/-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carbo
xamide (19 mg, 0.04 mmol) m methanol (8 mL) was added 10% Pd/C (10 mg)
Hydrogen was bubbled through the reaction mixture via a balloon for 2 h. The
resultant mixture was filtered through Cclite with methanol and dichloromethanc.
The filtrate was concentrated in* vacuo to give the tit le compound (6 mg, 38%) as a
white solid. 1H NMR (CDCl3) δ 11.73 (m, 1 H), 10.3G (m, J H), 8 31 (s, I H), 7,33 (m,
1 H), 6.78 (m, 2 H), 4,62 (m, 2 H), 4.50 (m, 1 H), 4,27-4, 19 (m, 2 H), 3.87-3.77 (m, 2 H), 3, 16-3,08 (m, 2 H), 2.83 (m, 1 H), 2. I M .65 (m, 4 H).1 KS-* MS: 431 (M+J).
Example Z-3'
(3a.9: i3a6)-iV- [(2,4-Difluoi.Ophenyl)methyl]-8-hydroxy7/J-dioxo-1 ,2,3,3a,4,5,7.9, 13, 13a
-decahvd]-opyrido[l',2':<t.5ipyra7!ino|.1,2-a1pyrrolo[i .2- g|pvrimidϊnot 10*carboxamide.
Figure imgf000134_0001
a) N-BOC-(2i5l-2-(Hydroxymethyl)-1-pyrrolidine. To a solution of _V\BOC-L-proline
(4 , 17 g, 19.4 mmol) in THF (40 mL) at 0 "C was added BHa-THF (21,4 mL, 1 M m THF,
21 A mmol) dropwise. The bath was removed and the resultant solution stirred at
room temperature for 2 h. Methanol was added to quench the mixture and the
solvents were removed Jn vacuo. The residue was taken up in ethyl acetate and
washed with sodium bicarbonate and brine. The aqueous layers were extracted twice
with ethyl acetate. The combined organics wore dried over Na2SO<i, filtered and
concentrated to give N-BOC-(2S)-2-(hydroxymethyl)-1-pyrro]idine (3,82 g, 98%) as a
clear oil, This material was used without further purification. 1H NMR (CDCl,)) δ
3.94 (m, 1 PI), 3.G2 (dd, J= 11.2, 3,2 Hz, 1 H), 3.56 (dd, J= 10.8, 7.2 Hz, 1 H), 3.44 (m,
1 H), 3.29 (m, 1 H), 2.62 (br, 1 H)r 1.98 (m, 1 H), 1.85- 1.72 (m, 2 H), 1.58 (m, 1 H).
b) N-BOC-(2S)-2-({[(4-Methylphenyl)sulfonynoxy}methyl)-1-pyrrolidine. To a cold
(0 0O solution of N-BOC-(2ΛS)-2-(hydroxymethyl)-1-pyrrolidine (350 mg, 1.74 mmol) in
dichloromethano (20 mL) was added triethylamine (0.29 πiL, 2.08 mmol), and toluoncsulfonyl chloride (398 mg, 2.08 mmol), ΛζΛf-deπiotliylaminopyridine (70 mg)
was added and the resultant solution was allowed to warm to rt as the bath warmed
and stirred for 4 h, Water was added and the layers separated . The aqueous layer
was washed with sodium bicarbonate and then with brine, The- combined organics
wore dried over NasSO'i, faltered and concentrated followed by flash chromatography
purification to give -
N-BOG-(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyJ-'rolidine (460 mg, 75%) as
a clear oil, *H NMR exists as rotomors (CDCl3) δ 7.77 (d, 2 H), 7.33 (m, 2 H), 4.08 (m,
1 H), 3.97-3 88 (m, 1 H), 3 35-3.25 (m, 2 H), 2.43 (s, 3 H), 1.95- 1.79 (m, 4 H), 1.40 and
1.35 (s, 9 H rotomeric BOC jJ-butyl).
c) _VBOC-(2>S)-2-Cyano-1-pyrrolidine. A mixture of -
N-13OC-(2ώ)-2-({[(4-methylphenyl)snlfonyl]oxy}methyl)-1-pyrrohdine (460 mg, 1 29
mmol) and KCN (256 mg, 3.88 mmol) wore boated at 90 "C in DMSO (10 niL) for 6.5 h.
The mixture was cooled to room temperature and IUtOAc and water were added. The
organics were washed with water twice and then with brine. The aqueous layers
were extracted with EtOAc and the combined organics dried over NasSO*), filtered and
concentrated followed by flash chromatography purification to give ./V-BOC-
(2S)-2-cyano-1-pyrrolidine (179 mg, 66%) as an oil. 1H NMR exists as rotomers
(CDCl3) δ 3.99 (m, 1 H), 3.43-3.37 (m, 2 H), 2.83-2 51 (m, 2 H), 2.17-1.83 (m, 4 H), 1.46
and 1,44 (s, 9 H rotomeric BOC £- butyl).
d) -V-BOC-(2S)-2-(2-Aminoethyl)-1-pyrrolidinc. A solution of NBOC- (2S) -2-cyano-1 -pyrrolidine (179 mg, 0.85 mmol) in ethanol saturated with anhydrous
ammonia was treated with Raney-Ni (1 mL of 50% aq. Suspension) and 50 psi of Hs
overnight, The mixture was filtered through Cclitc and the filtrate was concentrated
an vacuo. The residue was purified by flash chromatography (10% CH3OH/CH2CI2
with 1% NH-iOH gradient elution) through a short plug of silica gel to give -
7V-BOC-(2S)-2-(2-aminoethyl)-1-pyrrohdmo (90 mg, 50%) as a clear oil. 1H NMR
exists as rotomers (CDCl3) δ 3.88-3,77 (m, 1 H), 3.33-3.24 (m, 2 H), 2.66 (m, 2 H),
1.89- 1.54 (m, 6 H), 1.40 (s, 9 H),
e) {2-[(2<S)-2-Pyrrolidinyl]ethyl}amine, A solution of -
N-BOC-(2S)-2-(2-aminoethyl)-1-pyrrolidine (90 mg, 0.42 mmol) m THF (6 mL) was
treated with 4 N HCl (aq) (2 mL) and stirred at room temperature for 3 h, The
mixture was concentrated ni vacuo to give the title compound as its HCl salt. A
portion of this material (40 mg) was dissolved m methanol and treated with solid
supported carbonate resin (MP-Carbonate, Argonaut Technologies) to freebase the
aminos. After 30 minutes, the solution was filtered through a fritted tube and the
solvents removed carefully in vacuo to give {2-f(2<S)-2-pyrrolidinyl]ethyl}amine (30 mg)
as its free base. 1H NMR (CDCl3) δ 3,06 (m, 1 H ), 2.94 (m, 1 H), 2.83 (m, 1 H ),
2.79-2.69 (m, 2 H), 1.90-1.56 (m, 6 H).
f)
(3aS, J 3aS)-W- [(2,4-Difluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxyl-1,2,3,3a,4, 5,7,9, 13, 1 Sa-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrroloU,2-cJpyrimidine-1 Ocarb oxamide. A solution of 16a (30 mg, 0,06 mmol), {2-[(2S)-2-pyrrθlidinyl]ethyl}amine
(30 mg, 0.26mmol) and 2 drops of glacial acetic acid were heated under microwave
conditions at 140 "C for 10 min. Upon cooling, Celite was added to the mixture and
the solvents removed in vacuo and the material was purified via silica gel
chromatography (2% CHjOH/CHaCh gradient elution) to give
(3aS, 13a<5)-N-[(2,4-Difluorophenyl)methyl]-7,9-dioxo-8- [(phenylmethyl)oxy]- 1,2, 3,3a, 4,
5,7,9, 13, l3a-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrroloL1,2-dpyrimidine- 10-carb
oxamide. (25 mg, 74%) as a film. iH NMR (CDCl3) δ 10 44 (m, 1 H), 8.32 (s, 1 H),
7.59 (m, 2 H), 7 38-7.24 (m, 4 H), 6.80 (m, 2 H), 5.28-5.22 (m, 2 H), 4.67 (dd, J= 13.6,
2.8 Hz, 1 H), 4 ,62 (m, 2 H), 4.26 (m, 1 H), 4.11-4.03 (m, 2 H), 2 01 (m, 1 H), 2.81 (m,
1 H), 2.37 (m, 1 H), 2 24 (m, 1 H), i 92 (m, 1 H), 1,82- 1,76 (m, 3 H), 1.52- 1.38 (m, 2 H),
ES 1 MS: 535 (M+1).
e)
(3aS, 13aS)-N-[(2,4-Difluorophenyl)methyll-8-hydroxy-7,9-dioxo- l ,2,3,3a,4,5,7,9, 13, 13a
-decahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrroloC1,2- cJpyrimidine- 10-carhoxamide,
To a solution of
(3aS, 13aS')-AA[(2,4-difluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy1- 1,2,3,3a,4,
5,7,9, 13, 13a-decahydrapyrido[1\2^4,5lpyrazino[1,2-c7lpyrrolo[1,2-clpyrimidine-10-carb
oxamide (25 mg, 0.05 mmol) m methanol (8 mL) was added 10% Pd/C (10 mg).
Hydrogen was bubbled through the reaction mixture via a balloon for 38 h. The
resultant mixture was filtered through Celite with methanol and dichloromethane.
The filtrate was concentrated in vacuo to give the title compound (14 mg, 67%) as a white solid. "H NMR (CT)CIa) δ 12.53 (br, 1 H), 10.44 (s, 1 H), 8.29 (s, 1 H), 7.34 (m,
1 H), 6,78 (m, 2 H), 4.71 -4.58 (m, 3 H), 4.29-4.14 (m, 3 H), 2.99 (m, 1 H), 2.88 (m, 3 H),
2.44 (m, 1 H), 2,30 (m, 3 H), 1,97-1, 38 (m, 6 H); ES+ MS: 445 (M+l).
Example Z-A'-
(4aS, 13aig)-./V;[(2,4-Difluorophenyl)methyl1-10-hydroxy9, 11 -dioxo-2,3.4a,5,9, 11.13, 13a
Octahydro- lH-pyrido[1,2-a]pyr3Olo[r,2':3.4]imidazo[1,2-d]pyrazine-8-carboxamide
sodium salt.
Figure imgf000138_0001
a) [(2ϋ?)-2-Pyxτolidinyhnethyl]amine. To a solution of
-V-BOC-(2R)-2-(aminomethyl)-1-pyrrohdine (1.37 g, 6.85 mmol) in THF (20 mL) was
added 4 .VHCl (aq) (8 mL). The resultant solution was stirred at room temperature
overnight. The solvents were removed hi vacuo and the residue was treated with
MP -carbonate resin in methanol and dichloromethane. After 1 h, the resin was
removed via filtration through a fritted tube and the volatiles were removed carefully
in vacuo to produce the free based amine (760 mg crude > 100%) as a oil. This
material was used without further purification, 1H NMR (CDCLj) δ 3.13 (m, 1 H),
2.92 (m, 1 H), 2.82-2.62 (m, 5 H), . .88- ..30 (m, 4 H).
b)
(4aS,13aR)-N-[(2,4-Difluorophenyl)methyl]-9, 11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5
13G ,9, 11 , 13, 10a-octahydro-1i/-pyridof1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyraεine-8-carb
oxamide. In a similar manner as described in example %-2 from 16a (435 mg, 0.93
mmol) and [(2R)-2-pyrrolidinylmethyl]amine (200 mg, 2.0 mmol) in
1,2-dichloroethanc (20 mL) and 15 drops of glacial acetic acid was obtained
(da,5', 13a β)-N- [(2,4-difluorophenyl)methy)]-0, 11-dioxo- 10-[(phenylmethyl)oxy]-2,3,4a,5,
9, 11, 13, 13a-octahydro-3 AT-pyrido[1, 2- ajpyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carbo
xamide (321 mg, 67%) as a white solid. Η NMR (CDCl3) δ .0.41 (m, 1 H), 8.35 (s, 1
H), 7.56 (m, 2 H), 7.55-7.24 (m, 4 H), 6.80 (m, 2 H), 5.35 (d, J= 10.0 Hz, 1 H), 5 13 (d,
J= 10.0 Hz, 1 H), 4.60 (m, 2 H), 4.38 (dd, J= 10.4, 3.2 Hz, J H), 4.21 (dd, J= 32.0, 6.8
Hz, 1 H), 4.04 (dd, J= 12.4, 2,8 Hz, 1 H), 3.77 (apparent t, J= 11.6 Hz, J H), 3.68 (m,
1 H), 3.11-3.00 (m, 2 H), 2.75 (m, 1 H), 2.08- 1.84 (m, 3 H), 1.65 (m, 1 H); ES+ MS: 521
(M+ 1).
c)
(4aS, 13aR)-N-[(2,4-Difluorophenyl)methyl]- 10-hydroxy-9,11-dioxo-2,3,4a,5,9, 11, 13,13a
-octahydro- 1//-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine -8-carboxamide.
Tn a similar manner as described in example Z-2 from
(4aS, 13aR)-N-[(2,4-difluorophenyl)methyl]-9, 11-dioxo- 10- [(phenylmethyl)oxy]-2,3,4a,5,
D,11, 1S.13a-ocLahydro-1H'-pyridori,2-^pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carbo
xamide (518 mg, 0.99 mmol) and'10% Pd/C (35 mg) in methanol (40 mL) was obtained
(4a,Sr, 13a7f)-A'1[(2,4-Difluorophenyl)methyl]-10-hydroxy-9, n -dioxo-2,3,4a,5,9, n j 3,13a
-octahydro-1if-pyridoti ,2-dpyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide
(430 mg, 99%) as a whito solid. "H NMR (CDCl3) δ 11.73 (m, 1 H), 10.36 (m, 1 H), 8.32 (s, 1 H), 7.35 (m, 1 H), 6.79 (m, 2 H), 4.64 (m, 2 H), 4.54 (dd, J = 10,8, 4,0 Hz, 1
H), 4,28-4.19 (m, 2 H), 3.90-3.79 (m, 2 H), 3.18-3.10 (m, 2 H), 2.84 (m, 1 H), 2.14- 1.92
(m, 3 H), 1 72 (m, 1 H).
d)
(4aS,13aR)-N- [(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dαoxo-2,3,4a,5,9,11, 13, 13a
-octahydro-1N-pyrido[1,2-a1pyrroloLlτ,2'-3,4]iraidazo[1,2-d]pyrazine-8-cai.-boxaixLide
sodium salt In a similar manner as described in example Z- I from
(4a<S", 13a7e)-N-[(2,4-Difluorophenyl")methyl]- 10-hydroxy-9, 11-dioxo-2,3,4a,5,9, ll , 13, 13a
-octahydro-1//-py3-idori,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide
(430 mg, 1.0 mmol) and sodium hydroxide (1.0 mL, 1.0 M aq, 1.0 mmol) in 20 mL of
ethanol was formed the corresponding sodixim salt (425 mg, 94%) as a white solid.
IH NMR (DaO) δ 7.85 (s, i H), 7 23 (m, 1 H), 6.82 (m, 2 H), 4.53 -4.46 (m, 3 H), 4,28 (m,
1 H),3.95 (m, 1 H), 3.84 (m, 1 H), 3.62 (m, 1 H), 3.16 (m, 1 H), 2.89 (m, 1 H), 2,84 Gm,
1H), 1.90 (m, 2 H), 1.73 (m, I H), 1,60 (m, 1 H). ES 1 MS: 431 (M+i ).
Example Z-5:
(4a6: i3ai?)-7V-r(4-pΛIuorophenvI)methyl]- 10-hvdroxy9, 11-dioxo-2.3.4a.5.9, 11.13, 13a-ocl
ahydro- ]iy-pyrido[1,2-a1ρyrrolo[1',2':3,4]imidazo[1,2-d]pyra2ine-8-carboxamide
Figure imgf000140_0001
The title com/pound was made in two steps using a similar process to that described in example Z-2. 16 (60 mg, 0.13 mmol) and [(2R)-2-pyrrolidinylmethyl] amine (100
mg, 1.0 mmol) were reacted in dichloromethane (2 mb) with acetic acid to give
(4&S, 13a7i')-N-[(4-fluorophenyl)methylV9, l1-dioxo- 10-[(phenylmethyl)oxy]-2, 3^1,5, 9, 1
1,13, 13a-octahydro-1N-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxa
mido (60 mg, 91%). This material was hydrogcnated in a second step as described in
example Z-2 to give
(4aS, 13a7f)--V;[(4-fluorophenyl)methyl]-10-hydroxy-9, 11-dioxo-2,3,4a,5,9,11, 13,13a-oct
ahydro-1 /7-pyridoli ,2-,dpyrrolo[1',2':3,4]imidazo[1,2-d]pyra?;ine-8-carboxamide (21 mg,
42%) as a white solid. 1H NMR (CDCIj) δ 11,72 (m, 1 H), 1.37 (m, 3 H), 8.33 (s, 1
H), 7.29 (m, 2 H), 6,97 (m, 2 H), 4.57 (m, 2 H), 4,52 (m, 1 H), 4.24-4, 19 (m, 2 H),
3.87-3.76 (m, 2 H), 3.34-3.07 (m, 2 H), 2.82 (m, 1 H), 2.11-1.89 (m, 3 H), 1,68 (m, 1 H);
ES+ MS: 413 (M+ 1).
Example Z-6:
(3 S, 11a/^)-7v*-F(2,4-DifluoropliGnyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5.
7, 1 1.1 ] a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine~8-carboxamide
Figure imgf000141_0001
The title compound was made in two steps using a similar process to that described
in example Z-2. 16a (37 mg, 0.08 mmol) and (2S)-2-amino-3-phenyl-1-propanol (35
mg, 0.24 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give
(3S,] ] aij>)-N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-3-(phenylmethyl)-6-[(phenylmethy Doxy] -2.B.5.V,11,11a-liexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyras-ine-8-carboxamide
(41 mg, 91%). This material was hydrogenated in a second step as described in
example Z-2 to give
(3-S', 11aR)-N [(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phcnylmethyl)-2,3,5,
7, Il, 11a-hexahydro[1,3]oxazolo [3, 2-^PyI1JdO[1, 2- c/Jpyrazine-8-carboxamide. (25 mg,
75%) as a white solid. 1H NMR (CDCl3) δ 11,47 (br, 1 H), 30,28 (m, 1 H), 8.35 (m, 1
H), 7,37-7.26 (m, 4 H), 7.18 (m, 2 H), 6.79 (m, 2 H), 5,03 (m, 1 H), 4,64-4,61 (m, 3 H),
4.40 (m, 1 H), 4.23 (apparent t, J = 7.2 Hz, 1 H), 3,96 (dd, J = 8.8, 6,4 Hz, 1 H), 3.88
(apparent L, J= 11.2 Hz, 1 H), 3.37 (dd, J = 13,6, 3,2 Hz, 1 H), 2.99 (dd, J = 13.2 8,8
Hz,1 H ); ES+ MS: 482 (M+ 1).
Example Z- 7 •
(3aS,13aig)-jV-i.(4-FIuorophenvI)methyl]-8-hydroxy7,9-dioxo- 1,2,3.3a.4,5.7,9,13,13a-de
cahydropyndo[1',2':4,5]pyrazino[l, 2-a1pyrro]o[,1,2-c1py,rimidine- 10-carboxamide,
Figure imgf000142_0001
The title compound was made in two steps using a similar process to that described
in example Z-2. 16 (84 mg, 0J 3 mmol) and {2- [(2S)-2-Pyrrolidmyl]ethyl}amine (150
mg, 1.3 mmol) were reacted in dichloromethane (2 uiL) with acetic acid to give
(3aS, 13aS)-yV- [(4-fJuorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]- 1,2,3,3a,4,5,7,
O, 1S, 1Sa-decahydropyrido[1',2':4,5]pyrazino[1,2-^pyrroloCl,2-dpyrimidinc- 10-carboxa
mide (86 mg, 90%). This material was hydrogenated in a second step as described in example Z-2 to give
(3aι£?, 13aS)-N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo- 1,2,3,3a,4,5,7,9, 13,13a-de
cahydropyrido[1',2':4,5]pyrazino[i ,2-^pyrrolof1,2-dpyrimidine- 10-carboxamide. (63
mg, 88%) as a white solid. iH NMR (CDOl i/CDaOJD) δ 10,45 (m, 1 H), 8.23 (s, 1 H),
7.35 (m, 2 H), 6.04 (t, J = 8.8 Hz, 2 H), 4.63 (m, 1 H), 4.58-4.48 (m, 2 H), 4.33 (dd, J =
13.6, 3.6 Hz, 1 H), 4,21 (m, _ H), 4.11 (m, 1 H), 2.98 (m, 3 H), 2.85 (td, J= 13.2, 3.2 Hz,
1 H), 2.41 (ni, 1 H), 2.29 (m, 1 H), 1,92 (m, 1 H), 1,83-1.75 (m, 3 H), 1.54-1.35 (m, 2 H);
BS+ MS: 427 (M+ 1)
Example Z-8:
(3S,1] a/f)-N-[(2.4-Difluorophci-iyl)methyl]-6-hydroxy3-[(] ^l- l-methylr)voDyl]-5,7 idipxo
-2,3.5.7,31 , 11a-hexahydro[1 ,3]oxayiolol.3,2-a1i3yrido[1,2-d]pyrazinG-8-carboxamide
sodium salt.
Figure imgf000143_0001
The title compound was made in two steps using a similar process to that described
in example Z- I. 16a (437 mg, 0.89 mmol) and L-isoleucmol (259 mg-, 2,21 mmol) were
reacted in 1,2-dichIoroothano (40 niL) with acetic acid to give
(3*9,l1aR)-N [(2,4-difluorophenyl)methyl]-3- [(1S)-1-methylpropyl]-5,7-dioxo-6-[(phenyl
methyl)oxy]-2,3,5,7, 11 ,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carbox
amide (426 mg, 90%). This material was hydrogcnated in a second step as described
in example Z- I to give
341 (GS, 11a /d-N-UE/i-Difluorophenyl)methyl]-θ-hydroxy-3- tCKθ-1-methylpropyl]-5.Y-cUoxo
-2,3,5,7, l 1,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyra'zine-8-carboxamide
(376 mg, 99%) as a coarse white solid, JH NMR (CDCl3) δ 11.43 (br, 1 H), 10,27 (br,
1 H), 8,32 (s, 1 H), 7.33 (m, 1 H), 6.79 (m, 2 H), 5.26 (dd, J= 9,6, 4.0 Hz, 1 H), 4.62 (m,
2 H), 4.42-4.35 (m, 2 H), 4.19 (dd, J= 8,8, 7,2 Hz, _ H), 4,01 (dd, J= 8.8, 5.6 Hz, 1 H),
3.86 (dd, J= 12,0, 10.0 Hz, 1 H), *2.27 (m, 1 H), 1.40 (m, 1 H), 1.15 (m, 1 H), 0,97 (t, J
= 7,2 hz, 3 H), 0.91 (d, J= 6.8 Hz, 3 H); ES* MS: 448 (M+ 1), This material (360 mg,
0.81 mmol) was treated with sodium hydroxide (0.81 mL, 1.0 M, 0.81 mmol) in
othanol 05 mL) as described in example Z- I to provide its corresponding sodium salt
(384 mg, 99%) as a white solid . 1H NMR (DMS O -Λ) δ 10.82 (m, 1 H), 7.80 (m, 1 H),
7.33 (m, 1 H), 7.18 (m, 1 H), 7.00 (m, 3 H), 5.14 (m, 1 H), 4.47 (d, J= 5.6 Hz, 2 H), 4.31
(m, 1 H), 4, 18 (m, 1 H), 3.96 (m, 1 H), 3.84 (m, 1 H), 3.71 (m, 1 H), 3,40 (m, 1 H), 1.88
(m, 1 H), J .36 (m, 1 H), 1.04 (m, 1 H), 0,85 (t, J - 7.2 Hz, 3 H), 0.80 (d, J= 6.8 Hz, 3
H); ES+ MS: 448 (M-l-1).
Example Z-9-
(3£ 11aΛ^N-[(2.4-D-fluoroDhonyl)methyl] -6-hvdroxy-3-methyl-5.7-dioxo-2,3,5.7, n , 11 a
-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazino-8-carboxamide sodium salt.
Figure imgf000144_0001
The title compound was made in two steps using a similar process to that described
in example Z-I. 16a (510 mg, 1.08 mmol) and (2«5)-2-amino-1-propanol (0.17 mL, 2,17 mmol) were reacted in 1,2-dichloroethane (20 mL) with acetic acid to give
(3S, 11aR)-i\A[(2,4-diflιιorophenyl)methyl]-3-methyl-5,7-d.ioxo-6-[(phenylmethyl)oxy]-2,
3,5,7,11,1la-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (500
mg, 93%). This material was hydrogenated in a second step as described in example
Z- I to give
3S, 11a R)-7N-[(2,4-Diiαuorophenyl)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]pyraziine-8-carboxamide (386 mg, 94%) as a
tinted white solid. Η NMR (CDCL3) δ 11.46 (m, 1 H), 10.28 (m, 1 H), 8.32 (s, 1 H),
7.35 (m, 1 H), 6.80 (m, 2 H), 5.30 (dd, J = 10.0, 4.0 Hz, 1 H), 4.63 (m, 2 H), 4.48-4.37
(m, 3 H), 3.91 (dd, J = 12.0, 10.0 Hz, 1 H), 3.73 (m, 1 H), 1.48 (d, J - 6.0 Hz, 3 H);
ES 1 MS: 406 (M+ 1). This material (385 mg, 0.95 mmol) was treated with sodium
hydroxide (0,95 mL, 1.0 M, 0.95 mmol) m ethanol (15 mL) as described in example Z-1
to provide its corresponding sodrum sail (381 mg, 94%) as a white solid. 1H NMR
(DMSO- Λ) δ 10.66 (m, 1 PI), 7.93 (s, 1 H), 7.33 (m, 1 H), 7.20 (m, 1 H), 7.01 (m, 1 H),
5.19 (m, 1 H), 4.59 (m, 1 H), 4 48 (m, 2 H), 4.22 (m, 2 H), 3,75 (m, 1 H), 3.57 (m, 1 H),
1.24 (d, J= 5 6 Hz, 3 H).
Example Z-IQ:
(3^q] ai(!)-N-[.(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5.7-dioxo-2.3, 5,7, 11, 11 a-Iio
xahydro[1 ,3]oxazolo[3,2-a]pyrido[1.∑-riiDyrazinc-S-carboxamide.
Figure imgf000145_0001
The title compound was made in two stops using a similar process to that described
in example Z-2. 16 (100 mg, 0.22 mmol) and (2S)-2-amino-1-propanol (0.10 mL, 1.28
mmol) were reacted in dichloromethane (2 mL) with acetic acid to give
(3S, 11aR)-N-[(4- fluorophenyl)methyl] -3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy] -2,3,5,
7, 11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (100 mg,
95%), This material was hydrogenated in a second step as described in example Z-2
to give
(3S, 11aR)-,N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 11,11a-he
xahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (80 mg, 99%) as a
white solid, 1H NMR (CDCl3) δ 11.43 (br, 1 H), 10.28 (br, 1 H), 8.35 (s, 1 H), 7.28 (m,
2 H), 6.97 (m, 2 H), 5.29 (m, 1 H), 4.55-4.38 (m, 5 H), 3.89 (apparent t, J = 10.8 Hz, 1
H), 3.70 (m, 1 H), 1,45 (d, J= 5.6 Hz, 3 H); ES- MS: 386 (M- 1),
Example Z- 11:
(3S, 11 aR)-N-[(2,4-Difluorophenyl)methyl] -3-(1, 1-dimethylethyl)-6-hydroxy-5,7-dioxo-2
,3,5,7, 11 ,11a-hexahydro[1 ,3]oxazolo [3,2- a]pyrido[1 ,2-d]pyrazine-8-carboxamide
Figure imgf000146_0001
The title compound was made in two steps using a similar process to that described
in example Z-2. 16a (41 mg, 0,09 mmol) and freebased L- tert-leucinol (59 mg, 0,50
mmol) were reacted in dichloromethane (2 mL) with acetic acid to give
(3S, 11aR)-N-[(2,4-diflυorophenyl)methyl]-3- (1, 1-dimethylethyl)-5,7-dioxo-6-[(phenylm etliyl)oxy]-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyras5.no-8-carboxa
mide (40 mg, 86%). This material was hydrogenated in a second step as described in
example Z-2 to give
(3S, l'laR)-N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-5,7-dioxo-2
,3,5,7,11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (33
mg, 99%) as a tinted white solid. 1H NMR (CDCl3) δ 10,29 (s, 1 H ), 8,37 (s, 1 H),
7.34 (m, 1 H), 6.70 (m, 2 H), 5.43 (m, 1 H), 4,62 (m, 2 H), 4.36 (m, 2 H), 4.21 (m, 1 H),
3.99 (, 1 H), 3,81 (m, 1 H), 1,03 (s, 9 H); ES " MS: 448 (M+ 1).
Example Z- 12:
(3S.11aJ?)-3-(l. l-Dimethylethyl)-iV-r(4-fluoroDhenyl)methyl] -6-hydroxv-5.7-dioxo-2.3.5,
7, 11.11a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazuic-8-carboxam.ide.
Figure imgf000147_0001
The title compound was made m two steps using a similar process to that described
in example Z-2. 16 (41 mg, 0.09 mmol) and freebased L- tei't-lowinol (59 mg, 0.50
mmol) wore reacted in dichloromethane (2 rnL) with acetic acid to give
(3S, 11aR)-3-(1, 1-dimethylethyl)--V:[(4-fluorophcnyl)methyl]-5,7-dioxo-6-[(phenylmethy
l)oxyl-2,3,5,7, 11, l1a-hexahydro[1,3]oxaz,olo [3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(40 mg, 85%). This material was hydrogonated m a second stop as described in
example Z-2 to give
(3_S',] laR)-3-(l , 1-Dimethyletliyl)-//:K4-fliiorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5, 7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (32 mg,
97%) as a tinted white solid. 1H NMR (CDCIo) 6 11.15 (br, 1 H), 10.32 (a, 1 H), 8.38
(B, 1 H), 7.29 (m, 2 H), 6.98 (m, 2 11), 5.43 (m, 1 H), 4.58 (m, 2 H), 4.36 (m, 2 H), 4.21
(m, 1 H), 3.99 (, 1 H), 3.79 (m, 1 H), 1.02 (s, 9 H); ES+ MS: 430 (M+ 1).
Example Z-13:
(3>S'. lla7τ')-7V: r(2.4-DifluoroDhGnyl)methyl]-6-hydroxy-5,7-dioxo-3-nhonyl-2.3.5.7, 11 , 11 a
-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.
Figure imgf000148_0001
The title compound was made in two slops ufaing a similar process to that described
in example Z-2. 16a (33 mg, 0.07 mmol) and L-phenylg'lycinol (19 mg, 0.14 raraol)
were reacted in dichloromethane (2 ml) with acetic acid to give
(3<S; 11aR)-N-[(4-flιiorophenyl)methyl]-5,7-djoxo-3-phenyl-6-[(phenylmethyl)oxy]-2,3,5,
7, l 1, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (37 mg,
95%). This material was hydrogenated in a second step as described in example Z-2
to give
(3S, 11aR)-N:[(2,4-Diflυorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3,5,7,11, 11a
-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (33 mg, 99%) as a
tinted white solid. 1H NMR (CDCIj) δ 11.23 (br, 1 H), 10.27 (s, 1 H), 8,39 (s, 3 H),
7.43-7.32 (m, 6 H), 6,80 (m, 2 H), 5,58 (d, ,/= 6.8 Hz, 1 H), 5.37 (apparent t, J = 6.8 Hz,
1 H), 4.67-4.62 (m, 3 H), 4.54 (d, J - 10,4 Hz, 1 H), 4.11 (m, 1 H), 4.01 (m, 1 H); ES+ MS : 468 (M+ 1).
Example Z- 14 :
(3ff. n a.fl) -AAl(2.<L-Diflυorophenyl)melhyl] -6-hydroxy3-(-ivdroxymethyl)-5,7-dioxo-2.3.
5.7, 11. 3 la-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxaniide.
Figure imgf000149_0001
The title compound was made in two slept using1 a similar process to i hat described
m example Z-2. 16a (50 mg, 0.10 mmol) and
(2R)-2-amino-3- [(phenylmethyl)oxy]-1-propanol (0.3 niL) were reacted m
dichloromethanc (2 ml) with acetic acid to give
(3S, I laiτ')-N-[(2,4-difluorophenyl)methyl.]-5,7-dioxo-6-[(phenylmethyl)oxy]-3- {Kphenyl
m.ethyl)oxylmethyl}-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazincr
8-carboxamide (61 mg, 99%) . This material was hydrogenated in a second step as
described in example Z-2 to give
(3ff, 11a R)-N- [(2,4-Difluorophenyl)methyl]-6-hydroxy-3- (hydroxymethyl)-5,7-dioxo-2, 3,
5,7, 11, 1 l a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (37 mg,
87%) as a tinted white solid . Η NMR (CDCl3/CD*OD) δ 8.23 (s, 1 H), 7.32 (m, 1 H),
6.79 (m, 2 H), 5.31 (d, J= 7 6 Hz, 1 H), 4.56 (s, 2 H), 4.42-4.36 (m, 3 H), 4.17-4.11 (m,
2 H), 3,85 (m, 1 H), 3.62 (d, J= U .2 Hz, 1 H) ,
Example Z- 3 5 :
347 (2<y.3AVΛr-[(2.4-Difl\ιorophenyl)methyl]-6-hvdroxy-3-methyl-S.7-clioxo-2-i3honyl-2,3.5,7
,1l, 11a-hexahydro[1 ,3]oxa7,o]o[3,2-ralpyi4do[1,2-d]pyrazine-8-carboxamide.
Figure imgf000150_0001
Tho title compound was made in two steps using1 a similar process to that, described
in example Z-2. 16a (25 mg, 0,05 mmol) and (1jS',2R)-(+)-norephcdrine (0J mL) were
reacted in dichloromethane (2 mL) with acetic acid to give
(2S, 370-N [(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-2-phenyl-6- [(phenylmethyl)
oxy]-2, 3,5,7, J 1, 1 la-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(30 mg, 99%). This material was hydrogenated in a second step as described in
example Z~2 to give
(2S, 3R)- yV- [(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2, 3, 5,7,
11, 1 la -hexahydro[1,3]oxazolo [3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (25 mg, 91%)
as a white solid , This material is a single diastoreomer (>6:l diastereomeric ratio
but unconfirmed relative stereochemistry at the aminal center). -1H NMR
(CO Cla/CDaOD) δ 10.28 (m, 1 H), 8, 38 (s, 1 H), 7, 10-7,30 (m, 6 H), 6.78 (m, 2 H), 5,70
(d, J = 7,6 Hz, 1 H), 5.36 (d, J = 5.2 H7,, 1 H), 4 ,82 (m, 1 H), 4.61 (m, 2 H), 4.47 (d, J=-
10.4 Hz, 1 H), 4,00 (apparent t, J = 10.4 Hz, I H), 0.94 (d, J= 6.4 Hz, 3 H); ES^ MS :
482 (M+ 1).
Example Z- 16 :
(3/g, 1T aS)-N-r(2,4-Difluorophenyl)methyl]-6-hydroxv5,7-dioxo-3-(phenylmethyl)-2,3,5, 7.11, 11a-hoxahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidc
Figure imgf000151_0001
The title compound was made in two steps using a similar process to that described
in example Z-2, 16a (34 mg, 0.07 rnraol) and (2R)-2-amino-3-phenyM-propanol
(D-phenylalaninol) (50 mg-, 0.33 mmol) wore reacted in dichloromethane (2 mL) with
acetic acid to give
(3R 11aι?)-N-I(2,4-difluorophenyl)methyl]-5,7-dioxo-3-(phenylmethyl)-6-[(phenylmethy
Doxy] -2,3,5,7, 11, J 1a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-ca)'boxamide
(29 mg, 70%). This material was hydrogenated in a second step as described in
oxample Z-2 to give
(3R, 11aΛ5)-N- [(2,4-Difiuorophenyl)methyl)-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,
7, l1, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (24 mg,
98%) as a white solid. H-ϊ NMR (Cl)Cb) δ 11.46 (br, 1 H), 10.27 (m, 1 H), 8.33 (m, 1
H), 7.32-7.16 (m, 6 Ii), 6.78 (m, 2 H), 5.02 (m, 1 H), 4.61 (m, 3 H), 4.39 (m, 1 H), 4.22
(m, 1 H), 3.95 (m, 1 H), 3.87 (m, 1 H), 3,36 (m, 1 H), 2.97 (dd, J = 13.2 8.8 Hz, 1 H);
ES 1 MS: 482 (M+ 1)
Example Z- J T-
(3/^ 1Ia1S)-N- [(2,4- Difluoroi3honyl)methyl] -6-hydroxv-3-(2-methylmODyl)-5.7-dioxo-2.3.
5.7, 11 , l] a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrayane-8-carboxamide.
Figure imgf000152_0001
The UtJe compound was made in two steps using a similar process to that described
in example Z-2. 16a (32 mg, 0.07 mmol) and (2/t?)-2-amino-4-mct.hyM-pentanol (0.1
lnL) were reacted in dichloromethano (2 mL) with acetic acid to give (3R, 11aS)-N-[(2,4-difluorophenyl)methyl]-3-(2-methylpropyl)-5,7-dioxo-6-[(phenylmeth
yl)oxy] -2,3,5,7, 11 , 11 a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyra'^ine-8-carboxamid
e (43 mg, 99%). This material was hydrogenated in a second step as described in
example Z-2 to give
(3R41aS)-N- [(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-iiiethylpropyl)-5,7-dioxo-2,3,
5,7, 1l , 1la-hexahydro[1,3]oxazoloLS,2-dps'rido[1,2-d]pyrazine-8-carboxamide (32 mg,
90%) as a white solid. 1H NMR (COCb) δ H .47 (br, 1 H), 10 29 (m, J H), 8,35 (s,
1 H), 7.39 (m, 1 H), 6.80 (m, 2 H), 5.31 (m, ,1 H), 4,62 (m, 2 H), 4 ,44 (m, 2 H), 4.37 (m,
1 H), 3.88 (m, 1 H), 3.84 (dd, J= 8.0, 5,6 Hz, 1 H), 2.04 (m, 1 H), 1.62 (m, 1 H), 1.41 (m,
1 H), 1,00 (d, J= 5,6 Hu, 3 H), 0.99 (d, J= 6.0 Hz, 3 H); ES 1 MS: 448 (M+1).
Example Z- 18:
(5a ft 14 aR)-N- [(2,4-Difluorophoπyl)methyl]- 11 -hydroxy-10,12-dioxo-1,2.3,4,5a,6, 10,12,
14, 14a-decahydroBvπdo [ l,2*dpyrido[i \2'-3,4]imidazo[1,2-d]pyrazmc-9-carboxamide,
Figure imgf000152_0002
a) 1, 1-Dimethylethyl (2/tO-2-(aminocarbonyI)-1-piporidinecarboxylalc. To a cold (0
°C) solution of fe/iS-1-iUl, 1-dimethylethy^oxy]carbonyl]-2-piperidinecarboxylic acid
(1.0 g, 4.36 mmol) in THF (20 ml) was added triethylamine (0.60 mL, 4,36 rnmol)
followed by slow addition of methyl chloroform ate (0.34 mL, 4,36 rnmol). After a few
minutes a suspension had formed, To this mixture was added concentrated NI-LiOH
(1.5 mL) and the solution was allowed to warm to rt as the bath warmed and stirred
for a total of 4 h. The mixture was concentrated in vacuo and the residue was taken
up in EtOAc, The organic layer was washed with citric acid, bicard and then brine,
dried over NasSO-i. Filtration and concentration gave 1, 1-dimethylethyl
(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (3 .0 g, 99%). 1H NMR (CDCl3) δ 6,03
(br, 1 H), 5.45 (br, 1 H), 4.77 (br, 1 H), 4.06 (br, 1 H), 2.82 (m, 1 H), 2.29 (m, 1 H),
1.67- 1.43 (m, 13 H),
b) 1, 1-Dimethylethyl (2R)-2-cyano-1-piporidinecarboxylate. To a cold (0 °C) solution
of 1,1-dimethylethyl (2J?)-2-(aminocarbonyl)-1-piperidinecarboxylate (269 mg, 1.17
mmol) in THF (10 mL) was added triethylamme (0,33 mL, 2.34 mmol) and then
trifluoroacetic anhydride (0.17 mL, 1 J 7 mmol). The mixture was stirred at 0 °C for
1 h and concentrated in vacuo. The residue was taken up in EtOAc and washed
successively with sodium bicarbonate, 0,5 NHCl and brine. The organics were dried
over NasSO-j, filtered and concentrated to give 1, 1-dimethylethyl
(2/i?)-2-cyano-1-piperidinecarboxylate (255 mg, 99%) as a crystalline solid upon
standing, 1H NMR (CDCl3) δ 5.23 (br, 1 H), 4.05 (br, 1 H), 2.93 (br, 1 H), 1,93- 1.39 (m,
6 H), 1.46 (s, 9 H). c) 1,1-Dimethylethyl (2ii?)-2-(aminomethyl)-1-piperidinecarboxylafce. An ammonia
saturated ethanol solution of 1, 1-dimethylethyl (2/9-2-cyano-1-piporidinecarboxylate
(255 mg, 1,19 mmol) was reduced with Raney-Ni in a similar manner to that
described in example Z-3 to give after filtration through a short plug of silica,
1,1-dimethylethyl (2R)-2-(aminomethyl)-1-piperidinecarboxylatc (236 mg, 91%), as an
oil, Ui NMR (CDCl3/CD3OD) δ 4.15 (br, 1 H), 3.97 Om, 1 h), 2.96 (m, 1 H), 2.75-2.69 (m, 2 H), 2.23-2.08 (m, 3 H), 1.59-1.55 (m, 3 H), 1.43 (s, 9 H).
d) [(2R)-2-Piperidinylmethyl]amine bis HCl salt. A solution of 1,1-dimethylethyl (2ir')-2-(aminomethyl)-1-pipcridinecarboxylate (236 mg, 1.08 mmol) in THF (10 niL)
was treated with 4 NHCl (3 niL) as described in example Z-3 to give the bis HCl salt
of[(2/f)-2-Pipcridinylmei.hyl]amine. 1H NMR (DMSO- Λ,) δ 9.67 (br, 1 H), 9.48 (br, 1 PI), 8.48 (br, 2 H), 3.70 (br, 2 H), 3.20 (m, 1 H), 3.04 (m, 1 H), 2.86 (m, 1 H), 1.89-1.41
(m, 6 H),
e)
(5a ft, 14aR)-N-[(2,4-Difluorophenyl)methyll- 11-hydroxy-10,12-dioxo- 1,2,3,4,5a,6, 10, 12,
14, 14a-decahydropyrido[1,2-a]pyrido[r,2':3,4]imidazo[1,2-d]pyrazine-9-carboxamide.
The title compound was made in two stops using a similar process to that described
in example Z-2. 16a (50 mg, 0,11 mmol) and [(2ϋ>)-2-Piperidinylmethyl]amino (150
mg, 1.31 mmol) (free based using carbonate resin as described in example Z-3) were
reacted in dichlofomethane (2 mL) with acetic acid to give
152 (5aR, 14aR)-N-[(2,4-difluorophenyl]methyl]-10,12-dioxo- 11- [(phenylmethyl)oxyl- 1,2,3,4
,5a, 6, 10, 12, 14, 34a-decahydropyrido[1,2vi]pyridoLl\2^3,4]imidazo[1,2-d]pyrazine-9-car
boxamide (50 mg, 88%). This material was hydrogenated in a second step as
described in example Z-2 to give
(5aR, 14aR)-//-[(2,4-difluorophenyl)methyl]-11-hydroxy- 10, 12-dioxo- 1,2,3,4,Sa,6, 10,12,
14,34a-decahydropyrido[1,2-a]pyridolll,2l:3,4]imidazo[1,2-d]pyrazine-9-carboxamide
(11 mg, 44%) as a white solid, 1H NMR (CDaOD/CDCl3) δ 10,46 (m, 1 H), 8.32 (s, 1
H), 7.31 (m, 1 H), C.80 (m, 2 H), 4,64-4.52 (m, 3 H), 4.14 (dd, J = 10,4, 2.8 Hz, 3 H),
3.91-3,82 (m, 2 H), 3, 19 (apparenf t, J = 10 8 Hz, 1 H), 3.08 (d, J= 10.4 Hz, 1 H), 2.50
(m, 1 H), 2.27 (m, 1 H), 1.99-1.30 m, 6 H); ES" MS: 445 (M+l),
Example Z- 19:
(2S.3-S)-J^[(2.4-Diflυoronhonyl)methyl]-6-hydroxv-3- fGϊiolhyloxy)meth.yl] -δ,7-dioxo-2-p
henyl-2,3,5,7, 11 , 11a-hcxahydro[1 ,3]oxazo] o[3,2-a1ρvndo[1,2-d]pyraiϋine-8-carboxamido
Figure imgf000155_0001
The title compound was made 111 two steps using a similar process to that described
in example Z-2, 16a (36 mg, 0,07 mmol) and (2R)-2-amino-4-methyl-3 -pentanol (0.1
niL) were reacted in dichloromethanc (2 mL) with acetic acid to give
(2S,3S)-N-[(2,4-difluorophenyl)methyl]-3-[(methyloxy)methyl]-5,7-dioxo-2-phenyl-6- [(p
henybnethyl)oxy]-2,3,5,7, 1l, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-c
3 53 arboxamide. This material was hydrogonatcd in a second stop as described in
example Z-2 to give
(2S,3S)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3- r(methyloxy)methyl] -5,7-dioxo-2-p
henyl^S.S,7.l1, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(25 mg, 64% for 2 stops) as a white solid. This material is a single diastereomer
(>6'J diastereomeric ratio but unconfirmed relative stereochemistry at the ammal
center). iH NMR (CDCl3) δ 11 48 (br, 1 H), 10.30 (m, 1 H), 8.39 (s, 1 H), 7.39-7.24 (m,
6 H), 6.78 (m, 2 H), 5.46 (dd, J = 10.0, 3.6 Hz, 1 H), 5.33 (d, J= 7.2 Hz, 1 H), 4.63 (m,
2 H), 4 54 (dd, J = 12.4, 4.0 Hz, 1 H), 4.19 (m, 1 H), 4.12 (dd, J = 10.4, 3.2 Hz, 1 H),
4 06 (m, 1 H), 3.55 (dd, J= 10.4, 1.6 Hz, 1 H), 3.40 (s, 3 H); ES 1 MS' 512 (M+l).
Example Z-20
(36>.11a/e)-3-(CvclohexyImethyl)-N-[(2,4-dilluorophenv]) methyl] -6-hydioxy 5,7-dioxo-2,
3.5.7, 11,1la-hexahydro[l.3ioxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamido
Figure imgf000156_0001
The title compound was made in two steps using a similar process to that described
in example Z-2. 16a (36 mg, 0.08 mmol) and (2S)-2-armno-3-cyclohexyl- 1-propaπol
(30 mg, 0.19 mmol) were reacted in dichloromei hane (2 mL) with acetic acid to give
(3ώv, 11a7τ>)-3-(cyclohexylmethyl)-ΛtK2,4-difluorophenyl)methyl]-5,7-dioxo-6-[(phenylme
thyl)oxy]-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxa
mide (27 mg, 61%), This material was hydrogenated in a second step as described in example Z- 2 to give
(3.S;i. aR)-3-(cyclohexyhτiethyl)-N4(2,4-diflυorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,
3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (25 mg,
99%) as a white solid. Η NMR (CDCl3) δ 11.48 (br, 1 H), 30.28 (s, 1 H), 8.33 (s, 1 H),
7.33 (m, 1 H), 6,78 (m, 2 H), 5,29 (m, 1 H), 4,61 (m, 2 H), 4.47-4.33 (m, 3 H), 3.87-3.81
(m, 2 H), 2,05 (m, 1 H), 1.75- 1.64 (m, 6 H), 1.39 (m, 1 H), 1.25- 1, 14 (m, 3 H), 1.02-0.97
(m, 2 H); ES 1 MS: 488 (M+ 1).
Example Z-2i:
(36f, 11ai?)-N- [(2,4-Difluoroi3henyl)methyI]-6-hydroxy3-(l-methylethyl) -5,7-dioxo-2.3,5.
7,11, 11a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.
Figure imgf000157_0001
The title compound was made in two steps using a similar process Lo that described
in example Z-1. 16a (42 mg, 0.09 mmol) and (2-S)-2-amino-3-methyl-1-butanol (0J
mL) were reacted in 1,2-dichlorocthane (8 mL) with acetic acid to give
(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-3-(1-methylethyl)-5,7-dioxo-6- t(phenylme(.hy
l)oxy]-2,3,5,7, 11, l Ia-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-Ω']pyrazine-8-carboxamide
(40 mg, 86%). This material was hydrogcnated in a second step as described in
example Z-I to give
(3.9, 1 l a/i!)-N*-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,
V, 1l.11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (34 mg, 99%) as a while solid. 1H NMR (CDOb) δ 10.29 (br, I H), 8.36 (s, 1 H), 7.33 (m, 1 H),
6.79 (m, 2 H), 5.29 (d, J= 6.4 Hz, 1 H), 4.61 Cm, 2 H), 4.44 (d, J= 9.6 HK, 1 H), 4.34 (m,
1 H), 4.17 (m, 1 PI), 4.02 (dd, J= 8.4, 5.2 Hz, 1 H), 3,86 (m, 1 H), 2,37 (m, 1 H), 0,97 (m,
6 H); ES+ MS: 434 (M+t).
Example Z-22:
(5aJ?,14a^)-N-[(2.4-DifluorophenvI)methyl]- 12-hydroxy ] 1.1 3-dioxo-5a.6a.7, 11.13.14a-
hGxahydro-5//-iiidenol.l',2':4.5j [i ,3]oxazo]o[3,2-fl]pyrido[1,2-d]pyrazine- 10-carboxamid
e.
Figure imgf000158_0001
The title compound was made in two steps using a similar process to that described
in example Z-I. 16a (42 mg, 0 09 mmo]) and
Q ;SΥ,2/i0-1- amino-2,3-dihydro-1.#-inden-2-ol (100 mg, 0.67 mmol) were reacted m
] ,2-dichloroethane (5 mL) with acetic acid to give
(5aR,14aS)-N- [(2,4-difluorophenyl)methyl]-11, 13-dioxo- 12- [(phenyhnethyl)oxy]-5a,6a,7
, 11, 13, 14a-hexahydro-5if-indenolll,2l:4,5l [l,3loxazolo[3,2-a]pyrido[1,2-d]pyrazine- 10-c
arboxamide (55 mg, 99%), This material was hydrogenated in a second step as
described in example Z-I to give
(5a/f, 14a»5)--V-[(2,4-diflιιorophenyl)methyl]-12-hydroxy-11, 13-dioxo-5a,6a,7, 11, 13, 14a-
hexahydro-δΛr-indono[l',2'M.5lCl.SJoxazolo[3,2-a]pyrido[1,2-d]pyrazine-10-carboxamid
e (45 mg, 97%) as a white solid. 1H NMR (CDCU) δ 10,28 (m, 1 H), 8.33 (s, 1 H), 7.69 (d, J = 7 2 Hz, 1 H), 7,34-7.19 (m, 4 H), 6,78 (m, 2 H), 5.96 (d, J = 6,0 Hz, 1 H),
5,32 (m, 1 H), 5.22 (m, 1 H), 4,60 (m, 2 H), 4.45 (d, J = 9,2 Hz, 1 H), 3,96 (apparent t, J
= 10,8 Hz, 1 H), 3.40 (dd, J= 18,0, 6.8 HK, 1 H), 3,24 (d, J= 17,6 Hz, 1 H); ); ES+
MS: 480 (M+ 1).
Example Z-23 & Z-24 :
(2S/SR 11a6)-./V: [(2,4-Di£luorophenyl)methyl]-6-hydroxv5,7-dioxo-2,3-diphenyl-2.3,5,7,
11.11a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamido &
(2j^3i?,1laR)-N-[(2,4-difluorophenv])methyl]-6-hydroxy-5.7-dioxo-2.3-diphenyl-2,3,5.7,
11. ] 1 athexahydro[1 ,3]oxazolo[3,2-a]pyridof 3 ,2-c/lpyfa7i]ne-8- carboxaimde.
Figure imgf000159_0001
The title compounds were made in two steps using a similar process to that
described ;m example Z-I. 16a (40 mg, 0.09 mmol) and
(l S',2 /O-2-amino- 1,2-diphenylethanol (50 mg, 0.23 mmol) were reacted in
1,2-clichloroethane (5 mL) with acetic acid to give
(2S,372, n aS)-N [(2,4-difluorophenyl)methyl]-5,7-dioxo-2,3-diphenyl-6- [(phenylmethyl) oxy]-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyraz;inG-8-carboxamide
(34 mg, 63%) and
(2S,3/i>, 11aii>)-N [(2,4-difluorophenyl)methyl]-5,7-dioxo-2,3-diphenyl-6-[(phenylmethyl)
oxy]-2,3,5,7, 1l, 11a-hexahydro[1,3]oxazolor3,2-a]pyrido[1,2-d]pyrazine -8-carboxaiΩide
(13 mg, 24%). These materials were hydrogonated in a second step as described in
example Z-I to give
(2S,3R, 11a,S)-N-[(2,4-Difluorophenyl)methyll-6-hydroxy-5,7-dioxo-2,3-diplionyl-2,3,5,7,
11, 1la-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-B-carboxamide (example
Z-23, 20 mg, 99%) as a white solid and
(2S,3R, 11aiO-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphenyl-2, 3,5,7,
H ,11 a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (example
Z-24, 10 mg, 89%) as a white solid respectively. For example Z-23: 1H NMR
(DMSOnV) δ J 0.29 (t, J = 5.6 Hz, 3 H), 8.55 (s, 1 H), 7 38 (m, 1 H), 7 22 (m, 1 H),
7 11-6.95 (m, 11 H), 6.16 (dd, J = 10.4, 3.6 Ha, 1 H), 5.71 (m, 2 H), 4.90 (m, 1 H), 4,54
(m, 2 H), 4.38 (l, J = 11 2 Hz, 1 H); ES+ MS: 544 (M+l). For example Z-24: 1H NMR
(CDCl3) δ 11,64 (br, 1 H), 10.30 (s, 1 H), 8.45 (s, 1 H), 7.34 (m, 1 H), 7,01-6.90 (m, 10
H), 6,80 (m, 2 H), 5.56 (m, 2 IT), 5.42 (d, J= 6.4 Hz, 1 H), 4.73 (m, J H), 4.63 (m, 2 H),
4.49 (m, 1 H); ES+ MS: 544 (M+l)
Example Z-25-"
(3 /g, 11a6)-/V-[(2,4-DifluoroDhonvl)methyl] -6-hydroxy-3-(l-methylethyI)-5,7-dioxo-2.3.5,
7,11.11a-hcxahydro[1 ,3]oxazolo[3,2-fl3ρyrido[1,2-d]pyrazmo-8-carboxamido.
Figure imgf000161_0001
The title compound was made in two steps using a similar process to that described
in example Z- I . 16a (40 mg, 0,09 mmol) and (2iϋ)-2-amino-3-methyM-butanol (0J
mL) wore reacted in 1,2-dichloroethane (8 mL) with acetic acid to give
(3R, 11aώ>A';[(2,4-difluorophenyl)methyI]-3-(1-methylethyl)-5,7-dioxo-6- [(phenylmethy
])oxy]-2,3,5,7, l 1, J la-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyraiύine-8-carboxamide
(41 mg, 92%). This material was hydrogenated in a second step as described in
example Z- I to give
(3 /^11aS)-N-[(E,4-Difluorophenyl)methyl]-θ-hydroxy-B-(1-methylethy^-5,7-dioxo-2,3,5,
7, l- , 11a-hexahydro[1,3]oxazolo[3,2-,dpyrϊdo[1,2-d]pyrazine-8-carboxamide
(32 mg, 94%) as a white solid. 1H NMR (CDCl3) δ 11.42 (br, 1 H), 10.27 (br, 1 H),
8.34 (s, 1 H), 7.31 (m, 1 H), 6.78 (m, 2 H), 5 28 (d, J = 6.0 Hz, 1 H), 4.60 (m, 2 H), 4.42
(m, 1 H ), 4.33 (m, 1 H), 4.16 (m, 3 H), 4.01 (dd, J = 8.8, 5.2 Hz, 1 H), 3.85 (m, . H),
2.37 (m, 1 H ), 0.97 (d, J = 6.8 Hz, 3 Ii), 0.95 (d, J = 6.4 Hz, 3 H); KS"1 MS: 434
(M+ 1).
Example Z-26
(3-.SUlaR)--V- [C2.4-Difliiorophenyl)methyl] -6-hydroxy-3- l2-(methylthio)ethyl1-5.7-dioxo-
2,3,5,7, 11, 11a-hoxahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazjne-8"carboxamide.
Figure imgf000162_0001
The tiile compound was made in two steps using a similar process to that described
in example 7,- 1. 16a (43 mg, 0.09 m mol) and (2,S) -2-amino-4 -(methylthio)-1 -butanol
(0.1 mL) were reacted in 1,2-dichlorocthane (5 mL) with acetic acid to give
(3S, l la/^-N-[(E,4-difluorophenyl)methyl]-3-[2-Cmethylth^ethyl] -S,7-dioxo-6- LCphenyl
metliyl)oxy] -2,3.5.T,11^la-hexahydro[1,3]oxazoJo fS,2-a]ijyrido[1,2-d]pyrazine -8-carbox
amide (41 mg, 81%). This material (20 mg, 0.04 mmol) was treated with
trifluoroacctic acid (1 mL) in dichloromethane (3 mL) at 0 °C to rt over 6 h. The
mixture was concentrated m vacuo and subjected to reverse phase preparat ive HPLC
purification to provide
(3S, J i a/β-N- 1(2/1 -Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethyl]-5,7-dioxo-
2,3,5,7, 11, l1a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
(12 mg, 72%) as a white solid. . 1H NMR (Cl)Cb) δ 11.35 (br, 1 H), 10 25 (s, 1 H),
8.34 (s, 1 H), 7 33 (m, 1 H), 6.79 (m, 2 H), 5 32 (m, 1 H), 4.62-4 53 (m, 3 H), 4.43-4.39
(m, 2 H), 3 91-3.87 (m, 2 H), 2,63-2.53 (m, 2 H), 2,39 (m, 1 H), 2, 12 (s, 3 Pl), 1.89 (m, 1
H) , ES+ MS 466 (M+ 0
Example Z-27
LSS1 U a R) --V- [(2, 4- Ωifluoroi3henyl)me(hyl]-6-hydroχy-3-[2-(methylsulfonyl)ethyl]-5,7-di
oxo-2v3, 5,7, 11 , l ] a-hexahydro[l, 3]oxazolo[3,2-a]pyrido[1,2-d]pyrazme-8-carboxamidc.
360 H
Figure imgf000163_0001
To a solution of
(3S, 11aR)-N-[(2,4-difIuorophenyl)methyl]-3-[2-(methylthio)ethyl] -5,7-dioxo-6-[(phenyl
methyl)oxy]-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carbox
amide (20 mg, 0.04 mmol) in dichloromethane (5 mL) at 0 °C was added m-CPBA (20
mg, 70%, 0.082 mmol). The resultant solution was allowed to warm as the bath
warmed and stirred a total of 3 h. The reaction was quenched by the addition of
Na2S2O3 (aq) and sodium bicarbonate. The layers were separated and the organic
layer washed with brine. The aqueous layer was extracted with dichloromethane
and the combined organics dried over Na2SO 4. Filtration and concentration provided
(3S, 11aR)-N-[(2,4-difluorophenyl)methyl]-3- [2-(methylsulfonyl)ethyl]-5,7-dioxo-6- [(phe
nylmethyl)oxy]-2,3,5,7,11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-car
boxamide (26 mg, 99%) as a white solid. This material was hydrogenated in a second
step as described in example Z-1 to give
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3- [2-(methylsulfonyl)ethyl]-5,7-di
oxo-2,3,5,7, 11, 11a-hexahydro[1,3]oxazoIo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide
(22 mg, 99%) as a white solid. 1H NMR (CDCl3) δ 11.00 (br, 1 H), 10.16 (s, 1 H), 8,33
(s, 1 H), 7.36 (m, 1 H), 6.81 (m, 2 H), 5.42 (m, 1 H), 4.62 (m, 3 H), 4.41 (m,2 H), 3.93
(m, 2 H), 3.31 (m, 2 H), 2.98 (s, 3 H), 2,40 (m, 1 H), 2.28 (m, 1 H); ES+ MS: 498 (M+l).
Example Z-28: (3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1 H-indol-3-ylmethyl)-5.7-dioxo
-2,3,5,7, 11, 11 a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.
Figure imgf000164_0001
The title compound was made in two slops using a similar process to that described
in example Z-1. 16a (43 mg, 0,09 mmol) and
(2S)-2-amino-3-(1H-indol-3-yl)-1-propanol (100 mg, 0.52 mmol) were reacted in
1,2-dichloroethane (5 mL) with acetic acid to give
(3S, 11aR)-N- 1(2, 4-difluorophenyl)methyI]-3-(1H-indol-3-ylmethyl)-5,7-dioxo-6- [(phenyl
methyl)oxy]-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carbox
amide (36 mg, 64%). This material was hydrogenated in a second step as described
in example Z-1 to give
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1H-indol-3-ylmethyl)-5,7-dioxo
-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (29
mg, 95%) as a white solid. 1H NMR (CDCI3/CD3OD) δ 10.34 (m, 1 H), 8.98 (br, 1 H),
8,24 (s, 1 10 , 7.58 (d, J = 8.0 Hz, 1 H), 7.32 (m, 2 H), 7.15-7.01 (m, 3 H), 6,78 (m, 2 H),
4 94 (d, J= 6 8 Hz, 1 H), 4.71 (d, J= 5.6 Hz, 1 H), 4.59 (m, 2 H), 4.35 (d, J= 10.4 Hz, 1
H), 4.22 (m, 1 H), 3,99 (m, 1 H), 3,81 (m, 1 H), 3,40 (dd, J= 13.6, 11.6 Hz, 1 H), 3.18
(dd, J= 14.0, 8.4 Hz, 1 H); ES+ MS: 521 (M+ 1).
Example Z-29:
(4R,12aR)-N-[(4-fluorophenyl)methyl] -7-hydroxy-4-methyl-] -(2-methylpropyl)-6,8-diox Q- J , 2.3.4.6.8.12,12a-octahydiODVridol r,2':4,5ii3vr'azinol 3 ,2-a1r)yrimidinc-9-carboxamid
Figure imgf000165_0001
a) (2/tD-2-({[(1, 1-Dimethylethyl)oxy]carbonyl}amino)propyl methanesulfonate. To a
stirred solution of I ,1 -dimethylethyl [(1ϋ9-2-hydroxy-1-methylethyl]carbamaLc (5.00 g,
28.5 mmol) and triethylamine (5.92 mL, 42,9 inmol) in CH2CI2 (30 mL) cooled to 0 °C
and under a nitrogen atmosphere was added dropwise a solution of methanesulfonyl
chloride (2,43 mL, 31.5 mmol) m CH2CI2 (25 mL), Stirring was continued for 20
minutes at 0 °C, after which time the reaction was judged complete by TIJC analysis
(i :i hexanes/EtOAc). The solution was poured into water and the layers wore
separated. The organic phase was washed with 0.1 N HC1 and then with 5%
NaPICOs, dried over Na2SO'i, filtered and concentrated to give
(2/ij)-2-({i.(1, l -d]methylethyl)oxyjcarbonyl}amino)propyl methanesulfonate (7.08 g,
98%) as a white solid. 1H NMR (400 MHz, CDCL?) δ 1.23 (d, J = 6.8 Hz, 3H), 1.44 (s,
9H), 3 03 (s, 3H), 3.97 (m, 1H), 4.15 (dd, J= 4.2, 9.8 Hz, 1H), 4.21 (m, 1H), 4.61 (br s,
1H).
b) 1, 1-Dimefhylethyl [(1/τ!)-2-cyano-1-methylethyl]carbamate. To a stirred solution
of (22?)-2-({[(1, 1-dimethylethyl)oxy]carbonyl}amino)propyl methanesulfonate (7.08 g,
27.9 mmol) in DMSO (50 mL) was added NaCN (3.78 g, 84,0 mmol). The solution
was stirred at 70 °C for 2 hours, over which time the formation of a precipitate was
163 observed, After cooling at room temperature, water was added and the mixture was
extracted with EtaO, The ethereal layers wero washed with a brine solution, dried
over NaaSO'i, filtered and concentrated to give 1,1- dim ethyl ethyl
[(1R)-2-cyano-1-methylethyl]carbamate (3.81 g, 73%) as a pale yellow solid. 1H NMR
(400 MHz, CDCl3) 6 1.30 (d, J = 6.8 Hz, 3H), 1.42 (s, 9H), 2.53 (dd, J = 3.8, 16.6 Hz,
1H), 2.73 (m, -H), 3,93 (m, 1H), 4.G3 (br s, 1H),
c) 1 , 1 -Dimethylethyl [(I Λθ-3-amino-1-methylpropyl]carbamate, A solution of
1, .-dimethylethyl K1/i?)-2-cyano;.1-methylethyl]carbamate (1.30 g, 7.1 mmol) in
ethano] saturated with anhydrous ammonia was treated with Raney-Ni (1,5 mL of
50% aq. Suspension) and 55 psi of H2 overnight, The mixture was filtered through
Celite and the filtrate was concentrated in vacuo. The residue was purified by flash
chromatography (80:i9:l CI-lsCb/MeOH/NH-iOH (37%) gradient olution) through a
short plug of silica gel to give 1,1 -dimethylethyl
rθ /i9-3-amino- 1 -methylpropyl]carbamate (1,37 g, 100%) as a clear oil that solidified.
1H NMR (400 MHz, CDCl,)) δ 1.14 (d, J= 6.8 Hz, 3H), 1.43- 3.62 (m, 13H), 2.76 (m, 2H),
3.77 (m, 1H), 4.57 (m, Hi).
d) 1,1- Dimethylethyl {(3 R)- 3 -methyl-3-[(2-methylpropyl)amino]propyl}carbamate.
1, 1 -dimethylethyl [( l /t!)-3-amino-1-methylpropyl]carbamato (0.320 g, 1.70 mmol),
isobutyraldehydc (150 μL, 1,62 mmol), and sodium triacetoxyborohydride (0,512 g,
2.42 mmol) wore stirred in anhydrous dichloroethane (10 mL) at ambient temperature
overnight. The reaction was quenched by the addition of saturated NaHCO,I and then extracted with dichloromeihane, The combined extracts were washed with
water, dried over NasSO-i, filtered and concentrated. The residue was purified by
flash chromatography (80:19:1 ClhCb/McOH/NBUOH (37%) gradient elυtion) through
a short plug of silica gel to afford 1, 1-dimethylethyl
{(1R)-1-methyl-3-[(2-methylpropyl)aminoJpropyl}carbarnato (0.158 g, 40%) as a clear
O1I. iH NMR (400 MHz, CDCl3) 5 0,90 (d, J = 6.4 Hz, 6H), J .13 (d, J = 6.4 Hz, 3H),
1.42- 1.51 (m, HH), 1.67- 1.75 (m, 2H), 2,33-2.42 (m, 2H), 2.58-2.72 (m, 2H), 3.72 (m,
1H), 5,20 (m, 1H).
c) [(3/$-3-Aminobutyl](2-methylpropyl)amino. An ice cold solution of
1, 1-dimethylethyl {(1/i)-1-methyl-3- [(2-methylpropyl)amino]propyl}carbamate (0.158 g,
0.65 mmol) in TtIF (8 ml) was treated with 4 NHCl (aq) (2 mL) and then stirred at
room t emperature for 2 h. The mixture was concentrated in vacuo to give
[(3R)-3-aminobutyl](2-methylpropyl)amine dihydrochloride. The HCl salt was then
dissolved in dichloromethane and a minimal amount of methanol and treated with
solid supported carbonate resin (MP-Carbonate, Argonaut Technologies). After 30
minutes, the solution was filtered through a fritted tube and the solvents removed
carefully in vacuo to give [(3 R)-3-aminobutyl](2-methylpropyl)amino (65 mg). 1H
NMR (400 MHz, CDCL3) δ 0,88 (d, J= 6.0 Hz, 6H), 1.06 (d, J= 5.6 Hz, 3H), 1.23- 1 53
(m, 5H), 1.71- 1.74 (m, 1H), 2.39 (m, 2H), 2.65 (m, 2H), 2,97 (m, 1H).
f)
(4R,12aR)--VK4-Fluorophenyl)methyl]-7-hydroxyl-methyl-1-(2-methylpropyl)-6,8-dio xo- 1,2,3,4,6,8,12,J 2a-octahydropyrido[1',2':4,5]pyrazino[1,2-ej]pyrimidine-9-carboxami
de, The title compound was made in two steps using a similar process to that
described in example Z-2. 16 (40 mg, 0.09 mmol) and
[(32f)-3-aminobutyl](2-methylpropyl)amine (65 mg, 0.45 mmol) were reacted in
dichloromethanc (2 mL) with acetic acid to give
(47^ 12aR)-N- [(4-fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phen
ylmethyl)oxyl- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9
-carbαxamide (29 mg, 60%), This material was hydrogenated m a second step as
described in example Z-2 to give
(4 R,12aiϊ)-7V"-[(4-rluorophenyl)methj'l]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-diox
o- 1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamid
e (18 mg, 75%) as a tan solid. 1H NMR (400 MHz, GDCIa) δ 0.77 (d, J = 6.4 Hz, 3H),
0.84 (d, J - 6,4 Hz, 3H), 1.32 (d, J = 7.2 Hz), 1.45-1.49 (m, JH), 1.57-1.67 (m, 1H),
2.03-2.12 (m, 2H), 2.21-2.27 (m, "1H), 2.73-2.79 (m, 1H), 2.87-2.92 (m, 1H), 4, 16-4.24
(m, 2H), 4,45 (s, 1H), 4.54-4.64 (m, 2H), 4.96-4.99 (m, 1H), 6.96-7.00 (m, 2H),
7.29-7,32 (m, 2H), 8.27 (s, 1H), 10.46 (s, 1H), .12,55 (s, 1H); ES+ MS: 456 (M+ 1).
Example Z-3Q:
(4/^, 12a/d-N-[(4-Fluorophoiivl)methy1]-7-hydroxy-4-methyl-l-(] -methyl ethyl)-6,8-diox
o- 1,2,3.4,6.8.12.12aOctahydropyrido[1',2':4,5]pyrazin o[ 1,2-^1pyrimidine-9-carboxamid
Figure imgf000169_0001
a) [(3i$-3-Aminobxityl] (_ -methylethyl)amine. The free diamine was prepared in a
similar manner as described in example Z-29. 1H NMR (400 MHz, GDCIs) δ 1.04 (d,
J = 6.4 Hz, 6H), 1.06 (d, J = 6.4 Hz, OH), 1.41-1.58 (m, 5H), 2,62-2,66 (m, 2H),
2.74-2.80 (m, 1H), 2.92-3.00 (m, 1H).
b)
(4R, 12aR)-N-[(4-Fluorophenyl)methyl]-7-hydroxy-<|-mel.hyl-1-(1-mcfchylethyl)-6,8-diox
o- 1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamid
e. The UUe compound was made in two steps using a similar process to that
described in example Z~2. 16 (40 mg, 0.088 mmol) and
[(3R)-3-aminobutyl](1-methylethyl)an.ine (78 mg, 0.60 mmol) were reacted in
dichloromolhane (2 mL) with acetic acid to give
(4/^ 12aR)-N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7- [(phenyl
methyl)oxy] - 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-c3jpyrimidine-9-c
arboxamide (26 mg, 56%). This material was hydrogenated in a second step as
described in example Z-2 to give
(4R, 12aR)-N-[(4-iluorophenyl)methyl]-7-hydroxy-4-methyl-1-(l -methylethyl)-6,8-dioxo
- 1,2,3,4,6,8, 12, 12a-octahydropyrid.o[1',2';4,5lpyrazino[1,2-a]pyrimidine-9-carboxamide
(21 mg, 90%) as an off-white solid. JH NMR (400 MHz, COCl3) δ 1.01 (d, J= 5.6 Hz,
3H), 1.06 (d, J = 6.0 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H), J , 57 (m, 1H), 1,98 (m, 1H), 2.70-2.82 (m, 2H), 3.15 (m, 1H), 4.15-4, 19 (m, 1H), 4,30 (m, 1H), 4.48 (s, 1H), 4.54-4.59
(m, 2H), 4.97 (m, 1H), 6,98 (m, 2H), 7,29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H),
12.52 (s, 1H),
Examples Z-31:
(46f.] 2alg>-A^-|(2,4-Difluorophenvl)mefchyl] -7-hydroxy-4-methyl-1-(2-methylDropyl)-6,8-
dioxo- ] ,2.3, 4,6, 8 , 12.12a-ociahydropyrido[1',2':4,5]pyvazin o U,2-a]pyrimidine-9-carboxa
Figure imgf000170_0001
a) 1,1-Dimcihyleihyl [(1>S)-2-cyano-1-methylethyl]carbamat,e. The niirilo was
prepared in two slops using a modified procedure as described in example Z-29. To a
stirred solution of (2<S>-2-({[(1, 3 -dimethylethyl)oxy]carbonyl}amino)propyl
methanesulfonate (8.40 g, 33.2 mmol) in DMSO (50 ml.) and KCN (6.51 g, 100.0
mmol) coolod to 0 °C was added 18-crown-6 (9.05 g, 34.3 mmol). The solution was
allowed to warm to room temperature and then heated to 70 °C for 1 hour. After
cooling at room temperature, water was added and the mixture was extracted with
EtaO, The ethereal layers wore washed with a brine solution, dried over Na'iSO-i,
filtered and concentrated to give 1, 1-dimethylethyl
f(l S)-2-cyano-1-methylethyl]carbamate (5.37 g, 88%) as a pale yellow solid. 1H NMR
(400 MHz, CDCL5) δ 1,32 (d, J= 6.8 Hz, 3H), 1.44 (s, 9H), 2.52 (dd, J = 4,0, 16.4 Hz,
1H), 2,74 (m, 1H), 3.95 (m, 1H), 4.65 (br s, Hi). b) [(85)-3-Aminobutyl] (2-methylpropyl)amine dihydrochloridc was prepared in a
similar manner as described in example Z-29. 1H NMR (400 MHz, CDCI3/CD3OD) 8
0,99 (m, 6H), 1.34 (m, 3H), 2.3 3-2.27 (m, 3H), 2.76 (m, 2H), 3.07 (m, 2H), 3.47 (m, 1H),
8.22 (m, 1 H), 8.83 (m, <1 H),
c)
(4*SY, 12aS)-N'- [(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyM- (2-methylpropyl)-6,8-
dioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pj'rimidine-9-carboxa
made. The title compound was made in two si eps using a similar process to that
described in example Z-2. 16a (80 mg, 0.17 mmol) and free based
[(3jS)-3-amπiobutyl](2-mof,hylpropyl)amine (107 mg, 0,74 mmol) were reacted m
dichloromethaαie (2 mL) with acetic acid Lo give
(4,9, 12aS)-N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7- [(p
henylmethyl)oxy] - 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino| 1,2- a]pyrimidi
ne-9-carboxamide (76 mg, 76%) as a film, This material was hydrogenatcd in a
second stop as described in example Z-2 to give
(4/5r, 12aώ)-N- [(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl- 1-(2-methylpropyl) -6,8-
dioxo-1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyra2ino[1,2-a]pyrimidine-9-carboxa
mide (39 mg, 80%) as an off-white solid. 1H NMR (400 MHz, CDCI.3) δ 0.76 (d, J = 6.4
Hz, 3H), 0.84 (d, J= 6.4 Hz, 3H), 1.32 (d, J = 7.2 Hz, 3H), 1.45- 1.50 (m, 1H), 1.60-1.69
(m, 1H), 2.03-2, 12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79 (m, 1H), 2.87-2.93 (m, 1H),
4.16-4.25 (m, 2H), 4,45 (s, 1H), 4.57-4.68 (m, 2H), 4.96-5.01 (m, 1H), 6.75-6.82 (m, 2H),
169 7.32-7.38 (m, 1H), 8.26 (s, 1H), 10.45 (s, 1H), 12.56 (s, 1H); ES+ MS: 475 (M+ 1).
Example Z-32:
(4>g. l2a-5)- l-(Cvclopropylmethyl)-.V-[(2,4-difluoroph enyl)methyi|-7-hydroχy-4-methyl -6
,8-dioxo-1,2.3.4.6.8.12.12a-ociahvdropyrido[1',2':4,5]pyrazhio[J ,2-ff]pyri midine-9-carbo
xamide.
Figure imgf000172_0001
a) 1, 1-Dimethylethyl {(1S)-3-|(cyclopropylmethyl)aminoJ-1-methylpropyl}cavbamate,
The protected diamine was prepared using a modified procedure as described in
example Z-29. 1, 1-dimethyletlαyl [(1,5)-3-amino-1 -methylpropyl]carbamate (0.293 g,
1.56 mmol), cyclopropane carboxaldehydo (96 μL, 1,30 mmol), and sodium
triacotoxyborohydride (0,439 g, 2,07 mmol) were stirred in a I 'l mixture of anhydrous
dichloroethano and tetrahydrofuran (10 ml) at ambient temperature overnight.
The reaction was quenched by the addition of saturated NaIiCOa and then extracted
with EtOAc, The combined extracts were washed with saturated NaHGOa, then a
solution of brine, dried over NasSO-i, filtered and concentrated. The residue was
purified by flash chromatography (80:19:. ClbCk/MeOH/NtLiOH (37%) gradient
elution) through a short plug of silica gel to afford 1, 1-dimethylethyl
{(KS^-3-[(cyclopropylmethyl)aminoJ-1-methylpropy^carbamate (76 mg, 26%) as a clear
oil. 1H NMR (400 MHz, CT)Ch) 6 0.09-0.13 (m, 2H), 0,44-0.49 (m, 2H), 0.92-0.95 (m,
.1H), 1. 14 (d, J = 6.4 Hz, 3Ii), 1.43- 1,70 (m, 12Ii), 2,38-2.50 (m, 2H), 2,62-2.73 (m, 2H), 3.74 (m, 3 H), 4.88 (m, _ H) .
b) [(3ιS)-3-Aminobutyl](cyclopropylmethyl)amine dihydrochloride was prepared in a
similar manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CD.sOD) δ
0,40 (m, 2H), 0.64 (m, 2H), 3 .15 (m, 1H), 1.34 (m, 3H), 2.12-2,25 (m, 2H), 2.82 (m, 2H),
3.08 (m, 2H), 3.47 (m, 1H), 8.25 (br, < 1H), 9.04 (br, < 1H) ,
c)
(4S, 12aS)-1- (CyclopropylnietJiyl)-N-[(2,4 -difluorophenyl)methyl] -7-hydroxy-4-methyl-6
,8-dioxo- 1,2, 3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyraxino[1,2-a]pyrimidine-9-carbo
Tcamide, The title compound was made in two steps using a similar process to that
described in example Z-2. 16a (50 mg, 0.106 mmol) and free based
[(3jS)-3-aminobutyl](cyclopropylmethyl)amine (44 mg, 0.31 mmol) were reacted in
dichloromethane (2 mL) with acetic acid Lo give
(4£; 12aΛS)-1-(cyclopropylmethyl)-N- [(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7- [
(phenylmαthyl)oxyl - 1,2,3,4,G,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2- a)pyrimi
dine-9-carboxamide (50 mg, 83%) as a film, This material was hydrogenated in a
second step as described m example %-2 to give
{AS, 12a^5)-1-(cyclopropylmethyl)-A/: [(2,4-difluorophenyl)methyl]-7-hydroxy-4 -methyl-6,
8-dioxo- 1,2,3,4,6,8, 12, l 2a-ocfcahydropyrido[1',2':4,5]pyrazino[1,2v3lpyrimidine-9-carbo
xamide (23 mg, 56%) as an off-white solid 1H NMR (400 MHz, CDCIs) 5 0.11 (m, 2H),
0.56-0,59 (m, 2H), 0,77 (m, 1H), 1,34 (d, J = 7,2 Hz, 3H), 1 ,46- 1.50 (m, LH), 2.04-2.13
(m, 1H), 2.30-2.34 (m, 1H), 2.46-2.51 (m, 1H), 2,90-2.96 (m, 1H), 3.16-3 19 (m, 1H), 4.21-4.30 (m, 2H), 4.61 (s, 1H), 4.58-4.67 (m, 2H), 5,00-5.05 (m, 1H), 6.75-6.82 (m, 2H),
7.31-7.37 (m, 1H), 8.28 (s, 1H), 10,46 (s, 1H), 12.55 (br, 1H); ES " MS: 470 (M+1).
Example Z-33:
(4iff,12aS>-N-[(2,4-DifluoroDhcnyl)niGthyl]- l-(2-iuranylmofchyl)-7-hydroxy-4-molhyl-6,8
•dioxo- ] ,2,3,4,6,8.12, 12a-ociahydropyrido[1',2':4,5]pyrazinol 1,2-a1pyrimidine-9-carbox
amide.
Figure imgf000174_0001
a) [(3*_3-3-Aminobtityl](2-iuranylmethyl)aminβ dihydrochloride was prepared in a
similar manner as described in example Z-32. 1H NMIl (400 MHz, CDCI3/CD3OD) S
1,27 (d, J = 6.4 Hz, 3H), 1.96-2.05 (m, I B), 2Λ 4-2.19 (m, 1H), 3.00-3.04 (m, 2H),
3.38-3.39 (m, 1H), 4.11-4.18 Cm. 211), 6.34 (m, 1H), 6.59 (m, 1H), 7.40 (m, 1H), 8.18 (br,
<1 H), 9.41 (br, < 1 H).
b)
US, 12&3-N- [(2,4-Difluorophenyl)methyl] - 1 -(2-fυranylmethyl)-7-hydroxy-4-methyl-6,8
-dioxo- 1,2,3,4,6,8, 12, 12a-oclahydropyridoLr,2':4,5]p3'ra?;ino[1,2-a]pyrimidine-9-carbox
amide. The title compound was made in two steps using a similar process to that
described in example Z-2. 16a (36 mg, 0.076 mmol) and free based
[(3<S)-3-aminobutyl](2-furanylmethyl)amine (70 mg, 0.42 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give (4«S; 12ao>N-[(2,4-difluorophenyl)methyl]-1-(2-fiu1anylmethyl)-d-methyl-6,8-dioxo-7- [(p
henyln.cfchyl)oxyj- 1,2,3,4,6,8, 12, 12a-ociahydropyrido[1',2':4,5]pyrazino[l ,2-a]pyrimidi
ne-9-carboxamide (32 mg, 70%) as a film. This material was hydrogenated in a
second step as described in example Z-2 to give
(4)S; 12aS)-N- [(2,4-difltιorophenyl)inethyl]-1-(2-furaπylmethyl)-7-hydroxy-4-methyl-6,8-
dioxo-1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxa
mide (20 mg, 76%), as an off-white solid. JH NMR (400 MHz, CDCIs) δ 1.24 (d, J =
6,8 Hz, 3H), 1,45- 1.49 (m, 1H), 2.04-2.13 (m, 1H), 2,77-2.82 (m, 1H), 2.94-8.01 (m, 1H),
3.65 (d, J = 15.6 Hz, _ H), 3.89 (d, J = 16.0 Hz, 1H), 4.27-4.31 (m, 1H), 4.39-4.41 (m,
1H), 4.49-4.53 (m, 1H), 4 58-4.66 (m, 1H), 4.98-5.03 (m, 1H), 6 24 (m, 1H), 6.36 (m,
1H), 6.75-6.82 (m, 2H), 7.31-7.39 (m, IH), 7.40 (m, 1H), 8.26 (s, 1H), 10,47 (m, Hi),
12.50 Cbr, 1H); RS 1 MS: /J99 (M+ 1).
Example %• 34 =
(4>g; i 2a>5)-./V-[(2.4-DifInorophenvI)methyl]-7-hydroxv-4-methyl-6,8-dioxo-1 -(l.3-thia'zol-
2-ylmethyl)- 1.2,3, 4,6.8, 12, 12a-octahydrσpyrido[1',2':4,5]pyx'azino[1,2-a1pvrimidinc-9-c
arboxamide.
Figure imgf000175_0001
a) [(3S)-3-Aminobutyl](1,3-thiazol-2-ylmethyl)amine dihydrochloride was prepared
in a similar manner as described in example Z-32. 1H NMR (400 MHz, CDCWCDJ-
OD) δ 1.28 (d, J= 6.4 Hz, 3H), 2.05 (m, 1H), 2,17 (m, 1H), 3.20 (m, 2H), 3.39 (m, 1H), 4.51-4.58 (m, 2H), 7.52 (d, I Hl), 7.82 (d, 1H).
b)
(4<5', 12aS)-N- [(2,4-Diflυorophenyl)methyl] -7-hydroxy-4-iΩethyl-6,8-dioxo-1-(1,3-thiazol-
2-ylmethyl)-1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2- a]pyrimidine-9-c
arboxamide. The title compound was made in two steps tismg a similar process to
that described in example Z-2. 16a (35 mg, 0,074 mmol) and free based
[(3«S>-3-aminobutyl](1, 3-tliia'/5ol-2-yhiiethyl)amine wore reacted in dichloromethanc (2
ITiL) with acetic acid to give
(4<S', 12aS)-iV: [(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phΘnylmethyl)oxy|-1-
(1,3-thiazol-2-ylmethyl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2- a]pyr
imidine-9-carboxamide (36 mg, 80%) as a film. This material was debenzylated in a
second step to in a manner similar to Z-26 to give
(4S, 12a«5)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-thiazol-
2-ylmethyl) - J ,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-c
arboxamide (18 mg, 60%) as an off-white solid. 1H NMR (400 MHx, GDCL5) δ 1 .30 (d,
J= 7.2 Hz. 3H), 1.49- 1.53 (m, 1H), 2.12-2,18 (m, 1H), 2.93-2.96 (m, 1H), 3,07-3.13 (m,
1H), 3,99-4.03 (m, 1H), 4 13-4.17 (m, 1H), 4.24-4.27 (m, 1H), 4.57-4.61 (m, 3H),
5.03-5.06 (m, 1H), 6.75-6.82 (m, 2H), 7.26 (m, 1H), 7.31-7.37 (m, 2H), 7.76 (m, 1H),
7.94 (m, 1H), 10,40 (m, 1H), 12.48 (m, 1H), ES+ MS' 516 (M+ l),
Example Z-35:
racomiC'{4d- RQi\R< ] 4 a -S)- N-[(214-Difluorophenyl)methyl]- 12-hydroxv 1 1 , 1 3-dioxo- 1.3.4. da,5.6a,7, U, 13, 14a-docahydro-27j"-τ)yrido[1',2':4,5]pyrazino[ 1,2-fll f3,1ibGnzoxazine- 10-
carboxamide
Figure imgf000177_0001
a)
;v?cemi(7-(4a/f,6aR, 14aA≤)-Λt[(2,4-Difluorophenyl)methyl]-11, 13-dioxo- 12- [(phe
nylme(.hyl)oxy] -1,3,4,4a,5,Ga,7, 11, 13, 14a-decahydro-2i7:pyrido[1',2':4,5]pyrazino[1,2-a]
[3, l]benzoxazine- 10-carboxamide. iyiceijji'c-ci's-2-H.ydroxymethyl-1-cyclohexylammc
hydrochloride (24 mg, 0.186 mmol) was dissolved in a dichloromethane solution
containing a small amount of methanol (to dissolve) and excess MP-Carbonate
(Argonaut Technologies) was added, the mixture was stirred for 30 minutes, and the
MP-Carbonato was removed by filtration. The free amine solution was transferred to
a microwave vessel containing 16a (29 mg, 0.0617 mmol). One drop of glacial acetic
acid was added and the solution was heated for 10 minutes at M0 °C, The resultant
solution was absorbed on colitc and the material was purified by silica gel
chromatography (0- 12% methanol/dichloromethane gradient elution) to yield the
desired product as a white solid (18 mg, 53%), 1H NMR (CDCl3) δ 10,40 (m, 1 H),
8 35 (s, 1 H), 7.60 (m, 2 H), 7 34-7,26 (m, 4 H), 6.80 (m, 2 H), 5.35-5.23 (m, 2 H), 5.13
(m, 1 H ), 4.77 (m, 1 PI), 4.70 (m, 2 H), 4.22 (dd, J = 13.2, 3.2 Hz, 1 H), 4.07 (del, J -
13.2, 6.4, I H), 3.96 (m, 1 H), 3.76 (dd, J= 11 2, 4.4, 1 H), 2.22 (m, 1 H), 1.84 (m, 1 H),
1.74- 1.40 (m, 6 H), 1, 17 (m, 1 H)TES+ MS: 550 (M +J) b) racemic<4aR,6aR44aS)--V[(2/l-JDifluorophenyl)methyl]-12-hydroxy-11 ,13^10X0-1,3,4,
4a,5,6a,7,1l,13,14a-decahydro-2Hpyrido[1',2':4,5]pyrazino[1,2-a3[3,1]bGnzoxazine-10-
carboxamide. racemic-(4aJi,6aR, 14a£)-ΛM(2,4-Difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethy
I)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pynclo[li,2':4,5]pyrazino[1,2-<a][3,1]benz
oxazine-10-carboxamide (13 mg, 0,0236 mmol) was dissolved an totrahydrofuran and
10 w.i.% Pd/C (13 mg) was added. Hydrogen was passed through the solution several
times and the mixture was stirred at 1 atm hydrogen for 18 hours until the reaction
was determined complete by TLC (5% methanol/dichloromethane), The mixture was
filtered through Celtito, eluting with methanol/chloroform and the filtrate was
concentrated under reduced pressure and purified by HPIJC to yield the title
compound (7.3 mg, 73%) 1H NMR (CDClO δ 12.45 (m, 1 H), 10.38 (s, 1 H), 8.30 (s, 1
H), 7.32 (m, 1 H), 6,83-6.76 (m, 2 H), 5.23 (m, 1 H), 4.75 (m, 1 H), 4.63 (m, 2 H), 4.26
(m, 1 H), 4,12-4,01 (m, 2 H), 3.83 (m, 1 H), 2.30 (m, 1 H), 1.91 (m, 1 H), 1.80 (m, 1 H),
1.67-140 (m, 5 H), 120 (m, 1 H); ES+ MS: 460 (M +1).
Example Z-36:
racemic-(4a/^.6a/g.l4a>^-Λ^-[(4-FluoroDhcnyl)methyl]-12-hydroxv-11,13-dioxo-l,3.4,4a,
5,6a.7.1].13,14a-docahydro-2-y-;pyrido[1',2':4,5]pyraginoll,2-fl1f3.l1ben!goxazine-10-car
boxamidc.
Figure imgf000179_0001
a) racemicid&R,6aR, 14aS)-N- [(4-Fluorophenyl)meihyl]- 11, 13-dioxo- 12- [(phenyl
methyl)oxy]- 1,3,4,4a,5,6a,7, l1, 13,1'la-decahydro-2H-pyrido[1',2':4,5]py razino[1,2-a] [3,
l]benzoxazine-10-carboxamide, In a manner similar Lo thai described in example
Z-35, from racomj'o-cjs-2-H.ydτoxymeihyl- l -cyclohexylamino hydrochloride (50 mg,
0.303 mmol) and 16 (45 mg, 0.0995 mmol) was prepared
racemicH4aR,6aK, 14aS)-N- [(4 -flu orophenyl)methyl] -11, 13-dioxo- 12-[(phenylmethyl)ox
y]- 1,3,4,4a,5,6a,7, 11, 13, 14a-decahydro-2H-pyrido[1',2':4,5]pyra^ino[1,2-a] [3, ilben2θxa
zine- 10-carboxamide (48 mg, 91%) as a white solid. 1H NMR (CDCIi) δ 10.42 (m, 1
H), 8.37 (s, 1 H), 7.59 (m, 2 H), 7.38-7.24 (m, 5 H), 6.98 (m, 2 H), 5.26-5.18 (m, 2 H),
5.07 (m, 1 H), 4.74 (m, 1 H), 4.62-4.5l(m, 2 H), 4.20 (dd, J = 13.6, 4 Hz, I H), 4.04 (m,
1 H), 3.91 (m, 1 H), 3.71 (dd, J = 11.3, 4.8 Hz, 1 H), 2.18 (m, 1 H), 1.82 (m, 1 H),
1,73- 1.63 Cm, 2 H), 1.62-1.56 (m, 2 H), 1.48 (, 1 H), 1.38 (m, 1 H), 1.14 (m, 1 H); ES+
MS: 532 (M +3).
b)
racemic-(4aR,6aZτ?, 14aλ6)-N- [(4-Fluorophenyl)methyl]- 12-hydroxy- 11, 13-dioxo- 1,3,4,4a,
5,6a,7,11, 13, 14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a] [3,1lbenzoxazine-10-car
boxamide. En a manner similar to that described in example Z-37, from
racemic -(4aR,6aR, 14aS)-N-[(4 -flxιorophenyl)methyl]-1l , 13-dioxo-12-[(phenylmethyl)ox y]- 1,3,4,4a,5,Ga,7, 11, 13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a] [3,1lbGnzoxa
zine- 10-carboxamide (37 mg, 0.06O6 mmol) and 10 w.t. % Pd/C (3 mg) was prepared
the title compound (18 mg, 58%) as a white solid after purification by HPLC. 1H
NMR (CDCl3) δ 12.47 (s, 1 H), 10.39 (m, 3 H), 8.32 (s, 1 H), 7.30 (m, 2 H), 6.98 (m, 2
H), 5.22 (m, 1 H), 4.74 (m, 1 H), 4.58 (m, 2 H), 4,28 (dd, J= 13.2, 4 Hz, 1 H), 4 J 2-3.98
(m, 2 H), 3,81 (dd, J= 11.6, 4.8 Hz, 1 H), 2.29 (m, 1 H), 1.91-3.19 (m, 8 H); ES+ MS:
442 (M H-I).
Example Z-37:
racemic -(3<S!4ai?.6aif,14a6VN-[(2,4-Difluoroρhenyl)methyl]- 12-hydroxv- 11.13-dioxo-3-
ιphenyl-1.3,4,4a,5,6a,7,11, 13, 14a-decahydro-2H:pyi:ido[1',2':4,5]pyrazino[1,2-a1f3.3]bon
zoxazine-10-carboxam.de
Figure imgf000180_0001
a)
racemic -(3S/ia/^6aR, 14aS)-N-[(2,4-Diflυorophenyl)methyl]- 11, 13-dioxo-3-phG
nyl- 12-[(phenylmethyl)oxy]- 1,3,4,4a,5,6a,7, 11,33, 14a-decahydro-2^zr-pyrido[1',2':4,5]py
razino[l,2-a] tSjlbonzoxazine- 10-carboxamide. In a manner similar to that described
in example Z-35, from racemic-[(1/£,2)S',5S)-2-amino-5φhcnylcyclohexyl]methanol
hydrochloride (32 mg, 0 160 mmol) and 16a (30 mg, 0.064 mmol) was prepared
racemic-(3S,4aR,6aR, 14a*S)-Λ';[(2,4-difluorophenyl)methyl]- 11, 13-dioxo-3-phenyM2- [(
phenylmethy])oxyi- 1,3,4,4a,5,6a,7, 11, 13, 14a-decahydro-2i3r-pyrido[1',2':4,5]pyrazino[3 , 2-a][3, llbenzoxazine- 10-carboxamide (35 mg, 88%) as a white solid, 1H NMR (CDCl3)
δ 10.41 (m, 3 H), 8,38 (s, 1 H), 7,66 (m, 2 H), 7,40-7.26 (m, 6 H), 6,81 (m. 3 H),
5.32-5.25 (m, 2 H), 5.17 (m, 1 H), 4.89 (m, 1 H), 4.66-4.62 (m, 2 H), 4.26 (dd, J = 13,6,
A Hz, 3 H), 4.33-4.04 (m, 2 H), 3.85 (dd, «/=13 .2, 4.4 Hz, 1 H), 2.56 (m, 3 H), 2.37 (m, 1
H), 2.03- 1,64 (m, 6 H); ES 1 MS: 626 (M +l).
b)
ia ceΛ2yc-(3S,4aiϊ,6aR, 14a,5)-iN-[(2,4-DifIuoroplionyl)methyl] - 12-hydroxy- 11, 13-dioxo-3-
phenyl -1,3,4,4a,5,6a,7, 13 , 13, 14a-decahydro-2i:7-pyrido[1',2':4,5]pyrazino[1,2-al [3, l]ben
zoxazine- 30-carboxamide
raceij-ic-(3ώ"',4aR,6aR, 14a,5)-N-[(2,4-Difluorophenyl)methyl]- 11,13-dioxo-3-phenyl-12-[(
phenylmethyl)oxy]- 1,3,4,4a,5,6a,7, l l, 13, 14a-decahydro-2 /7-pyrido[1',2':4,5]pyrazino[1,
2-a][3, l]benzoxazine- 10-carboxamide (27 mg, 0.0432 mmol) was suspended m
methanol, 10 w.t, % Pd/C ( 3 mg) was added and hydrogen was bubbled through the
system several times until the reaction was determined complete by TLC (5%
methanol/dichloromethane), The suspension was filtered through Celite elutmg with
methanol/chlorofbrm and the filtrate was concentrated under reduced pressure and
purified by HPLC to give the title compound (13 mg, 57%) as a white solid, 1H NMK
(CDCl3) δ 12.40 Cbr s, 1 H), 10.37 (m, 1 H), 8.32 (s, 1 H), 7.37-7.28 (m, 3 H), 7.24-7.15
(m, 4 H), 6 79 (m, 2 H), 5.78 (br s, 3 H), 4.85 (m, 1 H), 4.62 (m, 2 H), 4.29 (m, 1 H),
4.16-4.09 fan, 2 H), 3.92 (dd, J = 11.6, 4.8 Hz, 1 H), 2.58 fan, 1 H), 2,46 fan, 1 H),
2 07-1,64 (m, 7 H); ES+ MS: 536 (M +l). Example Z-38:
Sodium racemic -(4aS,6aSj4aS)-10-({[(2,4^difluorophenv])methyl.lamino}carbonyl)-6-(2-methyl
propyl)- ll.,13-dioxo- 1,2.3.d.4a.5.6.6a.7,1l. l3.14a-dodocahydropyrido[1',2':4,5]pyrazino[
1,2-a]ouina^olin- 12-olate.
Figure imgf000182_0001
a) racemic -3 , 1-Diiriethylethyl [(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate.
racemic [(.lI?.,2S,5S)'2-Axnino-5-i^henylcyclohexyl]moth&iiol hydrochloride (800 mg,
4.82 mmol) was dissolved in MeOH (40 mL) and bis(1, 1-dimethylethyl) dicarbonate
(1, 16 g, 5.30 mmol) and t.riethylamine (4 mL, 28,92 mmol) were added and the
mixture was stirred 18 hours at ambient temperature. The solvents were removed
under reduced pressure, ethyl acetate and aqueous saturated sodium bicarbonate
were added and the product was extracted with ethyl acetate. The combined
organics were dried over sodium sulfate and the solvents were removed under reduced
pressure. Purification by silica gel chromatography (9U hexanos'- ethyl acetate to
ethyl acetate gradient elution) gave 1, 1-dimethylethyl
racemicH(1S,2Il)-2-(hydroxymethyl)eyclohexyl]carbamate (934 mg, 85%) as a white
solid. 1H NMR (CDCl3) δ 4.87 [m, 3 H), 4.03-3.95 (m, 2 H), 3.26 (m, 1 H), 3, 15 Cm, 1
H), 1,73- 1,48 (m, 5 H), 1 38 (s, 9 H). 1.27- 1, 15 (m, 3 H), 0.887 (m, 1 H),
b) racemic -l .1-Dimethylethyl t(1S,2R)-2-Formylcyclohexyl]carbamate. To a solution of dimethylsulfoxide (0.2 mJL, 2,88 mmol) in dichloromethane (3 mL) at -78 "C
was added oxalyl chloride (0.72 mL, 1.44 mmol) dropwise. The mixture was stirred
10 minutes and racaw.K.'-1.1-dimethylethyl
[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamaie (220 mg, 0.961 mmol) in
dichlormethane was added dropwise and stirred 10 minutes, Triethylamine (0.53 mL,
3.84 mmol) was added slowly and the reaction was stirred at -78 "C for one hour and
allowed to warm to ambαent temperature. Water was added and product was
extracted with dichloromethano, The combined organics were washed with brine and
dried over sodium sulfate. Removal of solvents under reduced pressure afforded
raccmicΛ, 1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (223 mg,
quantitative) as a yellow oil. 1H NMR (CDCl3) δ 9.61 (s, 1 H), 5.19 (m, 1 H), 3,88 (m,
1 H), 2.61 (m, 1 H), 1.85 (m, 1 H), 1.63-1,49 (m, 4 H), 1.37- 1 16 (m, 12 H),
c) 2-acei«/c- 1,1-dimet,hylethyl ((1S,2S)-2-{[(2-Methylpropyl)amino] methyl}
cyclohexyl)carbamate, race.mitrl.1-Dimethylethyl
[(1S,2R)-2-formylcyclohexyl]carbamate (223 mg, 0 982 mmol) was dissolved in
dichloroethane and 2-methylpropyl)amine (0.15 mL, 1.47 mmol) and sodium
triacetoxyborohydride (290 mg, 1.37 mmol) were added and the reaction was stirred
at ambient temperature for 18 hours. Aqueous sodium bicarbonate was added and
the product was extracted with dichloromethane. The combined extracts were dried
over sodium sulfate and the solvents were removed under reduced pressure.
Purification by silica gel chromatography (dichloromethane to 1% ammonium
hydroxide 19% methanol 80% dichloromethane gradient elution) afforded vacanic] , 1 -dimethylethyl
((1S,2S)-2-{[(2-methylpropyl)amino]methyl}cycIohGxyl)carbamate (112 mg-, AOVa) as a
clear colorless oil. ]H NMR (CDCL3) δ 6.06 (br s, 1 H), 3.76 (br s, 1 H), 2.63 (m, 1 H),
2,43-2.37 (m, 2 H), 2.25 (m, 1 H), 1.81 (m, 1 H), 1.71- 1.59 (m, 3 H), 3 .44- 1.32 (m, H H),
1.27- 1.19 (m, 2 H), 0.866 (m, 6 H).
d) racc?222ib-(1S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclohexanamine
hydrochloride.
In a manner similar to that describe in example Z-3, step o, from
raaβmic -1,1 -dimethylethyl ((1S,2S)-2-{[(2-methylpropyl)amino]methyl}
cyclohexyl)carbamate (112 mg, 0.394 mmol) was prepared
(1S,2S)-2- {r(2-methylpropyl)aminolmethyl}cyclohexanamine hydrochloride Q 30 mg, >
100%) as a white solid. 1H NMR (methanol-rfi/CDClj) δ 8,68-8.28 (m, 1 H), 3.62 (br
s, 1 H), 3.26 (m, 1 H), 2.83-2.78 Cm, 3 H), 2.54 (br s, 3 H), 2. Vl (m, 1 H), 1 82- 1 66 (m,
3 H), 1,53- 1,39 (m, 5 H), 0.96 (m, 6 H). 0.766 (m, 1 H).
e)
race77wσ-(4aS,6aS, 14aS)-N-[(2,4-DifKiorophenyl)methyl]-6-(2-methylpropyl)-11
, 13-dioxo-12-[(phenylmethyl)oxyl- 1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2'
^4,5] pyrazino[1,2-a]qninazoline-10-carboxamide. In a manner similar to that
described an Z-35, from
i-acei33yc-(1S,2S)-2-{[(2-methylpropy])amino]methyl}cyclohexanamine hydrochloride
(130 mg, 0.508 mmol) and 16a (55 mg, 0. LK 7 mmol) was prepared race«7Jrc-(4aS,6aS, 14aS)-N- [(2,4-difluorophenyl)methyl]-6-(2-methylpropyl)-11,13-diox
o-12-r(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13, 14a-dodecahydropyridolll,2l:4,5]
pyrazino[1,2-a]quinazoline-10-carboxamide (44 mg, 62%) with a 12: 1 d.r. 1H NMR
(CDCl3) δ 10.46 (m, 1H), 8.33 (s, 1 H), 7,59 (m, 2 H), 7.37-7,24 (m, 4 H), 6.79 (m, 2 H),
5.30-5,23 (m, 2 H), 4.75-4,56 (m, 3 H), 4.23-4.09 (m, 3 H), 2.69-2,66 (m, 2 H), 2.21- 1.98
(m, 3 H), 1,80 (m, 1 H), 1.71-1.33 (m, 6 H), 1.26- 1 19 (m, 2 H), 0.810 (m, 3 H), 0.720 (m,
3 H); ES+ MS. 605 (M +1).
f)
race7nyc-(4aS,6aS, 14aS)-N- [(2,4-Difluorophenyl)methyl] - 12-hydroxy-6-(2-meth
ylpropyl)- H, 13-dioxo- 1,2,3 A4a,5, 6,6a, 7, 11, 13, 14a-dodecahydropyridoll\2V4, 5jpyrazin
o[1,2-a]quinazoline- - 0-carboxamide. In a manner similar to thai, described in
example Z-37, from
race7»ic-(4aS,6aS, 14aS)-N-[(2,4-difluorophenyl)methyl]-6-(2-methylpropyl)- 11, l3-diox
o-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7, 11, 13, 14a-dodecahydropyridoLr,2':4,5]
pyrazino[1,2-a]quinazoline- 10-caχ-boxamide (39 mg, 0.064 mmol) and 10 w.i. % Pd/C (7
mg) was prepared
i"acc773ic-(4aS,6aS, 14aS)-N- r(2,4-difluorophenyl)methyl]- 12-hydroxy-6-(2-meihylp)-opyl)
- I l, 13-dioxo-1,2,3,4,4a,5,6,6a,7,11,] 3,14a-dodecahydropyrido[1',2':4,5]pyrazjno[1,2-ajq
uinazoline-10-carboxamide (36 mg, > 100%) as a tan solid. 1H NMR (CDC],)) δ 12.60
(br s, 1 H), 10.43 (br s, 1 H), 8.25 (s, 1 H), 7.35 (m, 1 H), 6.78 (m, 2 H), 4.77 (m, 1 H),
4.63 (m, 2 H), 4.49 (br s, 1 H), 4.30-4.13 (m, 2 H), 3,63-3.40 (m, 2 Ii), 2.88-2.71 (m, 2
H), 2.32-2.21 (m, 2 H), 2.05 (m, 1 H), 1.88- 1.13 (m, 7 H), 0.830 (m, 3 H), 0.760 (m, 3 H); AP 1- MS: 515 (M +l).
g) Sodium racemic -(4aS,6aS, 14aS)-10-({[(2,4-Diflιιorophenyl)methyl]amino}carbonyl)-6-(2-methyl
propyl)- 11, 13-dioxo-1,2,3,4,4a,5,6,6a,7, 11, 13,14a-dodecahydropyrido[1',2':4,5]pyrazinor
1,2-a]quinazo)in-12-olale. In a manner similar to thai described in example Z- 1,
from racemic -(4aS,6aS,14aS)-N- r(2,4-diπuorophenyl)methyI]-12-hydroxy-6-(2-methylpropyl)
- Il, 13-dioxo- 1,2,3,4,4a,5,e,6a,7, 11i l3, 14a-dodecahydropyriclo[r,2l:4,5]pyrazinoh ,2-a]q
uinazoline-10-carboxamide (37 mg, 0.071 mmol) and 1 N sodium hydroxide (0,07 mL)
the title compound was prepared as a yellow solid (26 mg, 68 %). 1H NMR
(J)MSO- dβ) δ 10.73 (m, 1 H), 7.94 (β, 1 H), 7.32 (m, 1 H), 7,19 (m, 1 H), 7 00 (m, 1 PI),
4.59-4.41 (m, 3 H), 4.28 (m, 2 H), 4.14 (br s, 1 H), 2.63-2.60 (m, 2 H), 1.98- 1.61 (m, 5
H), 1 48- 1,36 (m, 4 H), 0.997 (m, 3 H), 0.760 (m, 3 H), 0.6G0 (m, 2 H); AP"1 MS: 515
(M +1 of free acid).
Example Z- 39:
(6aR.7aS,1l aS)-N-|(2,4-ϋifluoronhenyl)methyl]- l-hydroxy-2,13-dioxo-2.6a.7,7a,8.9, 10.
11.11a. lS-decahydro-βH-PVrido[1',2':4,5]pyraaino[1.∑-a.lbonziniidazolo-S-carboxamidc
.& Example Z-4Q:
(6aS,7aS. HaS)-N- [(2.4-Difluorophenyl)methyl]-l-hydroxy-2.13-dioxo-2.6a,7, 7a, 8.9, 10.
11.1 l a. lS-dQcahydro-GH-pyrido[1',2':4,5]pyrazino[1.∑-albGnzimidazolo-S-carboxamide.
Figure imgf000187_0001
a)
(6aR,7aS, 11aS)-N- [(2, 4-Difluorophenyl)methyn-2,13-dioxo-1-[(phenylmethyl)o
-xy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido [}',2':4,δ] pyrazino[l ,2-a]
benzamidazαle-3-carboxaiτiide and
(6aS,7aS,11aS)-N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phGnyImethyl)oxy]-2,6a,
7,7a,8,9, 10,11,11a,13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazole-3-ca
rboxamide. In a manner similar to that described in example Z-2, from
[(1S,2S)-2-aminocyclohexyl]amine (122 mg, 107 mrnol) and 16a (200 mg-, 0426 mmol)
was prepared
(6all,7aS,11aS)-N-[(2,4-diΩuoi.-ophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxyl-2,6a,
7, 7a, 8, 9, 10, J 1, 11a, 33-decahydro-βH-pyrido f l',2':4,5j pyrazino[1,2-aj
benzimidazolo-3-carboxamide (58 mg) and
(6aS,7aS,31aS)-N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,
7, 7a, 8, 9, 10,11, 1 Ia,13 -deca hydro- 6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazolo-3-ca
rboxamide (.10.6 mg) after separation of the diastorcomers using silica gel
chromatography (0-12% methanol/dichloromethane),
(6aR,7aS,11aS)-N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-f(phenylmethyl)oxy]-2,6a,
7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido [1',21M, 5] pyrazino[1,2-a]
benzimidazole-3-carboxamide (major): 1H NMR (CDCk) δ 10.40 (m, 1 H), 8.33 (s, 1
H), 7.57 (m, 2 H), 7.40-7.25 (m, Λ H), 681 (m, 2 H), 5.32 (d, J= 10 Hz, 1 H), 5.13 (d, J = 10 Hz, 1 H), 4.64-4.58 (m, 3 H), 4,21 (dd, J = 12,4, 3,2 11«, 1 H), 3,79 (m, 1 H), 3,04
(m, 1 H), 2.73 (m, 1 H), 2,53 (m, 1 H), 2.01- 1.79 (m, 4 H), 1.36- 1.24 (m, 4 H); ES+ MS:
535 (M +1).
(6aS,7aS, n aS)-N- [(2,4-difluorophenyl)methyl]-2, 13-dioxo-1-[(phenylmethyl)oxy] -2,6a,
7,7a,8,9, 10, 11, 11a, 13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazole-3-ca
rboxamide (minor diastcroomer): 1H NMR (CDCl3) δ 10,33 (m, 1 H), 8,28 (s, 1 H),
7,61 (m, 2 H), 7,39-7,28 (m, 3 H), 6.79 (m, 2 H), 5,29 (d, J = 9,6 Hz, 1 H), 5.05 (d, J =
9,6 Hz, 1 H), 4 ,84 (m, 1 H), 4,C0 (m, 2 H), 3.90-3,84 (m, 2 H), 3,07 (m, 1 H), 2,75 (m, 1
H), 2 49 (m, 1 H), 2,07 (m, 1 H), 1,90- 1 51 (m, 4 H), 1 33- 1, 19 (m, 4 H); MS data
matehes that of its diastereomer,
b) (For example Z- 39),
(6aR,7aS, 11aS)-N-[(2,4-Difluorophenyl)methyl] -1-hydroxy-2, K3-dioxo-2,6a,7,7a,8,9, 10,
11, 11a, 13-decahydro-6Ii-pyrido[1',2':4,5]pyrazinoli ,2-a]benzimidazole-3-carboxamide.
In a manner similar Lo that described in example Z-37, from the minor diastcroomer
prepared in stop a
(6aS,7aS, 11aS)-N- [(2, 4-difluorophenyl)methyl]-2, 13-dioxo-1-[(phenylmethyl)oxy]-2,6a,
7,7a,8,9, 10, 11, 11a, 13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazolo-3-ca
rboxamide (7 mg, 0,0131 mmol) and 10 w,t, % Pd/C (catalytic amount) was prepared
(6aR,7aS, 11aS)-N-[(2,4-difJuorophenyl)methyl]-1-hydroxy-2, 13-dioxo-2,6a,7,7a,8,9, 10,
l 1, 11a, 13-decahydro-6H-pyrido[1',2':4,5]pyrazino(1,2-a]benzimidaz;ole-3-carboxamide
(2.8 mg, 48%) after purification by HPLC. 1H NMIi (CDCl,?) δ 12.15 (br s, 1 H),
10,42 (br s, 1 H), 8,31 (s, 1 H), 7.36 (m, 1 H), 6.80 (m, 2 H), 5,01 (m, 1 H), 4,63 (m, 2 H), 4.16 (m, 1 H), 3.96 (m, 1H), 3.06-2.93 (m, 2 H), 2,61 (m, 1 H), 2,18 (m, 1 H), 1.90
(m, 1 H), 1.60-1,13 (m, 4 H), 0,893-0.840 (m, 2 H); ES+" MS: 445 (M+l).
c) (For example Z-40).
(6aS,7aS,11aS)-N-[(2,4-Difluorophenyl)mci,hyl]-t-hydroxy-2,13-dioxo-2,6a,7, 7a,8,9,10,
11,11a, 13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazolo-3-carboxa]nide.
In a manner similar to that described in example Z- 37, from the major diastoreomer
(30 mg, 0,0561 mmol) prepared in step a and 10 w.t. % Pd/C (catalytic amount),
(6aS,7aS,llaS)-N-[(2,4-Difluo]Ophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,
l.l,11a,-3-decaliydrc>ι-6H-pyrido[1',2':4,5]pyrazπiol1,2-a]bαnzimjdazole-3-carboxamide
was prepared as a white solid (15 mg, 60%) after purification by HPLC, 1H NMR
(methanol- d4/CDCl3) δ 10.41 (m, 1 H), 8,25 (s, 1 H), 7,30 (m, 1 H), 6.77 (m, 2 H), 4.77
(m, 1 H ), 4,57 (m, 2 H), 4.45 (m, 1 H), 3.91 (m, 1 H), 3.12 (m, _ H), 2,67 (m, 1 H), 2,12
(m, 1 H), 1,87-1,84 (m, 2 H), 1,47-1.33 (m, 4 H); ES+" MS: 445 (M +1).
Example Z-41:
(5aS.HaS)-N-l(2.4-Difluoronhenyl)methyn-11-hydroxv 10, 12-dioxo- 1.2.3.4,5a.6, 10, 12.
14.14a-decahydropyrido[],2-a]pyrido[l',2'!8.4]imida'/o[1,2-d]pyrazinG-9-carbQxamide,
Figure imgf000189_0001
(5aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-10,12-dioxo-11-[(phGnyhnethyl)oxy]- 1,2,3,4 .Sa.O.10. lB. ld.14a-decahydropyridon ,2-a lpyridoll',2'JS.iJimidazo[1,2-d]pyrazine-O-car
boxamide, In a manner similar to that described in example Z- 18, from 16a (50 mg,
0.108 mmol) and [(2S)-2-piperidinylmethyl]amine hydrochloride (50 mg, 0.2B9 mmol,
made in a similar manner as described in example Z- 18) was prepared
(5aS, 14aS)-N-[(2,4-difluorophenyl)methyl]-10, 12-dioxo- 11- [(phenylmethyl)oxyj- 1,2,3,-1,
5a,6, 10, 12, 14, 14a-decahydropyrido[1,2-a]pyridoU\2':3,4]imidazo[1,2-d]pyrazine-9-car
boxamide (40 mg, 78 %), 1H NMR (CDCL3) δ 10.43 (m, 1 H), 8,38 (s, 3 H), 7,59 (m, 2
H), 7,59-7.25 (m, 4 H), 6,81 (m, 2 H), 5,38 (d, J= 10 Hz, 1 H), 5, 19 (d, J= 10 Hz, 1 H),
4.65-4,62 (m, 2 H), 4 20 (dd, J= 12, 2,8 Hz, 1 H), 4,00 (dd, J= I ZA, 2,8 Hz, 1 H), 3,85
(m, 1 H), 3.74 (m, 1 H), 3.27 (m, 1 H), 2,99 (m, 1 H), 2.43 (m, 1 H), 2,24 (m, 1 H),
1.94- 1.87 (m, 2 H), 1,77- 1,58 (m, 2 H), 1,39- 1,24 (m, 2 H); ES 1 MS: 535 (M + l)
b)
(5aS, 14aS)-N-[(2,4-Difluorophenyl)methyl]-11 -hydroxy- 10, 12-dioxo- 1,2,3, 4,5a, 6, 10, 12,
14, 14a-decahydropyrido[1,2-a]pyridoll',2':3,4]imidazo[1,2-d]pyrazine-9-carboxamide.
Tn a manner similar to that desw ibed in example Z-37, from
(5aS, 14aS)-N-[(2,4-diflυorophenyl)methyl]-10, 12-dioxo-11- [(phenylmethyl)oxy]- 1,2,3,4,
5a, 6, 10, 12, 14, 14a-decahydropyrido[1,2-a]pyrido[r,2'.3,4]imidazo[1,2-d]pyrazine-9-car
boxamide (18 mg, 0.0337 mmol) and J 0 w.t.% Pd/C (catalytic amount) was prepared
the title compound as a white solid (13 mg, 87%) after purification by HPLC, 1H
NMR (CDCl,?) δ J 1,71 (br s, 1 H), 10.36 (br s, 1 H), 8.31 (s, 1 H), 7.34 (m, 1 H), 6.78
(m, 2 H), 4.64-4.57 (m, 2 H), 4,28 (m, 1 H), 4, 12 (m, 1 H), 3.92-3,89 (m, 2 H), 3,22 (m, 1
H), 3.04 (m, 1 H), 2.49 (m, 1 H), 2.28 (m, 1 H), 1.97-1.89 (m, 2 H), 1.78 (m, 1 H), 1.66- 1.60 (m, 2 H), 1.43- 1.36 (m, 2 H) i ES+ MS: 445 (M +1).
Example Z-42:
(4aIl. l4aR)-N- [(2,4-Difluorophenyl)mcihyll-9-hvdroxy8, 10-dioxo-2.3,4,4a.5.6.8, 10.14,
14a>decahydro- lH-Pyrido[1,2-c]pyridoi I',2':4.δ1pyra2inol,1,2-a1pyrimidine- 11-carboxam
ide.
Figure imgf000191_0001
a) Phenylmethyl (2R)-2"(hydroxymethyl)-1"piperidinecarboxylate. in a manner
similar - to that described in example Z"3a, from
(2R)-1-{| (phenylmethyl)oxylcarbonyl}-2-pjpendinecai"boxylic acid (4.93 g, 18.75 mmol)
was prepared pheαylmethyl (2R)-2-(hydroxymethyl)- 1-piperidinecarboxylate (2.24 g,
48%) as an oil that solidified upon standing to a whito solid . 1H NMR (CDCl3) δ
7.3G-7 26 (m, 5 H), 5..18-5.10 (m, 2 H), 4.37 (m, 1 H), 4.03 (m, 1 H), 3.84 (, m, 1 H),
3.63 (m, 1 H), 2,96 (br s, 1 H), _ ,71- 1.42 (m, 6 H),
b) Phenylmethyl (2R)-2-(cyanomethyl)-1-piperidinecarboxylatc, Tn a manner
similar to that described in example Z-3b, from phenylmethyl
(2R)-2-(hydroxymethyl)- 1-piperidinecarboxylatc O .0Og, 4,38 mmol) was prepared
phenyl methyl (2R) -2- ({1(4 -methylphenyl)sulfonyl]oxy} methyl) -1-piperidinecarboxy late
(1.05g, 59% impure with uncharacterizod byproduct) as a clear colorless oil after
purification using silica gel chromatography (10- 100% ethyl acetate-hexanes). It is necessary to use lhis material in the next step as soon as possible or yields
deteriorate dramatically, I n a manner similar to that described in example Z-3c,
from phenylmethyl
(2R)-2r({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylatc (1,05 g, 2,61
mmol) and sodium cyanide (383 mg, 7,82 mmol) was prepared phenylmethyl
(2Tt)-2-(cyanomethyl)-1-pipeπdinecarboxylate (171 mg, 25 %) as a yellow oil, 1H
NMR (CDClϋ) δ 7.35-7,29 (m, 5 H), 5, 13 (s, 2 H), 4,65 (m, 1 H), 4, 10 (m, 1 H), 2.96 (m,
I H), 2,60 (m, 2 H), 1,82- 1.67 (m, 4 H), 1.54- 1.39 (m, 2 H).
d) Phenylmethyl (2R)-2-(2-aminoethyl)-1-piporidmecarboxylatc. In a mannαr
similar to that described in example Z-Sd, from phenylmethyl
(2R.)-2-(cyanomethyl)-1-piperidinecarboxylate (171 mg, 0.663 mmol) was prepared
phenylmethyl (2R)-2-(2-aminoethyl)-1-piperidinecarboxylate (119 mg, 68%) as a cloar
colorless residue, 1H NMR (CDCl3) δ 7,32-7,25 (m, 5 H), 5.08 (m, 2 H), 4.39 (br s, 1
H), 4.01 (br s, 1 H), 2,78 (m, 3 H), 2,60-2,56 (m, 2 H), 1,05-1,86 (m, 3 H), 1,63- 1,35 (m,
6 H).
e) {2- [(2R)-2-Piperidinyl]ethyl}amino, Phonylmethyl
(2R)-2-(2-aminoethyl)-1-piperidinecarboxylate (119 mg, 0 454 mmol) was dissolved in
methanol and 10 w.t.% Pd/C (120 mg) was added, Hydrogen was bubbled through
the solution for 15 minutes and the reaction was stirred under 1 atm hydrogen for 18
hours until determined complete by TLC (1% ammonium hydroxide 19% methanol
80% dichloromethane). The suspension was filtered through Celite eluting with methanol and the filtrate was carefully concentrated unci or reduce pressure to yiold a
clear colorless liquid (58 mg, quantitative). Ui NMR (CDCL3) δ 2.99 (m, 1 H),
2,71-2,66 (m, 2 H), 2.57-2.48 (m, 2 H), 1.72 (m, 1 H), 1.61- 1.52 (m, 2 H), 1,48- 1.42 (m,
2 H), 1.35- 1 25 (m, 2 H), 1.05 (m, 1 H).
f)
(4aR, 14aR)-N- [(2,4-Difluorophenyl)methyl]-8, 10-dioxo-9-[(phenylmethyl)oxy] -
2,3,4,4a,5,6,8, 10, 14, 14a-decahydro- 1H-pyrido[1,2-cJpyridoll1,2':4,5]pyrazino[1,2-a]pyri
midine- 11-carboxamide. In a manner similar to that described in example Z-35, from
16a (50 mg, 0, 106 mmol) and {2-[(2R)-2-piperidinyl]ethyl}amme (58 mg, 0,454 mmol)
was prepared
(4aR, 14aR)-N-[(2,4-difluorophenyl)methyl] -8, 10-dioxo-9-[(phenylmethyl)oxy] -2,3,4,4a,
5,6,8, 10, 14, 14a -deca hydro- 1H-pyrido[1,2-c]pyrido[r,2':4,5]pyrazino[1,2-a]pyrimidme-1
1-carboxamide (47 mg, 81%). >H NMR (CDCI3) δ 10.50 (br s, 1 H), 8.33 (s, 1 H),
7.60 (s, 2 H), 7,38-7,24 (m, 4 H), 6,80 (m, 2 H), 5.29-5.22 (m, 2 H), 4.66-4.56 (m, 3 H),
4.30 (m, 1 H), 4, 19 (m, 1 H), 3,78 (br s, 1 H), 2,86-2,80 (m, 2 H), 2, 18 (br s, 1 H), 1,94
(m, 1 H), 1,68- 1.36 (m, 6 H), 1,23 (br s, 2 H); ES+ MS: 549 (M +l).
g)
(4aR, 14aR)-N-[(2,4 -Diflυorophenyl)methyl]-9-hydroxy-8, 10-dioxo-2,3,4,4a,5,6,
8, 10, 14, 14a-decahydro- JH-pyridoii ,2-c)pyrido[1',2':4,5]pyrazino[1,2-a]pynmidine-1J -c
arboxamide. In a manner similar to that described in example Z-37, from
(4aR, 14aR)-N-[(2,4-difluorophenyl)methyl] -8, 10-dioxo-9- [(phenylmcihyl)oxy]-2,3,4,4a, 5.β.β.10. H. l4a-decahydro- 1H-pyridoL1,2-cJpyridoll',2 ^4.5jpyrazino[1, 2-a]pyrimidinβ-1
1-cai?boxamide (47 mg, 0,0857 mmol) and a catalytic amount of 10 w,t,% Pd/C was
prepared tho title compound as a white solid (19 mg, 54%) after purification by HPLC.
)R NMR (CDCl3) δ 10.49 (m, 1 H), 8.29 (s, 1 H), 7,34 (m, 1 H), 6,79 (m, 2 H),
4.67-4.56 (m, 3 H), 4.41 (m, 1 H), 4.20 (m, 1 H), 3,93 (s, 1 H), 2,94-2,87 (m, 2 H), 2,28
(br s, 1 H), 2,01 (m, 1 H), 1.68- 1,54 (m, 4 H), 1.44 (m, 1 H), 1.29- 1.23 (m, 3 H), 0,850
(m, 1 H); ES-" MS: 459 (M +1).
Example Z-43:
(4R, 12ai?)-//-[(2,4-Difluorophenyl)methyl] -7-hydroxy-4-methyl-1-(3-methylbutyl)-6.8-d
ioxo- 1,2.3,4,6,8, 12, 12a-octahydropιyrido[1',2':4,5]pyra2ino[1,2-fl1pyrimidine-9-carboxa
mide.
a) [(3R)-3-Amobutyl](3-methylbulyl)amino d ihydrochloride was prepared in a
similar manner as described in example Z-32. 1H NMR (400 MHz, CDCI3/CD3OD) δ
0.87 (d, J = 5.2 Hz, 6H), 1.32 (m, 3H), 1,61 (m, 3H), 2, 10-2,20 (m, 211), 2.90-3.04 (m,
411), 3,45 (m, J H), 8.23 (br, < 1 H), 8.96 (br, < 1 H)._
b)
(4R, 12aR)-N- [(2,4 -Dfluorophenyl)methyl]-7-hydroxy-4-methyl- 1-(3-methylbutyl)-6,8-di
oxo- 1,2,3,4,6,8, ] 2, ] 2a-octahydropyrido[1',2':4,5]pyrazinol3 ,2-/i]pyrimidine-9-carboxam ide. The UUo compound was made in two slops using a similar process to that
described in example Z-2. 16a (40 mg, 0,085 raraol) and free
[(37?)-3-aminobutyl] (3-methylbutyl)amine (46 mg, 0,35 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(4R, 12a/^)-N- [(2,4-difluorophenyl)methyl]-4-methyl-1-(3-methylbutyl)-6,8-dioxo-7- |(ph
GnyLmethyl)oxy]- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine
-9-carboxamide (44 mg, 90%) as a film, This material was hydrogenated in a second
step as described in example Z-2 to give
(4R, 12aR)-.N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl- 1-(3-methylbntyl)-6,8-d
ioxo- 1,2,3,4,6, 8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[ 1,2- a]pyrimidine-9-carboxa
mide (11 mg, 30%) as an off-white faohd 1H NM R (400 MHz, CDCId) δ 0.84 (d, J = 6,8
HU, 3H), 0.86 (d, J = 6.8 Hz, 3H), 1.24- 1.80 (m, 5H), 1,47- 1.53 (m, 2H), 2 02-2.11 (m,
1H), 2,36-2.43 (m, 1H), 2,54-2,61 (m, 1H), 2.77-2,92 (m, 2H), 4.16-4.26 (m, 2H), 4.44
(m, 1H), 4,02-4,64 (m, 2H), 4 95-5,02 (m, 1H), 6 75-6,83 (m, 2H), 7,31-7 37 (m, 1H),
8,27 (s, 1H), 10 43 (m, 1H), 12,54 (s, 1H) ; BS ' MS" 489 (M+l),
Example Z-44:
(4^, 12aS)-N-[(2,4-Ωifltιorophenyl)methy]l-7-hydroxy4-methyl-l-(l-methylethyl)-6,8-di
oxQ- 1 , 2.3, 4 Jo, 8.12.12a-octahydropyrido[1',2':4,5]pyraziπo[3 ,2-a]pyrimidine-9-carboxam
ide,
Figure imgf000195_0001
a) [(3*S)-3-Aminobutyl](1-methylethyl)amine dihydrochlonde was prepared in a
similar manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CDaOD) δ
1.20- 1.25 (m, 9H), 1.93-2.02 (m, 2H), 2,92 (m, 2H), 3.20-3.29 (m, 2H), 8 04 (br, < 1 H),
8.64 (br, < 1 H).
b)
(4S, 12aS)--N-[(2,4-Difluorophenyl)iriethyl]-7-hydroxy-4-methyl-1-(1-methylothyl)-6,8-di
oxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[l ,2-a]pyrimidine-9-carboxam
ido The title compound was made in two stops using a similar process, to that
described in example Z-2, 16a (60 mg, 0.13 mmol) and free based
[(3.S)-3-aminobutyl](1-methylethyl)amine (55 mg, 0,42 mmol) were reacted in
dichloromethane (2 inL) with acetic acid to give
(4S, 12aS)-N [(2,4-difluorophenyl)methyl] -4-methyM-(1-methylethyl)-6,8-dioxo-7-[(pho
nylmethyl)oxy] - 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-
9-carboxamide (40 mg, 57%) as a film. This material was hydrogenated in a second
step as described in example %-2 to givo
(4S, 12aSl-ΛA[(2,4-difluorophenyl)methyl]-7-hydioxy-4-methyM-(1-methylethyl)-6,8-di
oxo- 1,2,3,4,6,8, 12, 12a-Octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxam
idc (17 mg, 50%) as an off-white solid. 1H NMR (400 MHz, COCb) 8 1 02 (d, J = 6.4
Hz, 3H), 1,07 (d, J = 6.4 Hz, 3H), 1.33 (d, J= 7.2 Hz, 3H), 1.55- 1,58 (m, 1H), 1.94-2.03
(m, 1H), 2.70-2.77 (m, 1H), 2.81-2,86 (m, 1H), 3,11-3 18 (m, 1H), 4.17 (dd, J= 3 0, 13.8
Hz, 1H), 4.32 (dd, J= 3 2, 14.0 Hz, 1H), A 48 (m, 1H), 4.59-4.69 (m, 2H), 4.97-5,00 (m,
1H), 6.77-6 83 (m, 2H), 7.33-7.39 (m, 1H), 8,28 (s, 1H), 10.50 (m, 1H), 12.55 (s, 1H);
3 94 ES+ MS: 461 (M+l),
Example Z-45:
(4S, 12aS)-N-[ (2.4-Difluorophenyl)methyl] -7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-d
ioxo- 1,2.3.4.6.8.12.12a-octahydropyrido[1',2':4,5]pyrazino[1,2- a]pyrimidine-9-carboxa
mide.
Figure imgf000197_0001
a) [(3S)-3-Aminobutyl](3-methylbutyl)amine dihydrochloride was prepared in a
similar manner as described in example Z-32. 1H NMR (400 MHz, CDCl3/CD3OD) δ
0.86 (d, J = 5.6 Hz, 6H), 1.27 (d, J = 6.0 Hz, 3H), 1.58 (m, 3H), 2.03-2.14 (m, 2H),
2.87-2.99 (m, 4H), 3.38 (m, 1H), 8.15 (br, < 1 H), 8.87 (br, < 1 H) .
b)
(4S, 12aS)-N-f(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-d
ioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimadine-9-carboxa
mide, The title compound was made in two steps using a similar process to that
described in example Z-2. 16a (0.100 g, 0,21 mmol) and free based
[(3S)-3-aminobutyl](3-methylbutyl)amine (0. 104 g, 0 66 mmol) were reacted in
dichloromethane (2 ml) with acetic acid to give
(4S, 12aS)- N-[(2,4-difluorophenyl)methyl]-4-methyl- 1-(3-methylbutyl)-6,8-dioxo-7-[(ph
enylmethyl)oxy]- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1 ,2-a]pyrimidine -9-carboxamide (88 mg, 72%) as a film, This material was hydrogenatcd in a second
step as described in example Z-2 to give
(4S, 12aS)-iV;[(2,4 -difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-di
oxo- 1,2,3,4,6,8, 12, 12a-oclahydropyrido[1',2':4,5]pyras;ino[1,2-s]pyriinidine-9-carboxam
idc (55 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 0,84 (d, J - 6.4 Hz, 3H), 0.85 (d , J =
6,4 Hz, 3H), 1,24- 1,37 (m, 5H), 1.45- 1,63 (m, 2H), 2,02-2, 11 (m, 1H), 2,37-2,44 (m, 1H),
2.56-2.63 (m, 1H), 2.80-2.92 (m, 2H), 4,22-4.29 (m, 2H), 4.45 (s, 1H), 4.62-4.63 (m, 2H),
4,97-5,00 (m, 1H), 6,75-6,82 (m, 2H), 7.31-7.37 (m, 1H), 8,37 (s, 1H), 10.48 (m, 3 H),
12.53 (br, 1H); ES+ MS: 489 (M+ 1).
Example Z-46:
(4ig42a^-Λ^ [(2.4-UiΩuorophenyl)methyl]-ι7-hydroxy-4-mΘthyi-6.8-dioxo^-(3-i3yridinyl
methyl)- 1,2,3,4,6.8, 12, 12a-octahydropyrido[1',2':4,5]pyx'a2ino [LJL- a) py.ri m id ino-9-carbo
xamide.
Figure imgf000198_0001
a) 1, 1-Dimethylethyl {(l S)-1-methyl-3- [(3-pyridinylmethyl)amino]propyl}carbamaLe.
The protected diamine was prepared using a modified procedure as described in
example Z-32 A solution of I, 1-dπnethylethyl
[(l £)-3-amino-1-methylpropyl]carbamate (0.296 g, 1.6 mmol) and
3-pyridinocarboxaldohyde (120 μL, 1 3 mmol) in a 1.1 mixluro of anhydiouw
dichloroethane and totrahydrofuran (10 mL) was treated with acetic acid (374 μL, 6.6 mmol) and stirred for Li0 minutes. Sodium triacetoxyborohydride (0,444 g, 2, 1 inmol)
was added and tho solution was stirred for 2 hours, The resultant was subjected to a
workup and purification procedure as described in example Z-32 to give
1, 1 -dime thylethyl {(1£V 1-methyl-3-[(3-pyridinylmethy0amino]propyl}carbamate
(0.245 g, 66%) as a clear oil. 1H NMR (400 MHz, CDCl3) 6 1. Ϊ 2 (d, c/ = 6.4 Hz, 3H),
1,42 (s, 9H), 1.46- 1,54 (m, 1H), 1,68 (m, 1H), 2,61-2.75 (m, 2H), 3.73- 3,80 (m, 3H),
4,86 (m, 1H), 7.22-7.24 (m, 1H), 7.68 (d, J~ 8.0 HU, 1H), 8.48 (m, 1H), 8,53 (m, 1H).
b) [(3S)-3-Aminobutyl](3-pyridinylmethyl)amine dihydrochloride was prepared in a
similar manner as described in example Z-29.
c)
(4S, 12ajS)--N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4 -methyl-6,8-dioxo-1-(3-pyridinyl
methyl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-ajpyrimidine-9-carbo
xamide. The title compound was made in two steps using a similar process to that
described in example Z-2, 16a (60 mg, 0.13 mmol) and free based
[(3S)-3-aminobutyl](3-pyridinylmethyl)amine (83 mg, 0.47 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to gjvo
US, 12a»5)-^/- [(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7- [(phenylmethyl)oxy| -1-
(3-pyridinylmethyl)- 1,2.S,4.e^.12.12a-octahydropyrido[1',2':4,5]pyrazino[1,2-aipyiimi
dine-9-carboxamide (72 mg, 95%) as a film. This material was hydrogenated in a
second step as described in example Z-2 to give
(4S, 12a»δ)-N-[(2,4-diflxiorophenyl)methyl] -7-hydroxy-4-methyl-6,8-dioxo-1-(3-pyridinyl
J 97 methyl)- 1,2,3,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carbo
xamidβ (3d mg, 56%) as an off-white solid. >H NMR (400 MHz, CDCl3) δ 1.37 (d, J -
6.8 Hu, 3H), 1.43- 1,47 (m, 1H), 2, 12 (m, 1H), 2,60-2 92 (m, 2H), 3 53 (d, J - 1-1.0 Hz,
1H). 3.82 (d, J = 34,4 Hz, 1H), 4.23-4 ,31 (m, 2H), 4.55-4.64 (m, 3H), 5.06-5, 11 (m, 1H),
6.75-6,82 (m, 2H), 7,20-7,20 (m, 1H), 7,31-7,36 (m, 1H), 7,50 (m, 1H), 7,92 (s, 1H), 8,48
(s, 1H), 10.39 (m, 1H), 12,5 (br, 1H); ES* MS: 510 (M+ 1).
Example Z-47:
(dS, 12a6)- l-Cvclopropyl-Λ;'-[(2,4-difluo)Ophenyl)ιmϋthyi1 -7-hydroxy4-mothyl- 6,8-dioxo-
1,2,3,4,6.8, 12.12a-octahydropyrido[r, 2' :4.5invrazino[ 1,2- a]pyrimidine -9 -carboxamid o.
Figure imgf000200_0001
a) l . l - Dimethylethyl [(1S)-1-methyl-G-oxopropyl]carbamalc To a stirred solution of
1, 1 -dimethylethyl Kl*5)-2-cyano-1-methylethyl]carbamato (0,656 g, 3,56 mmol) in
anhydrous other cooled to -40 °C was added chopwise a 1.0 M solution of
dπsobutylalummum hydnde in hexanes (14 2 ml, 14.2 mmol) over 20 minutes.
Stirring was continued at this temperature for an additional 20 minutes. The yellow
solution was quenched with Rochelle's salt and the resultant .stirred at room
temperature for 1 hour, The solids wore filtered off through celitc and rinsed with
EtOAc The organics wore washed with buna, concentrated, and flash
chromatographod (10- 100% KtOAc/hexancs) to give 1, 1 -dimethylethyl
[(1S)-1-methyl-3-oxopropyl]carbamate (0.193 g, 30 %) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.22 (d, J = 6.8 PIz, 3H), 1.41 (s, OH), 2,53-2,65 (m, 2H), 4.08-4. 13 (m,
1H), 4.63 (m, LH), 9,74-9,75 (m, 1H),
b) 1, 1-Dimethylethyl [(1(S)-3-(cyclopropylamino)-1-methylpropyl]carbamate, The
protected diamine was prepared using a modified procedure as described in example
Z-32. A solution of 1, 1-dimethylethyl f(1o!>-1-methyl-3-oxopropyl]carbamate (0.178 g,
0.95 mmol) and cyclopropylaraine (197 μL, 2.85 mrnol) in anhydrous dichloroethane
(10 mL) was treated with acetic acid (272 μL, 4,8 mmol) and stirred for 30 minutes,
Sodium triacetoxyborohydridø (0.444 g, 2,1 mmol) was added and the solution was
stirred for 20 hours. The resultant was subjected to a workup and purification
procedxire as described in example Z-32 to give 1 , 1-dπnethylethyl
[(l iS)-3-(cyclopropylamino)-1-methylpropyl]carbamato (0.136 g, 63°/o) as a clear oil,
1H NMR (400 MHz, CDCh) δ 0,32-0,42 (m, 4H), 3 .12 (d, J = 6.8 Hz, 3H), 1,39- 1,51 (m,
10H), 1,58- 1.92 (m, 2H), 2,05-2.10 (m, Ui), 2,67-2.80 (m, 2H), 3.71 (m, 1H), 4,78 (m,
1H).
c) [(3S)-3-Aminobutyl]cyclopropylamino dihydrochloride was prepared in a similar
manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CDjOϋ) 6
0,70-0,75 (m, 2H), 0,90-0,94 (m, 2H), 1, 18 (d, ,/ = 6.8 Hz, 3H), 3 ,84- 1,94 (m, 1H),
1.97-2,05 (m, 1H), 2,49-2.54 (m, 1H), 2.99-3,04 (m, 2H), 3,23-3,28 (m, 1H).
d)
(4S, 12a<.^-1-Cyclopropyl-N-[(2,4-difluorophenyl)methyl1-7-hydroxy-4>methyl-6,8-dioxo- 1,2,3/l,6,8, 12, 12a-octahydi:opyrido[1',2':4,5]pyrazino[1,2-a]pyriraidine-9-(:avboxaτnide.
The title compound was made in two steps using a similar process to that described in
example Z-2. 16a (80 mg, 0, 17 mmol) and free based
f(3)5)-3-amάnobutyπcyclop.-opylamine (75 mg, 0.59 mmol) were reacted in
dichloromethanc (2 mL) with acetic acid to give
(4<S', 12aS)-1-cyclopropyl-A''-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenyl
methyl)oxy]- 1,2,3,4,6,8, 12, 12a-octahydropyrklo[1.l,2':4,5]pyrazino[1,2-fl]pyrimidine-9-c
arboxamide (74 mg, 80%) as a film. This material was hydrogenated in a .second step
as described in example Z-2 to give
(451, 12aS)-1-cyclopropyl-N-[(2,4-difluorophenyl)methyl] -7-hydroxy-4-methyl-6,8-dioxo-
1,2,3,4,6,8, J.2, 12a -octahydropyrido[1',2':4,5]pyrazino 11,2- a]pyrimidine-9-carboxamide
(32 mg, 52%) as an off-white solid, 1H NMR (400 MHz, CDCIj) δ 0,37-0,54 (m, 3H),
0.64-0,70 (m, 1H), 1.35 (d, J - 7.2 Hz, 3H), 1.45- 1.49 (m, J H), 1,76- 1,80 (m, 1H),
2.03-2J 2 (m, 1H), 2,86-2,93 (m, 1H), 2.99-3,04 (m, 1H), 4.30 (dd, J = 4.0, 13,6 Hz, 1H),
4.49-4.67 (m, 4H), 5.00-5.07 (m, 1H), 6,75-6,82 (m, 2H), 7,32-7.36 (m, 1H), 8.28 (s, 1H),
10,49 (m, 1H), 12.53 (s, 1H); ES 1 MS: 459 (M+ l).
Example Z-48:
US, l2aS)-N- l(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyM- [2-(methylox,y)βthyl1-
6,8-dioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazιno [ 1,2-a1pyrimidinc-9-carb
oxamido,
Figure imgf000203_0001
a) [(3<S)-3-Aminobutyl] l2-(mct,hyloxy)ethyl]amine dihydrochloride, The protected
diamine, 1, 1-dimethylethyl
((1S)- J -methyl-3-{[2-(methyloxy)ethyl]amino}propyl)carbarnato was prepared in a
similar manner as described in example Z-47, Subsequently,
[(3,S)-3-aminobutylU2-(methyloxy)ethyl]amine dihydrochloride was prepared in n
similar manner as described in example Z-29, 1H NMR (400 MHz, CDCl3/CDsOO) δ
1,21 (d, J - 5.6 Hz, 3Ii), 1,93 (m, 1H), 2,04 On, 1H), 2,98-3.05 (m, 4H), 3,22 (m, 2H),
3 26-3.31 (m, 4H), 8,06 (br, < 1 H), 8,81 (br, < 1 H).
b)
(4S, 12aS>N- [(2,4-Difluorophenyl)methyl]-7-h,ydroxy-4-methyM- [2-(methyloxy)ethyl3-
6,8-dioxo- 1,2,3,4,6,8, 12, 12a-ocLahydropyrido[1',2':4,5]pyrazino[1,2-(!jlpyrimidine-9-carb
oxamide, The title compound was made in two steps using a similar px-ocess to that
described in example Z-2. 16a (60 mg, 0, 13 raraol) and free based
[(3S)-3-aminobutyl] [2-(methyloxy)ethyl] amine (53 mg, 0 37 mmol) were reacted in
clichloromethane (2 mL) with acetic acid to give
(4S, 12aA5)-N-[(2,4-difluorophenyl)methyl]-4-methyl-1-[2-(methylox,y)ethyl)-6,8-dioxo-7-
[(phenylmethyl)oxy]- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimi
dine-9-carboxamide (47 mg, 63%) as a film. This material was hydrogenated in a second step as described in example Z%2 to give
US, i 2aS)-yV-f(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyM-[2-(methyloxy)o(-,hyl]-6
,8τhoxo-1,2,3,d,6,8, 12,12a-octahydropyrido[1',2':4,5]py]'azino[1,2-a)pyrim)dine-9>carbo
xamide (38 mg, 97%) as an off-white solid, >H NMR (400 MHz, CDCIs) δ 1.34 (d, J =
7,2 Hz, 3H), 1.49 (m, 1H), 2.03-2.12 (m, 1H), 2,67-2.70 (m, 1H), 2.8 1-2,92 (m, 2H),
3,06-3.15 (m, 1H), 3.30-3,37 (m, 4H), 3,58-3.63 (m, 1H), 4,20 (dd, J = 3,4, M,2 Hz, 1H),
4,50-4.59 (m, 1H), 4,62-4.65 (m, 3H), 5,00-5,03 (m, 1H), 6,75-6,81 (m, 2H), 7.8J -7.37 (m, 1H), 8.27 (s, 1H), 10.46 (s, 1H), 12,54 (s, 1H); ES" MS: 477 (M+l).
Example Z-49:
racemic -(8aS,5aS, 13ιaS)-N-[(2 ,4-Difluoropheny))methyl]- 11-hydroxy-5-(2-methγlpropyl llilL.L2; d ioxo-2,3.3a,4,5,5a,6.10, 12,13a-decahydro- lH-cvcloΩβntare1pyrido[l',2':4,5]pvr a'/,ino[1,2-a1pyrimidine-9-carboxamide,
Figure imgf000204_0001
a) racemic-(i S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclopentanamine hydrochloride,
In a manner similar to example Z-18a-c, from
racemic -(IR, 2S)-2- ({[(1, 1 -dime thylethyl)oxy]carbonyl}amino)cy clop en tanecarboxyhc
acid (255 mg, 1, 31 mmol) was prepared racemicΛ , 1-dimo,thylcl,hyl
L(1S,2S)-2-(aminomethyl)cyclopentyl]carbamate (353 mg, 64 % over 3 stops) as a white green residue, Reductive amination with isobutyraldehyde followed by deprotection as described in Z-38 steps c and d respectively, gave
racemic- (1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclopentanamine hydrochloride
(305 mg, 39% over 5 steps from amino acid). 1H NMR (methanol-d4/CDCl3) 8,90
(br s, <1 H), 8.64 (br s, <1 H), 8.28 (m, 1 H), 3.97 (br s, 1 H), 3,37 (m, 1 H), 2,83-2,69
(m, 3 H), 2, 18- 1,69 (m, 7 H), 0.996 (m, 6 H).
b)
racemic-(3aS,5aS, 13aS)-N-[(2,4- Difluorophenyl)methyl]- 11-hydroxy-5-(2-meth
ylpropyl)- 10, 12-dioxo-2,3,3a,4,5,5a,6, 10, 12, 13a-decahydro- 1H-cyclopenta[c]pyrido[1',2'
:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. In a manner similar to that described
in example Z-35, from
racemic- (1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclopentanamine hydrochloride
105 mg, 0.434 mmol) and 16a ( 56 mg, 0.119 mmol) was prepared
racemic- (3aS,5aS, 13aS)-N-[(2,4-difluorophenyI)methyl] -5-(2-methylpropyl)- 10, 12-diox
o- 11- [(phenylmethyl)oxyl-2,3,3a,4,5,5a,6, 10, 12, 13a-decahydro- 1H-cyclopenta[e]pyrido[
1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (52 mg, 74%) This material was
deprotected in a second step similar to the procedure described in example Z-37,
Thus, from
racemic- (3aS,5aS, 13aS)-N-[(2,4-difluorophenyl)methyl] -5-(2-methylpropyl)- 10, 12-diox
o-11-[(phenylmethyl)oxy]-2,3,3a,4,5,5a,6, 10, 12, 13a-decahydro- 1H-cyclopenta[e]pyrido[
1', 2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (48 mg, 0,081 mmol) and 10% Pd/C
(catalytic amount), the title compound was prepared as a white solid after purification
by HPLC (30 mg, 75%). 1H NMR (CDCl3) 12,59 (s, 1 H), 10.42 (s, 1 H), 828 (s, 1 H), 7.34 (m, 1 H), 6,79 (m, 2 H), 4.83 (s, 1 H), 4.63-4.58 (m, 3 H), 4.29 (m, 1 H), 4. 14 (m, 1
H), 2.91 fan, 1 H), 2.46-2.32 (m, 3 H), 2, 15-2.09 (m, 2 H), 3 .85- 1, 6.1 (m, 5 H), 1.39 (m, 1
H), 0,88 (m, 6 H); ES* MS: 501 (M+ l ),
Example Z-5Q:
(3^, 11aS)-N- [(2.4-DifluorophGnyl)methyn-3-ethyl-6-hydroxy5,7-dioxo-2.3.5.7, 11.11a-h
cxahydro[1 ,3]oxati;o3o[3,2-a1pyrido[1,2-d]pyrazine-8-carboxamide.
Figure imgf000206_0001
The title compound was made in two stops vising a similar process to that described in
example Z-2. 16a (40 mg, 0,09 mmol) and (2 #)-2-amάno\l -butanol (0.02 mL, 0,21
mmol) were reacted in dichloromethano (2 mL) with acetic acid to give
(3R, l1aS)-Λ/:[(2,4-difluorophenyl)methyl] -3-ethyl-5,7-dioxo-6- [(phenylmethyl)oxy]-2,3,
5,7, 11, 11a-hexahydro[1,3]oxazolo [3,2-c?]pyrido[1,2-d]pyrazine-8-carboxamide (40 mg,
93%). This material was hydrogenated in a second step as described in example Z-2
to gxve
(37^ 11aS>-N- [(2,4-Difluorophenyl)methyl)-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7, 11, 11a-h
exahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (30 mg, 91%) as a
white solid. 'Il NMR (CDCl3) δ 3 1.49 (br, 1 H), 10.28 (m, 1 H), 8,35 (s, 1 H), 7.34
(m, 1 H), 6,79 (m, 2 ), 5,30 (m, 3 If), 4.62 (m, 2 H), 4 ,45-4.32 (m, 3 H), 3,93-3.86 (m, 2
H), 2, 11 (m, 1 H), 1.65 (m, 1 H), 0.98 (t, J = 7.6 Hz, 3 H); ES+ MS-1 420 (M +l). Example Z- 51 :
racemic- (4aS.6aS, 14aS)-N- [(2,4-Difluorophenyl)methyl] - 12-hydroxy-6- 1,2-(4-morpholin
yl)ethyl] - 11, 13-dioxo -1, 2,3,4,4a.5,6,6a.7, 11 , 13, 34a-dodecahydropyrido[1',2':4,5]pyrazin
o[1,2-a]quinazoline- 10-carboxamide
Figure imgf000207_0001
a) racemic- 1,1-Dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate. An alternative procedure from the one given in example Z-38b follows: To a solution of
Dess-Martin Periodane (564 mg, 1.33 mmol) in dichloromethane was added racemic- 1, 1-dimethylethyl [(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (305 mg, 1.33 mmol, see example Z-38a) dropwise as a solution in dichloromethane. The reaction was stirred 1 hour at ambient temperature until judged complete by TLC (1:1
hexanes: ethyl acetate KMnO4 stain), The reaction was quenched with aqueous
sodium bicarbonate and sodium thiosυlfate solutions, extracted with dichloromethane, and the combined organics were dried over sodium sulfate. Silica gel
chromatography (0-50% ethyl acetate/ hexanes gradient elution) gave
racemic- 1, 1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (280, 93%), See
example Z-38b for NMR data,
b) racemic- {[(1S,2S)-2-Aminocyclohexyl]methyl}[2-(4-morpholinyl)ethyl]amino hydrochloride. In a manner similar to that described in example Z-38c-d from racemic-_ , 1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (78 mg, 0.34-1 minol,
prepared using the procedure from example Z-38b) and [2-(4-morpholinyl)ethyl]amino
(67 mg, 0.515 mmol) was prepared
racemic -{K1S,2S)-2-aminocyclohexyl]methyl}[2¥(4-niorpholinyl)ethyl]amine
hydrochloride (95 mg, 78% over 2 steps) as a white solid, 1H NMR
(methanol-A/CDCl3) 8.18 (br s, 1 H), 3,84- 3,493 (m. 11 H), 3.19-3, 119 (m, 5 H), 2.42
(m, 1 H), 2.11 (br s, 2 H), 1.87- 1. J 7 (m, 10 H).
c) racemic-4aS,6aS, 14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-l2-(4-mo rpholinyl)ethyl]- 11,13-dioxo- 1,2,3,4,4a,5,6,6a,7,l1,13,14a-dodecahydropyrido[1',2':4,5]
pyrazino[l ,2-a]quinazoline-10-carboxamide, In a manner similar to that described in
example Z-35, from racemic-{[{ IS, 2S)-2-aminocyclohexyl] methyl} [2-(4-morpholinyl)ethyl]amino hydrochloride (95 mg, 0 272 mmol) and 16a (45 mg, 0.0957 mmol) was prepared
racemic-(4aS,6aS,14aS)-N-[(2,4-difluorophenyl)methyl]-C-l2-(4-movpholinyl)othyn- 11, 13-dioxo-12-[(phenylmethyl)oxyl-1,2,3,4,4a,5,6,6a,7, 11,13,14a-dodecahydropyridoll',2l:
4,5jpyrazino[1,2-a]quinazoline-10-carboxamide (27 mg, 43%), This material was deprotected in a second step similar to the procedure described in example Z-37. From
racemic -(4aS,6aS, UaS)-N- [(2, 4-difluorophenyl)methyl]-6-[2-(4-morpholinyl)ethyl]-1l,
I S-dioxo-12-[(phenyJmethyl)oxyl- 1,2.S,4,4a.5.β.βa,7, 1l. l S. Ua-dodecahydropyridot11,21: 4,5|pyrazino[1,2-a]quina£θline-10-carboxamido (27 mg, 0.0408 mmol) and 10% Pd/C (1
mg) the title compound was prepared as a white solid after purification by H PLC, 1H
NMR (CDC]3) 12.30 (br s, <1 H), 10,41 (br s, 1 H), 8,29 (s, 1 H), 7,34 (m, 2 H), 6.78 (m,
2 H), 4,76 (m, 1 H), 4,62-4,54 (m, 3 H), 4,29 (m, 2 H), 3,65 (m, 4 H), 3,01 (m, 1 H), 2.76
(m, 2 H), 2.58-2.42 (m, 7 H), 2.21 (m, 1 H), 1,89- 1.23 (m, 8 H); ES 1 MS: 572 (M +1).
Example Z-52:
rflco77j/c-(3aR.5aR, 13aS)-N-l(2.4-Difiuoror)henvI)methvn - 11-hydroxv- 10, 12-dioxo- 1,2.3,
Sa-, 4j 5 a..6, 10, 12.13a-docahydrocyclopentafd]pyrido[1',2':4,5]pyrazmor2.1-b1 f l,.3ioxazino
•9-carboxamide.
Figure imgf000209_0001
a) i"ace;H/c- 1,1-Dimethylethyl [(1S,2R)-2-(hydroxymethyl)cyclopentyl]carbamate,
race JiH c -(I R, 2S) -2- ({1(1, 1 -Dime thylethyl)oxy]carbαnyl}amino)cyclopentanecarbαxylic
acid (22 mg, 0,096 mmol) was dissolved in tetrahydrofuran and placed in an ice-water
bath. Triethylamine was added, followed by the slow addition of methyl
chloroformate. The reaction was stirred ten minutes in the ice-bath and sodium
borohydrido was added . Methanol was then added slowly and stirring was continued
for two hours while the ice-bath expired, 1 M Potassium hydrogen sulfate was added,
the reaction was partially concentrated, and product was extracted with
dichloromethane, The combined organics wore washed with sodium bicarbonate,
brine, and driod over sodium sulfate. Removal of solvents under reduced pressure afforded racemic-1, 1-dimethylethyl [(1S,2R)-2-(hydroxymethyI)cyclopentyl]carbamate
(25 mg, >100%), 1H NMR (CDCl3) 4.50 (br s, 1 H), 4.06 (m, 1 H), 3.54 (m, 1 H), 3.37
(m, 1 H), 2.09 (m, 1 H), 1.96 (m, 1 H), 1.64 (m, 3 H), 1.52 (m, 1 H), 3.43 (s, 9 H), 1.11
(m, 2 H).
b) racemic-[(1R,2S)-2-Aminocyclopentyl]methanol hydrochloride. In a manner
similar to that described in example, from racemic-1,1-dimethylethyl
[(1S,2R)-2-(hydroxymethyl)cyclopentyl]carbamate and 4 N HCl was prepared
racemic-[(1R,2S)-2-aminocyclopentyl]methanol hydrochloride (20 mg, quantitative),
1H NMR (methanol-d4- CDCl3) 7.76 (br s, <1 H), 3.73 (m, 1 H), 3.61- 3.28 (m, 3 H),
2.27 (br s, 1 H), 2.01 (m, 201 (m, 1 H), 1.74-1.70 (m, 2 H), 1.56-1.42 (m, 2 H), 1.16 (br
s, 1 H), 1.05 (br s, 1 H).
c)
racemic-(3aR,13aS)-N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,
2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxa
zine-9-carboxamide. In a manner similar to that described in example Z-35, from
racemic-[(1R,2S)-2-aminocyclopentyl]methanol hydrochloride (20 mg, 0.132 mmol)
and 16a (24 mg, 0.051 mmol) was prepared
racemic-(3aR,13aS)-N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy
]-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazino[2,1-b][1,3]
oxazine-9-carboxamide (7 mg, 26 %) as a white solid. This material was deprotected
in a second step similar to the procedure described in example Z-37. Thus, from racemic-(3aR,13aS)-N-[(2,4-difluorophenyl)methy)]- 10, 12-d joxo-11-f(phenylmethyl)oxy
]-1,2,3,3a,4,5a,6,l0,12,10a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazinol2,1-b][1,3]
oxazine-9-carboxamide (7 mg, 0,012 mmol) and 10% Pd/C (1 mg),
racemic-OaR,! SaS)-N- [(2,4-difluorophenyl)methyl]-11 -hydroxy- 10, 12-dioxo- 1,2,3,38,4, 5a,6,10,12,13a-decahydrocyclopenta[djpyrido[1',2':4,5]pyrazinor2,1-blfl,3loxnzπie-0-ca
rboxamide (4 mg, 72%) white solid. 1H NMR (CDCL3) 12,20 (br s, 1 H), 1037 (br ft,
1 H), 8,31 (s, 1 H), 7.35 (m, 1 H), 6.80 (m, 2 H), 5,16 (m, 1 H), 4.77 (m, 1 H), 4.64 (m, 2
H), 4.28 (m, 1 H), 4.09 (m, 3 H), 3,97 (m, 1 H), 345 (m, 1 H), 2.49-2.20 (m, 2 H),
1, 89-1, 58 (m, 4 H), 0,936-0,840 (m, 1 H); KS"1 MS: 446 (M +1).
Example Z-S3:
racemic-(4aS.6aS.14aS)-N-[(2.4-DifluorophenvI)methyl]-]2-hydroxγ-6-methyl-11,13-di
oxo-],2,3,4,4a,5,6,6a,7.n,13,14a-dodecahydropvrido[1',2':4,5]pyrazino[1,2.-a1quinazoh
ne-10-carboxamido,
Figure imgf000211_0001
a) racemic-{[(iS,2S)-2-Aminocyclohexyl]methyl}methylamino hydrochloride, In
a manner similar to that described in example Z-38c-d from racemic-1j-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (0,410 mmol) and
methyl amine (0,5 mL of a 2 M tetrahydrofuran solution) was prepared
racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}methylaminc hydrochloride in two steps
as a white solid (46 mg, 53% 2 steps). >H NMR (methanol- A/CD ClO 9.05 (br ,s,<J H), 8,72 (br s, < 1 H), 8.24 (br s, 1 H), 3,34 (m, 1 H), 3,29 (m, 1 H), 2,85 (br s, 1H), 2,66
(br 8, 4 H), 2,38 (br s, 1 H), 2.07-1.83 (m, 2 H), 1.67- 1.14 (m, 6 H),
b)
racemic-(4aS,6aS,14aS)-N-[(2,4 -Diflυorophenyl)methyl]-12-hydroxy-6-methyl-
11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]q
uinazoline-10-carboxamide. In a manner similar to that described in example Z-35,
from racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}methylamine hydrochloride (46 mg,
0.215 rnmol) and 16a (35 mg, 0.0744 mmol) was prepared
racemic-(4aS,6aS,14aS)-N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dioxo-12-[(phe
nylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-
a]quinazoline-10-carboxamide(17 mg, 41%) as a white solid. This material was
deprotected in s second step similar to the procedure described in example Z-37.
Thus, from
racemic-(4aS,6aS,14aS)-N-[(2,4-difluorophenyl)methyl]-6-methyI-11,13-dioxo-12-[(phe
nylmethyl)oxy]-1,2,3,4,4a.5.6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-
a]quinazoline-10-carboxamide (17 mg, 0,0302 mmol) and 10% Pd/C (1 mg) was
prepared the title compound as a white solid (9 mg, 64%), 1H NMR (CDCI3) 10.44
(m, 1 H), 8.29 (s, 1 H), 7,34 (m, 1 H), 6,79 (m, 2 H), 4,78 (m, 1 H), 4,62 (br s, 2 H), 4.29
(br s, 2 H), 3.41 (β, 1 H), 2.92 (m, 1 H), 2.66 (m, 1 H), 2,35-2.25 (m, 4 H), 1,90-1.74 (m,
2 H), 1.07-1.24 (m, 6 H); ES+ MS: 473(M +l).
Example Z-54: racemic -(4aS.βaS,14aS)-N-f.(2,4-Difluorophonyl)methyl] - 12-hydroxy6-f2-(methyloxy)e
thylHl, 13-dioxo- 1,2,3.4.4av5,6,6a, ZJΛJ 3, Ha-clodocaIwdropyrido[Y,2':4,5ipyra74no LL
2-alqxnnazoline-lO-carboxamido,
Figure imgf000213_0001
a) racemic-{[(1S,2S)-2-Aminocyclohexy)lmethyl}[2-(methyloxy)ethyllamine hydrochloride.
In a manner similar to that described in example Z-38cd from
racemic- 1,l-diπiΘthylethyl [(1S,2R)-2-formylcyclohoxyl]carbamate (93 mg, 0.410
mmol) and [2-(methyloxy)ethyl]amine (0,05 mL, 0.615 mtnol) was prepared in two
stops racemic -(K1S, 2S) -2-aminocyclohexyl] methyl} [2- (methyloxy)ethyl] amine hydrochloride (63 mg, 60% 2 steps) as a while solid. 1H NMR (methanol-d4/CDCl3)
0.02 (br s, <1 H), 8.78 (br s, <1, H), 8.29 (br s, 1 H), 3.69 (br s, 2 H), 3.46 )s, 3 H),
3.36-3.38 (m, 4 H), 2.97 (br s, 3 H), 2,46 (br s, 1 H), J .86-1.40 (m, 8 H).
b)
racemic-4aS,6aS, 14aS)-N- 1(2,4-Difluorophenyl)methyl] - 12-hydroxy -6- l2-(meth
yloxy)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7, 11, 13, 14a-dodecahydropyrido[1',2':4,5]pyra 2ino| 1,2-a]quinazoline-10-carboxamide. In a manner similar to that described in
example Z-35, from
racemic {[(lS, 2S) -2-aminocyclohexyli methyl} [2-(methyloxy)ethyl] amine hydrochloride
(63mg. 0,244 mmol) and 16a (40 mg, 0,0851 mmol) was prepared
211 2VJCc^7c-(4aS,6aS, 14aS)-N- [(2,4-difluorophenyl)methyl]-6- [2-(methyloxy)eLhyl]- 11, 13-d
ioxo-12- f(phenylmethyl)oxy]- 1,2,3/I,4a,5,6,6a,7, 11, 13, 14a-dodecahydropyrido[1',21:4,i5j
pyrazino[1,2-a]quinazoline- 10-carboxamide (44 mg, 81%) as a white solid, This
material was deprotected in a second step similar Lo the procedure described in
example Z-37, Tims, from rncemic
(4aS,6aS, 14aS)-N- [(2,4-difluorophenyl)methyl] -6- l2-(methyloxy)ethyl]- 1l, 13-dioxo- 12- [
(phenylmethyl)oxyl- 1,2,3,4,4a,5,6,6a,7, 11. "l-3, 14a-dodecahydropyrido[1',2':4,5]pyrazino
[1,2-a]qιύnazoline- 10-carboxamide (44 mg, 0.0726mmol) and 10% Pd/C (1 mg) the title
compound was prepared as a white solid (37 mg, quantitative) 1H NMIi (CDCl3)
12.60 (br s, 1 H), 10,47 (m, 1 H), 8,28 (a, I H), 7,34 (m, 1 H), 6,79 (m, 2 H), 4 ,81 (m, 1
H), 4,64 (m 3 H), 4.51 (m, 1 H), 4,26 (m, 1 H), 3.63 (m, 1 H), 3.31 (s, 3 H), 3.19 (m, 1
H), 2.86 (m, 1 H), 2.67 (2m, 2 H), 2.21 (m, 1 H), 1.91-1.78 (m, 2 H), 1.671.52 (m, A H),
1.46- 1.24 (m, 3 H); ES+ MS: 517 (M +l).
Example Z-55:
rflCG;;77c-(4aS,6aS, πaS)-6-l2-(AQotylamino)othv]]-N-|(2,4-difluorophenyl)methyl]- 12-h
vdroxy 11, 13-dioxo- 1 ,2,3,4, 4a, 5, 6, 6a, 7 ,11.13, 14a-dodecahydropvndo[j ',2' : 4 J3]p yrazinoj,
i .∑-alαuinazolino- lQ-carboxamide.
Figure imgf000214_0001
a) i<ae6'772y6-N-l2-({[(1S,2S)-2-Aminocyclohexyl]methyl}amino)ethyl]acelamide hydrochloride. In a manner similar to thai described in example Z-38cd from racemic 'l, 1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (93 mg, 0,41 mmol)
and N-(2-aminoethyl)acetamide (63 mg, 0.615 mmol),
racemic -N- [2-({[(1S,2S)-2-aminocyclohexyl]mc thy l}amino)efchy Ij ace tamide
hydrochloride was prepared in two steps as a white solid (82 mg), 71% 2 steps). 1H
NMK (methanol- A/CDCl3) 8.86 (br s, 1 H), 8,29 (br s, 1 H), 3,62-3.51 (m, 3 H),
3.40-3,28 (m, 4 H), 3,22-2.93 (m, 3 H), 2.47 (m, 1 H), 2,08-2.06 (m, 4 H), 1.83- 3 .75 (m,
2 H), 1,56- 1.44 (m, 3 H), 1.23 (m, 1 H).
b)
racemic -4 aS,6aS,14aS) -6- [2- (Acetylamino)ethyl]- N-[(2,4-difluoropbenyl)methy
D- 12-hydroxy-1l , 1S-dioxo- 1,2,3,4,4a.5.e.βa,7.11.13.14a-dodecahydropyrido[1',2':4,5]pyr
azino[l ,2-a]quinazolino- I 0-carboxamide. In a manner similar to that described in
example Z-35, from racemic-N-[2-({((1S,2S)-2-aminocyclohexyl]methyl}amino)ethyl]acetamide
hydrochloride (82 mg", 0,349 mmol) and 16a (50 mg, 0, 106 mmol) was prepared the
title compound (24 mg, 36%). This material was deprolected in a second .stop
similar to the procedure described in example Z-37, Thus, from i^acemic
(4aS,6aS, 14aS)-6- [2-(acotylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]- 11, 13-dioxo-1
2-[(phenylmethyl)oxy] - 1,2,3,4,4a,5,6,6a,7, 11, 13, 14a-dodecahydropyrido[1',2':4,5]pyrazi
no[] ,2-a]qvunazohne-10-carboxamide (24 mg, 0,0379 mmol) and 10% Pd/C (1 mg) was
prepared the title compound as a white solid after purification by HPLC, 1H NMR
(CDCI3) 12,59 (s, 1 H), 30.44 (s, 1 H), 8.35 (s, 1 H), 7,32 (m, 1 H), 6,79 (m, 2 H), 5.86 (s, 1 H), 4.78 (m, 1 H), 4.61-4 ,50 (m, 3 H), 4.30 (m, 1 H), 3.35 (m, 1 H), 3. 18 (m, 1 H),
2.96 (m, 1 H), 2.76 (m, 2 H), 2,48 (m, 1 H), 2, 19 (m, 1 H), 1,89- 1,23 (m, 12 H); ES+
MS: 544 (M+ l ).
Example Z-56 :
(3S, 11aR)-N- [(2.4-Difluorophenyl)melhyl] -3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7, 11 , 11a-h
exahydro[1 ,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.
Figure imgf000216_0001
The title compound was made in two steps using a similar process to that described in
example Z-2. 16a (40 mg, 0 09 mmol) and (2S)-2-amino-1-butanol (0 1 mL) were
reacted in dichloromethane (2 mL) with acetic acid to give
(3S, 11a R)-N-[(2,4-d)fluorophenyl)methyl]-3-ethyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,
5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (39 mg,
90%). This material was hydrogenated in a second step as described in example Z-2
to give
(3S, 11aR)-N-[(2,4-difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7, 11, 11a-h
exahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (37 mg, 99%) as a
tinted white solid. 1H NMR (CDCl3) δ 11.47 (br, 1 H), 10.26 (m, 1 H), 8,35 (s, 1 H),
7.32 (m, 1 H), 6,77 (m, 2 ), 5.29 (m, 1 H), 4.60 (m, 2 H), 4.47-4.32 (m, 3 H), 3.93-3,85
(m, 2 H), 2.08 (m, 1 H), 1.68 (m, 1 H), 0.95 (t, J = 7.6 Hz, 3 H); ES+ MS: 420 (M + L) Example Z-57:
(3S,11aR)-3-Butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-h
exahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide,
Figure imgf000217_0001
The title compound was made in two stops using a similar process to that described in
example Z-2, 16a (40 mg, 009 mmol) and (2S)-2-amino-1-hexanol (100 mg) were
reacted in dichloromethane (2 mL) with acetic acid to give
(3S,11aR)-3-butyl-N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxyl-2,3,
5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (43 mg,
94%). This material was hydrogenated in a second step as described in example Z-2
to give
(3S,11aR)-3-butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-h
exahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (33 mg, 92%) as a
tinted white solid. 1H NMR (CDCl3) δ 11.48 (br, 1 H), 10.27 (br, 1 H), 8,36 (br, 1 H),
7.31 (m, 1 H), 6.77 (m, 2 ), 5.28 (m, 1 H), 4.59-4.36 (m, 5 H), 3,83 (m, 2 H), 2.08 (m, 1
H), 1.58 (m, 1 H), 1.39-1.23 (m, 4 H), 090 (t, J = 6.8 Hz, 3 H); ES+ MS: 448 (M+l).
Example Z- 58:
(3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(4-hydroxyphenyl)methyl]-5,7-
dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide
Figure imgf000218_0001
The title compound was made in two steps using a similar process to that described m
examples Z-2, 16a (40 mg, 0.09 mmol) and 4- [(2,$)-2-amino-3-hydroxypropyl]phonol
(43 mg, 0.21 mmol) wore reacted in dichloromethane (2 mL) with acetic acid to give
(3SUlai9-N-f(2,4-difluorophenyl)methyl]-3- [(4-hydroxyphenyl)methyl]-5,7-dioxo-6-[(p
henylmethyl)oxy]v2,S,β,7, 11ι 11a-hexahydro[1,3]oxazolo[3,2-a]pyri do[1,2-d]pyrazine-8-c
arboxamide (10 mg, 20%) This material was hydrogcnatcd in a second step as
described in example Z-2 and purified via preparative HPLC to give
(3S, 1laϋ;')-N-[(2,4-diflnorophenyl)methyl] -6-hydroxy-3- [(4-hydroxyphenyl)methyl]-5,7-
dioxo-2.S.O,7.11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide
(7 mg, 63%) as a white solid. 1If NMR (CDaOD) δ 10.43 (m, 1 H), 8.34 (s, 1 H),
7.33 (m, 1 H), 7.00 (d, J = 8.4 Hz, 2 H), 6.82 (m, 2 H), 6.7 L (d, «/= 8.4 Hz, 2 H), 5.05 (m,
1 H), 4.67-4.57 (m, 4 H), 4.21 (dd, J = 8.8, 7,2 Hz, 1 H), 3.94 (dd, J - 8.8, 6,4 Hz, 1 H),
3.21 (dd, J = 13 2, 3 2 Hz, 1 H), 2.90 (dd, J= 13.6, 8,8 Hz, 1 H) i ES"1 MS: 498 (M+ 1).
Example Z-59:
(4S, 12aS)-l-Cvclobutyl-N- [(2,4-difluorophenyl)methyl]-7-hydroxy4-methyl-6,8-dioxo- ]
,2,3,4.6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2;a]pyrimidine-9-carboxamide,
Figure imgf000219_0001
a) |(3i5V3-Aminobutyl]cyclobutylamino dihydrochloride was prepared in a similar
manner as described in example Z-47, 1H NMR (400 MHz, CDClβ/CDaOD) δ 1.23 (d,
J = 6,4 Hz, 3H), 1.69-2,26 (m, 8H), 2,83 (m, 2H), 3.31-3.33 (m, 1H), 3.55 (m, 1H), 8,08
(br, <1H), 9.07 (br, <1H).
b)
(4S,12aS)-1-Cyclobutyl-N-[(2,4-dif]uorophenyl)methyl] -7-b.ydroxy-4-methyl-6,8-dioxo-1
,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[l ,2-a]pyrimidine-9-carboxamide,
The title compound was made in two steps using a similar process to that described in
example Z-2. 16a (80 mg, 0, 17 mmol) and froo based
f(3S)-3-aminobutyl]cyclobutylamine (96 mg, 0,68 mmol) were reacted in
dichloromethane (2 ml) with acetic acid to give
(4S,12a..'S'-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7- [(phenylm
etlvyl)oxyl- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-tflpyrimidine-9-car
boxamide (68 mg, 70%) as a film. This material was hydrogenated in a second step
as described in example Z-2 to give
(άS, 12aiS)-1-cyclobutyl- /V- [(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-choxo-1
,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a1pyrimidine>9-carboxamide
(57 mg, 100%) as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 1.31 (d, J = 6.8 Hz,
3H), 1.46- 1.70 (m, 4H), 1.91-2, 12 (m, 4H), 2.52 (m, 1H), 2.90-2.93 (m, Hi), 3.06 (m, 1H), 4.16-4.29 (m, 3H), 4.57-4.06 (m, 2H), 4.99-5.05 (m, 1H), 6.75-6.82 (m, 2H),
7.32-7.38 (m, 1H), 8,20 (s, 1H), 10.44 (s, 1H), 12,51 (s, 1H), ES+ MS: 473 (M+l).
Example Z-60:
(4S.12aS)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-
2H-thiopyran-4-yl)- 1 ,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[ 1,2-a]pyrimid
ine-9-carboxamide
Figure imgf000220_0001
a) [(3S)-3-Aminobutyl]tetrahydro-2H-thiopyran-4-ylamine dihydrochloride was
prepared in a similar manner as described in example Z-47, 1H NMR (400 MHz,
CDCl3/CD 3OD) δ 1,21 (d, J - 6,4 Hz , 3H), 1,65- 1,75 (m, 2H), 1.90-2.10 (m, 2H), 2.35 (m, 2H), 2,56-2,61 (m, 4H), 2,92-2.98 (m, 311), 3,27-3,31 (m, 1H), 8,05 (br, <1H), 8.90
(br, <1H).
b)
(4S, 12aS)-N- (2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-
2H-thiopyran-4-yl)-1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimid
ine-9-carboxamide, The title compound was made in two stops using a similar
process to that described in example Z-2. 16a (80 mg, 0.17 mmol) and free based
[(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamino (108 mg, 0 58 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give (4ώ"', 12aS -yV-[(2,4-difluorophenyl)meth.yl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy] -1-
(fcetrahydro-2H-thiopyran-4-yl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,
2-#]pyrimidine-9-carboxamide (56 mg, 54%) as a film. This material was
debenzylafcod in a second step to in a manner similar to Z-26 to give
(4S, 12aS)-N-[(2,4-difluorophβnyl)methyl] -7-hydroxy-4-methyl-6,8-dioxo- . -(tetrahydro-
2N-thiopyran-4-yl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimid
ine-9-carboxamide (56 mg, >100%) as an off-white solid, 'Η NMR (400 MHz, CDCl3)
5 1,30 (d, J = 6.8 Hz , 3H), 3 ,54- 1,58 (m, 1H), .1,72- 1.82 (m, 3H), 1,97-2, 11 (m, 2H),
2.60-2,76 (5H), 2.86 (m, 2H), 4 , 17-4.30 (m, 2H), 4.62-4,66 (m, 3H), 4.92-4.96 (m, 1H),
6.75-6.82 (m, 2H), 7,32-7,38 (m, 1H), 8 31 (a, 1H), 30,46 (s, 1H), 12,48 (s, 1H); ES+
MS: 519 (M+ 1).
Example Z-6 H
(46r, 12a6)-N- [(2,4-Difluorophenγl)meth,yl]-7-hydroxy l,4-bis(2-methylpropyl)-6,8-dioxo
- 1,2,3,4,6,8.12, 12a-octahydropyrido[1',2':4,5]pyra2ino[1,2-a]pyrimidine-9-carboxamide.
Figure imgf000221_0001
a) [(3<S)-3-Amino-5-methylhoxyl](2-methylpropyl)amine dihydrochloride was
prepared in a similar manner as described in example Z-32. 1H NMR (400 MHz,
CDCl3/CD3OD) δ 0.87 (d, J = 6.4 Hz ,6H), 0,97 (d, J= 6,8 Hz , 6H), 1.34- 1.41 (m, J H),
1.45- 1,52 (m, 1H), 1,58- 1.66 (m, 1H), 2,01-2, 13 (m, 2H), 2,72-2,73 (m, 2H), 3,03-3,06 (m, 2H), 3.29 (ni, 2H), 8,07 (br, <1H), 8,71 (br, <1H).
b)
(4ώv, 12a.S)-N-[(2,4-Difluorophenyl)methyl3-7-hydroxy- 1,4-bis(2-methylpropyl)-6,8-dioxo
• 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1, 2- dpyrimidine-9-carboxn mid o,
The title compound was made in two steps using a similar process to that described in
example Z-2. 16a (80 mg, 0, 17 mmol) and free based
[(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (117 mg, 0,63 mmol) were
reacted in dichloromethane (2 mL) with acetic acid to give
(άS, 12a5)-//- [(2,4-difhiorophenyl)methyπ- 1,4-bis(2-methylpropyl)-6,8-dioxo^7- [(phenyl
methyl)oxy]- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrav;in.of1,2-fl]pyrimid)ne-9-c
arboxamide (68 mg, 66%) as a film, This material was hydrogonated in a second step
as described in example Z-2 to give
(4,Sf, 12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-
1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide
(56 mg, 97%) as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J= 6 4 Hz,
3H), 0,84 (d, e/ = 6 4 Hz, 3H), 0,97- 1.00 (m, GH), 1.37- 1,83 (m, 5Ii), 2,03-2, 12 (m, 2H),
2.21-2.28 (m, 1H), 2.77 (m, 1H), 2,00-2,93 (m, 1H), 4, 19-4.40 (m, 3H), 4.59-4.70 (m,
2H), 4.96-4,97 (m, 1H), 6,77-6,83 (m, 2H), 7,33-7,39 (m, 1H), 8.28 (s, IfI), 10,47 (s, 1H),
12,59 (br, 1H),1 ES 1 MS: 5 J 7 (M+l).
Example Z-62:
racemic-(4aS,6aS, 14a5)-N4(2,4-ϋifIuorophenyl)mcihyl] - 12-hydroxy6-(2-hydroxveιthyl )- 11. l3-dioxo- 1,2,3,4.4a,5,6.6a,7, l] .13, 34a-dodocahydrQpvrido[1',2':4,5]pyrazinof ] ,2-a]
cιuinazolino- 1 O-carboxamide,
Figure imgf000223_0001
a) racemic-2-({[(1S,2S)-2-Aminocyclohexyl]methyl}amino)cthanol hydrochloride,
In a manner similar to that described in example Z-55a, from racemic-1.1-dimet-hylethyl [(1S,2^-2-formylcyclohexyl]carbamato (I 12 mg, 0.497
mmol) and 2-aminoethanol (0,04 niLm 0,746 mmol) was prepared
racemic'2-({{{ IS, 2S) -2- aminocyclohexyl] methyl} amino) ethanol bis-hydrochlorido in
two steps (102 nig, 84% over 2 steps). >H NMR (methanol-d4/CDCl3) 8.81-8,40 (m,
< 2 H), 8, 16 (br s, 1 H), 4.02-3.93 (m, 2 H), 3,80 (br s, 2 H), 3,53 (m, 1 H), 3,36-2.93 (m,
6 H), 2 41 (br s, 1 H), 2,05 (m, 1 H), 1.76- 1.41 (m, 4 H)
b)
racemic -(4aS,6aS, 14aS)-N-[(2,4-Difluorophen,yl)methyl]- 12-hydroxy-6-(2-hydr
oxyethyl)- 11, l3-dioxo-1,2,3,4,4a,5,6,6a,7, 11, 13,14a-dodecahydropyrido[1',2':4,5]pyrazi
no[1,2-a]quinazoline- 10-carboxamide I n a manner similar to that described in
example Z-35, from 16a (45 mg, 0.0957 mmol) and
racemic-2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethanol hydrochloride (102 mg,
0,418 mmol) was prepared
racemic-(4aS,6aS, 14aS)-N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-11, 13-dioxo
- 12-[(phenylmethyl)oxy]- 1,2,3,4,4a,5,6,6a,7, l1, 13, 14a-dodecahydropyrido[1',2':4,5]pyra zino[1,2-a]q\unazoline- 10-carboxamide (7 mg, 12 %) as a white solid after silica gel
chromatography (1- 12% methanol/dichloromethane gradient ehition). This material
was deprotectcd in a second step similar to the procedure described in example Z-37.
Thus, from
raccmϊc<Λ&S,6&S, 14aS)-N- [(2,4-difluorophenyl)methyl'|-6-(2-hydroxyethyl)- 11, 13-dioxo
■ 12- [(phenylmethyl)oxy]- 1,2,3,4,4a,5,6,6a,7, 11, 13, 14a-dodecahydropyrido[1',2':4,5]pyra
zino[1,2-a]quinaτ;oline- 10-carboxamide (7 mg, 0,0118 mmol) the title compound was
prepared after purification by HPLG (3 mg, 50 %), 1H NMR (CDCIΛ) 12.57 (br s, 1
H), 10,45 (m, 1 H), 8.29 (s, 1 H), 7 34 (m, 1 H), 6,78 (m, 2 H), 4,80 (m, 1 H), 4 71 Cs, 1
H), 4.62 (m, 2 H), 4,44 (m, 1 H), 4.33 (m, 1 H), 3.75 (m, 1 H), 3,62-3,20 (m, 3 H), 3 13
(m, 1 H), 2.74-2.71 (m, 2 H), 2.24 (m, 3 H), 1.90- 137 (m, 12 H), 1,27- 1,23 (m, 3 H) I.12
(m, 1 H); ES+ MS: 503 (M +l),
Example Z-63:
jiflceijJic-(4aS,6aS, 14aS)-6-CγcloprQpyl-N-[(2,4-d]fluorophenyl)methyl]- 12-hydroxy- 11 , 1.
3-dioxo- 3 ,2,3,4,4a,5.6.6a,7, ll, 13, 14a-dodecahydropvrido[1',2':4,5]pyrazino[1,2-alquina
zoline- lQ-carboxamide.
Figure imgf000224_0001
a) ra<?crayc-(1S,2S)-2- [(Cyclopropylamino)methyl]cyclohexanaminc hydrochloride
Tn a manner similar to that described in example Z-55a, from
iwce;njc- 1,1-dimethylethyl [(1S,2ll)-2-formylcyclohexyl]carbamate (112 mg, 0.497 mmol) and cyclopropylamine (0.05 mL, 0.746 mmol) was prepared
racemic (1S,2S)-2- [(cyclop ropylamino)methyl]cyclohexanamine bis hydrochloride salt
in two steps (102 mg, 86% over 2 steps). This material was used without further
purification, 1H NMR (mαthanol-rfi/CDClu) 8,31 (br s, 1 H), 3,75 (br s, 1 H), 3.54
(m, 1 H), 2,96 (m, 1 H), 2,73 (m, 1 H), 2,27 (m, 1 H), 1,94 (m, 1 H), 1.76-1.35 (m, 8 H),
0.88-0.78 (m, S H).
b) racemic "(4aS,6aS, 14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]- 12-hyd
roxy- 11, 13-dioxo- 1,2, 3,4,4a, 5,6,Ba,7, I l , 13, 14a-dodecahydropyrido[1',2':4,5]pyrazino[l ,
2-a]quinazoline- 10-carboxamide. In a manner similar to that described in example
Z-35, from 16a (45 mg, 0.0957 mmol) and racenuc-
(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexanamine hydrochloride (102 mg, 0,425
mmol) was prepared
racemic<4aS,6aS, l4aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]- 11 ,13-dioxo- 12-U
phenylmethyl)oxy] - 1,2,3,4,4a,5,6,6a,7,11, 13, 14a-dodecahydropyrido[1',2':4,5]pyrazinol
1,2-ajquinazolino- 10-carboxamide as a white solid after silica gel chromatography
(1- 12% methanol/dichloromethanc gradient clutxon). This material was deprotectod
in a second step similar to tho procedure described in example Z-37. Thus, from
racemic-(4aS,6aS, 14aS)-6-cyclopropyl-N- [(2,4-difluorophenyl)methyl]-11, 13-dioxo- 12-[(
phenylmethyl)oxy]- 3 ,2,3,4,4a,5,6,6a,7, l l , 13, 14a-dodecahydropyrido[1',2':4,5]pyrazino[
T ,2-a]quinazoline-10-carboxamide (56 mg, 0,0949 mmol) the title compound was
prepared as a white solid (41 mg, 81%). Η NMR (CDCl3) 12.10 (br s, < 1 H), 10.45 (m, 1 H), 8,27 (s, 1 H), 7,33 (m, 1 H), 6,88 (m, 2 H), 4,77 (m, 1 H), 4 ,61-4 ,49 (m, 4 H),
4,33 (m, 1 H), 2,04 (m, 1 H), 2,79 (m, 1 H), 2.17 (m, 1 H), 1,86-0.86 Gm, 10 H), 0,658 (m,
1 H), 0.499-0,32 (m, 2 H); ES-* MS: 499 (M +1),
Example 2-64 :
racemic-(4aS,6aS, 14aS)-N-[(2,4-pifluorophenvI)methyl] - 12-hydroxy 11, 18-dioxo-6- l2-(
1-pyrrolidinyl)ethyl1- 1,2,3,4,4a,5,6,6a ,7, 11 , 13, 14a-dodecahydropyrido[1',2':4,5]pyrazin
o[1,2-a.lquinazoli ne- 10-carboxamκle formic acid salt
Figure imgf000226_0001
a) racemic -(1S,2S)-2-({[2-(i-Pyrrohdinyl)oLhyl]amino}methyl)cyclohexanamine
hydrochloride. In a manner similar to that described in example Z-55a, from
racemic 1, 1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate Q 32 mg, 0.497
mmo]) and 2-(1-pyrrolidinyl)ethanamine (0.09 mL, 0.746 minol) was prepared
racomio'ii S, 2S)- 2- ({[2-(1-pyrrolidinyl)ethyl] amino} me tbyl)cyclohexanamine (88 mg, 60% 2 steps) as the bis hydrochloride salt in two steps as a white solid, 1H NMR.
(methanol- flVCDCl3) 9.68 (br s, < 1 H), 9,24 (br s, < 1 H), 8.25 (br s, 1 H), 3.75- 3,04
(m, 11 H), 2,37 (br s, 1 H), 2.06-1.20 (m, 12 H).
b)
racemic<7-(4aS,6aS, 14aS)-N-[(2,4-Diflxiorophenyl)methyl]- 12-hydroxy- 11, L3-dio xo-6- [2-(1-pyrrolidinyl)ethyl]-1.,2,3,4,4a,5,6,6a,7, 11,13,14a-dodecah.ydropyrido[r,2':4,5]
pyrazino[1,2-a]quinazo]ine-1Q-carboxamide formic acid salt,
In a manner similar to that described in example Z-35, from 16a (30 mg, 0,0638
mmol) and
iτ(3ee;n/<?-(1S,2S)-2-({[2-(1-pyrrolidinyl)o<,hyl]amino}methyl)cyclohexanamine
hydrochloride (88 mg, ' 0,296 mmol) was prepared
i<acey;j7'c-(4aS,6aS, 14aS)-N-[(2,4-cUfluorophenyl)methyl] - 11, 13-dioxo- 12-[(phenylmct-hyl
)oxy]-6-[2-(1-pyrrolidinyl)ethyl]- 1,2,3,4,4a,5,6,6a,7, ,11, 13, 14a-dodecahydropyrido[l',2l:
4,5]pyrazino(1,2-a]qtύnazoline- 10-carboxamide as a white solid (31 mg, 76%) after
silica gel chromatography (1- 12% methaπol/dichloromethane gradient elution), This
material was deprotected in a second step similar to the procedure described in
example Z-37, Thus, from
rac?(?;«ic -(4aS,6aS, 14aS) -N- f (2,4 -difluorophenyl)nio thy I] - 11, 13 -dioxo- 12- [(phenyl methyl
)oxy]-6-[2-(1 -pyrrolidinyl)ethyl]- 1,2,3,4,4a,5,6,6a,7, 11, 13, 14a-dodecahydropyridol1',2':
4,5jpyrazinoU ,2-a1quinazoline- 10-carboxamide (31 mg, 0.048 mmol) the title
compound was prepared as a yellow solid after purification by HFLC (18 mg, 66%),
i11 NMR (CDCl3) 10.39 (br s, 1 H), 8,56 (br s, 1 H), 8,39 (br s, J H), 7,34 (m, 1 H),
6,78 (m, 2 H), 4,76-4,40 (m, 6 H), 3.26-2.89 (m, 7 H), 2,73 (m, 1 H), 2, 15 (m, 1 H),
2.02- 1.18 (m, 14 H); KS" MS: 556 (M +l),
.Example Z-65:
(4aS, 14aS)-N- [(2.4-Difluorophenvl)inothyl1-9-hydroxy8,10-dioxo-2,3.4,4a.5,6,8, 10, 14, l
4a-decahydro- lH-pyrido[1,2-ciDyridol r, 2':4,5]pyra;zino[3 ,2-aipvrimidinc- l l-c a r b oxa_mi do.
Figure imgf000228_0001
a) {2-[(2S)-2-Pipcridinyl]ethyl}aminc. This compound was prepared in a
similar manner as its enantiomor described in example Z-42a,
b)
(4aS,14aS)-N-[(2,4-Difluorophenyl)mel,hyll-9-hyrlroxy-8,10-d]oxo-2,3,4/Ja,5,6,
8,30,14,14a-decahydro-1H-pyrido[1,2-c]pyridol.1 ',2"4,5lpyrazinoU,2-a]pyrimicline-11 -c
arboxainido. In a manner similar to that described in example Z-35, from
{2-[(2S)-2-piporidinyl]ethyl}amino (28 mg, 0.218 mmol) and 16a (30 mg, 0.0G38 mmol)
was prepared
(4aS,14aS)-N-[(2,d-di{Jιiorophenyl)meihyl]-8,10-dioxo-9-[(phenylmethyl)oxyl-2,3,4,4a,5
,6,8,10,l/l,14a-decahydr0-1H-pyrido[1,2-clpyridolr,2';4,5]pyra'/ano[1,2-a]pyrimidine-11
-carboxamide (29 mg, 82%) , This material was deprotected in a second step similar
to that described in example Z-37 to give the title compound as a white solid (26 mg,
quantitative). UI NMR (CDCl3) δ 12.44 (br s, 1 H), 30.48 (s, 1 H), 8.26 (s, 1 H), 7.35
(m, 1 PI), 6.80 (m, 2 H), 4.68-4.57 (m, 2 JH), 4.38 (m, 1 H), 420 (m, 1 H), 3.93 (s, 1H),
3,63-3,39 (m, 2 H), 2,91 (m, 2 H), 2.29 (br s, 1 H), 2.02 (m, 1 H), 1.69-1,45 (m, 4 H),
1.30-1.24 (m, 2 H), J.12 (br a, 1 H); ES' MS: 459 (M-H). Example Z-66:
.(48, 12aS)-N-[(4-Fluorophenyl)methyl]-7-hydroxyd -methyl- ] - [2-(msthy]oxy)ofchyll-6,8-
dioxQ- 1 ,2,3.4,6.8, 1 2, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a.1 pyrimidinc-9-carboxa
mide.
Figure imgf000229_0001
a) [(3S)-3-Aminobutyl] l2-(methyloxy)ethyl]amine bis hydrochloride, In a
manner similar to that described in example Z-47, from 1,1-dimethylethyl
[(1S)-1-methyl-3-oxopropyl]carbamate (76 mg, 0.406 mmol) and
2-(methyloxy)ethyl]amine (0.05 ml, 0.609 mmol) was prepared
[(3S)-3-aminobυtyl] [2-(methyloxy)ethyl]amine as the bis hydrochloride salt in two
steps (19 mg, ciuantαtativc), ' H NMR (methanol-di/CDOh) δ 9.02 (< 1 H), 8 24 (< 1
H), 3.68 (br s, 2 H), 3.49 (br s, 1 H), 3.34 (br s, 4 H), 3, 15 (br s, 4 H), 2.26-2.11 (m, 2 H),
1.35 (br s, 3 H).
b)
(4S, 12aS)-N- [(4 -Fluorophenyl)methyl] -7-hydroxy-4-methyl- 1-[2-(methyloxy)et
hyl]-6,8-dioxo-] ,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9
-carboxamide, In a manner similar to that described in example Z-35, from 16 (15 mg, 0.034 mmol) and K3S)-3-Aminobulyl] [2-(methyloxy)ethyl]amme bis hydrochloride
(19 mg, 0,087 mmol),
(4S, 12aS)-N-[(''l-fluorophenyl)methyl]-4-methyM-[2-(methyloxy)ethyl]-6,8-dioxo-7-[(ph
enylmethyl)oxyM,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino.1,2-a]pyrimidine
-9-carboxamide was prepared as a white solid after silica gel chromatography (1- 12%
methanol/dichloromethanc), This material was deprotected in a second step similar
to that described in example Z-37 to give the title compoimd as a yellow solid (9 mg,
60 %, 2 steps). 1H NM Ii (CDCl3) δ 12,56 (s, 1 H), 10.51 (m, 1 H), 8,29 (s, 1 H), 7.32
(m, 2 H), 6,98 (m, 2 H), 5.03 (m, 1 H), 4.65-4.59 (m, 2 H), 4,53 (m, 1 H), 4.21 (m, 1 H),
3.61-3,40 (m, 2 H), 3.34-3.13 (m, 3 H), 3,08 (m, 1 H), 2.94-2.84 (m, 2 H), 2.68 (m, 1 H),
2.07 (m, 1 H), 1.50 (m, 1 H), 1,35 (d, «7 = 7.2 Hz, 3 H), 1.14 (m, 1 H); ES 1 MS: 459
(M + l).
Example Z-67:
(4S.12aS)- l-Cvclobutyl-N- [(4-fluorophenyl)methyl1-7-hydroxy-4-methyl-6,8-dioxo- 1 ,2,3
,4.6.8.12, 12a-octahydropvrido[1',2':4,5]pyrazino[l,2-a1pyrimidine-9-carboxamide,
Figure imgf000230_0001
a) [(3S)-3-Aminobutyl]cyclobutylamino bis-hydrochlαride, In a manner
similar to that described in example Z-47, from 1,1-dimethylethyl [(1S)t l -methyl-3>oxopropyl]carbamato (76 mg, 0,406 mmol) and cyclobutylamine (0,05
mL, 0,609 inmol) was prepared [(3S)-3Αminobυtyl]cyclobυlylamine bis-hydrochlorido
in two steps (23 mg, 27%). 1H NMR (methanol-d4/CDCl3) δ 8.86 (s, < 1 H), 7.97 (s, <
1 H), 3.46 (m, 1 H), 3.21 (m, 1 H), 2.74 (m, 2 H), 2,14-2.08 (m, 4 H), 1.94- 1,62 (m, 5 H),
1.13 (d, =7= 6 Hz, 1 H),
b)
(4S, 12aS)-1-Cyclobutyl-N- [(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-di
oxo- 1,2,3,4,6,8, 12, 32a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxam
ide. In a similar manner to that described in example Z-35a, from 16 (18 mg, 0.39
mmol) and [(3S)-3-Aminobutyl!cyclobutylamine bis-hydrochloride (23 mg, 0.107
mmol),
(4S,12aS)-1-cyclobutyl-N-[(4-fluorophcπyl)methyl]-4-meth.yl-6,8-dioxo-7-[(phenylmeth
yl)oxy]- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carbox
amide was prepared as a white solid. This material was deprotected in a second step
similar to that described in example Z-37 to give the title compound as a white solid
after purification by HPLC (4,5 mg, 25 % 2 steps), 1H NMR (CDCl3) δ 12.54 (s, 1 H),
10 48 (β, 1 H), 8,20 (s, 1 H), 7,31 (m, 2 H), 6,98 (m, 2 H), 5,02 (m, 1 H), 4 ,61 -4,57 (m, 2
H), 4.26-4 , 14 (m, 3 H), 3,05 (m, 1 H), 2.90 (m, 1 H), 2,49 (m, 1 H), 2.12 (m, 1 H),
2.05- 1.87 (m, 3 H), 1,84-1, 61 (m, 3 H), 1.46 (m, 1 H), 1.32 (m, 3 H); ES* MS: 455
(M+ 1).
Example Z-68: (4S, 12aS)-N-[(4-Fluorophenyl)methyl]-7-hydroxy-4 -methyl - 1-(2-methy]propyl)-6,8-diox
o- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidino-9-carboxamid
e
Figure imgf000232_0001
a) [(3S)-3-Aminobutyl](2-methylpropyl)amine bis-hydrochloride. In a manner
similar to that described in example Z-47, this compound was prepared from
1, 1-dimethylethyl [(1S)-1-methyl-3-oxopropyl]carbamate (76 mg, 0 406 mmol ) and
(2-methylpropyl)amine (0.06 mL, 0.609 mmol) in two steps as the bis-hydrochloride
salt (22 mg, 25 %) 1H NMR (methanol -d4/CDCl3) δ 3,25 (br s, 1 H), 2.91 (br s, 2
H), 2.64 (m, 2 H), 2,02- 1.93 (m, 3 H), 1.17 (m, 3 H), 0,88 (m, 6 H).
b)
(4S, 12aS)-N-[(4-Fluorophenyl)methyl] -7-hydroxy-4-methyl- 1-(2-methylpropyl)
-6,8-dioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-car
boxamide. In a similar manner to that described in example Z-35, from 16 (16 mg,
0,035 mmol) and [(3S)-3-Aminobutyl](2-methylpropyl)amine bis-hydrochloride (20 mg,
0,0925 mmol),
(4S, 12aS)-N-[(4 -fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(pheny
lmethyl)oxy]- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2 -a]pyrimidine-9- carb ox amide was prepared as a white solid, This material was dcprotected in a
second step similar to that described in example Z-37 to give the title compound as a
tan solid (13 mg, 68% 2 steps). 1H NMR (CDCl3) δ 12,57 (s, 1 H), 10,46 (s, 1 H),
8,27 (s, 1 H), 7,32 (m, 2 H), 6,99 (m, 2 H), 4 98 (m, 1 H), 4.63-4, 54 (m, 2 H), 4.45 (m, 1
H),4.26-4.16 (m, 2 H), 2,91 (m, 1 H)r2-.77-(m, 1 H), 2.24 (m, 1 H), 2, 14-2,03 (m, 2 H),
1.63 (m, 1 H), 1.48 (m, 1 H), 1,33 (m, 3 H), 1,09 (m, 1 H), 0.850 (m, 3 H), 0.789 (m, 3
H); ES+ MS: 457 (M+ 1).
Example Z-69:
(4S, 12aS)-N- [(4-FluoiOphenyl)methyl]-7-hydroxy-1,4-dimethvI-6,8- d io XQJ - L, 2, 3_, 4 , 6 , 8 , 11
,12a-octah VcIrOpVi1JdOU'.2' :4.5]pyrazxno 1.3 ,2r alp vrimidinθ-9-carboxamide.
Figure imgf000233_0001
a) [(3S)-3-Aminobutyl]methylamine bis-hydrochloπde, In a manner similar to
that described in example Z-47, this compound was prepared from 1, 1-dimethylethyl
[0 S)-1-methyl-3-oxopropyl}carbamalc (76 mg, 0,409 mmol) and excess methylamine
(2 M in tetrhydrofuran) in two steps as the bis hydrochloride salt (17% 2 steps). 1H
NMR (methanol-rfi/CDCl3) 6 3 16 (m, 1 H), 3.08 (s, 2 H), 2,83 (m, 2 H), 2.45 (s, 3
H), 1,88 (m, . H), 1.75 (m, 1 H), 1.09 (m, 3 H). b)
(4S, 12aS)-N- ('(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,
4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. In a
similar manner to that described in example Z-35, from 16 (18 mg, 0.0398 mmol) and
[(3S)-3-aminobutyl]methylamine bis-hydrochlox-ide (19 mg, 0, 109 mmol,
(4wS, 12aS)-N- [(d-fluorophenyl)methyl]-1,4-dimethyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,
2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine>9-carboxamide
was prepared as a white solid, This material was deprotected m a second step
similar to that described in example Z-37 to give (he title compound as a tan solid (7
mg, 44% 2 steps), 1H NMR, (CDCI3) δ 12.53 (a, 1 H), 10.47 (a, 1 H), 8.29 (a, 1 H),
7.32 (m, 2 H), 6,99 (m, 2 H), 5.04 (1 H), 4.60 (m, 2 H), 4.23 (s, 3 H), 2.83-2.80 (m, 2 H),
2.32 (s, 3 H), 2.13 (m, 1 H), 1,48 (m, 1 H), 1.34 (m, 3 H), ES+ MS: 415 (M+l),
Example Z-7Q:
(4 iff 12aS)-N-[(4-Fluoroph enyl)methyl1-7-hydroxv4-methyl-6,8-dioxo- 3 -(totrahydro-2H
-thiopyran-4-yl)- 1,2,3,4,6,8, 12,lι2a-ρctahydroDyrido[1',2':4,5]pyrazino[3 ,2-fl]pyrimidine
,-9,-carboxamide.
Figure imgf000234_0001
The title compound was made in two steps using a similar process to that
described in example Z*2, 16 (25 mg, 0,055 mmol) and free based
[(3-S)-3-aminobutyl]totrahydro-2/ir-tlHopyran-4-ylamine (48 mg, 0.26 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give
(4S,12aS)-N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]- 1-(tet
rahydro-2H-thiopyran-4-yl)- 1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[ 1,2- a
]pyrimidine-9-carboxamide (16 mg, 49%) as a film, This material was debenzylated
in a second step in a manner similar to Z-26 to give
(4S, 12aS)-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo- 1-(tetrahydro-2 H-
thiopyran-4-yl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-
9-carboxamiclo (8 mg, 59%) as an off-white solid , 1H NMR (400 MHz, CDCl3) δ 1,30
(d, J = 7,2 Hz, 3H), 3 .63-3 .58 (m, 1H), 1,72-2.10 (m, 5H), 2.56-2.76 (m, 5H), 2.84-2,87
(m, 2H), 4.18 (dd, J = 2,8, 14,0 Hz, 1H), 4,26 (dd, J = 3.4, 14.2 Hz, 1H), 4,92-4,97 (m,
1H), 6.96-7,00 (m, 2H), 7,29-7 36 (m, 2H), 8.31 (s, 1H), 10.48 (m, 1H), 12.48 (br, 1H);
ES+ MS: 501 (M+ l).
Example Z-71 :
(4S, 12aS)-N-[(2,4-Difluorophenyl)methyl] -7-hydroxy-1,4-dimethyl-6.8-dioxo- 1,2.3.4,6.8
, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1 ,2-a]pyrimidine-9-carboxamide
Figure imgf000235_0001
a) [(3S)-3-Aminobutyl]methylamino dihydrochloride was prepared in a similar
manner as described in example 21-47. 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J= 6.8
Hz, 3H), 1,82- 1,93 (m, 1H), 1.94-2.03 (m, 1H), 2,53 (s, 3H), 2,89-2.93 (m, 2H),
3.22-3 30 (m, 1H), 8.02 (br, <1H), 8,81 (br, <1H), b)
(4S, 12aS)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo- 1,2,3,4,6,8
,12, 12a-Octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title
compound was made in two steps using a similar process to that described in example
Z-2. 16a (40 mg, 0.085 mmol) and free based [(3S)-3-aminobυtyl]methylamine (24
mg, 0,23 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give
(4S, 12aS)-N-[(2,4-difluorophenyl)methyl] -1,4-dimethyl-6,8-dioxo-7-[(phenylmethyl)oxy
]- 1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide
(39 mg, 89%) as a film. This material was hydrogenated in a second step as
described in example Z-2 to give
(4S, 12aS)-N-[(2,4-diflυorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8
, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimid ine-9-carboxamide (32 mg,
97%) as an off-white solid, 1H NMR (400 MHz, CDCl3) δ 1.33 (d, J = 6,4 Hz, 3H),
1.46- 1.50 (m, 1H), 2.12-2.14 (m, 1H), 2,32 (s, 3H), 2,83 (m, 2H), 4.24 (m, 3H), 4,62 (m,
2H), 5.02 (m, 1H), 6.77-6.79 (m, 2H), 7.33 (m, 1H), 8.30 (s, 1H), 10,43 (s, 1H), 32,50 (br,
1H); ES+ MS; 433 (M+ 1),
Example Z-72:
(4S, 12aS)- N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo
-1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1 ,2-a]pyrimidino-9-carboxamide
Figure imgf000237_0001
The title compound was made in two steps using a similar process to that
described in example Z-2. 16 (27 mg, 0,060 mmol) and free based
[(3S)-3-aminobutyl] (1-methyIethyl)amino (67 mg, 0.51 mmol) were reacted in
dichloromethane (2 mL) with acetic acid to give
(4S, 12aS)-N- [(4-fluorophenyl)methyl]-4 -methyl-1-(1-methylethyl)-6,8-dioxo-7- [(phenyl
methyl)oxy] - 1,2,3,4,6,8, 12, 12a -octahydropyrido[1',2':4,5]pyrazino[ 1,2-a]pyrimidine-9-c
arboxamide (18 mg, 56%) as a film. This material was hydrogenated in a second step
as described in example Z-2 to give
(4S, 12aS)-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl- 1-(1-methylethyl)-6,8-dioxo-
1,2,3,4,6,8, 12, .12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide
(15 mg, > 100%) as an off-white solid. 1H NMR (400 MHz, CDC18) δ 1.02 (d, J = 6.4
Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.54- 1.58 (m, 1H), 1.94-2.03
(m, 1H), 2.71-2.76 (m, 1H), 2.82-2,88 (m, 1H), 3.13-3.16 (m, 1H), 4.16-4.19 (m, 1H),
4.30-4.33 (m, 1H), 4.48 (m, 1H), 4.55-4,65 (m, 2H), 4.97-5.00 (m, 1H), 6.97-7.01 (m,
2H), 7.30-7.34 (m, 2H), 8,28 (s, 1H), 10.51 (m, 1H), 12.55 (s, 1H); ES+ MS: 443 (M+ l).
Example Z-73:
(4S, 12aS)-N- [(4-FIuorophenyl)methyl]-7-hydroxy- 3 ,4-bis(2-methylpropyl)-6,8-dioxo- 1,2
.3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[ 1,2-a]pyrimidino-9-carboxamide.
Figure imgf000238_0001
Tho title compound was made in two steps using a similar process to that described in
example Z-2, 16 (25 mg, 0.055 mmol) and free based
[(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (21 mg, 0.11 mmol) were reacted
in dichloromethane (2 mL) with acetic acid to give
(4S, 12aS)-N-[(4-flυorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dioxo-7-[(phenylmet
hyl)oxy]-1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carbo
xamide (8 mg, 25%) as a film. This material was hydrogenated in a second step as
described in example Z-2 to give
(4S, 12aS)-N-[(4-fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo- 1,2,
3,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (5
mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 0.74 (d, J = 6.4 Hz, 3H),
0.84 (d, J = 6.4 Hz, 3H), 0.97- 1.00 (m, 6H), 1.37- 1.66 (m, 5H), 1.76- 1.82 (m, 1H),
2.05-2.09 (m, 2H), 2.21 -2,26 (m, 1H), 2,72-2,79 (m, 1H), 2.87-2.93 (m, 1H), 4, 16-4,26
(m, 2H), 4.38 (m, 1H), 4 55-4.66 (m, 2H), 4 ,93-4,99 (m, 1H), 6,97-7.02 (m, 2H),
7,33 -7,34 (m, 2H), 8.27 (s, 1H), 10.49 (m, 1H), 12,61 (s, 1H); ES+ MS: 499 (M+l),
Example ZZ-1 to ZZ-24
Examples in table below were isolated as a mixture of diastereomers ranging from
1:1 to >10:1 ratios of stereoisomers at the center indicated as undefined. Characterisation data reported herein consists of observed mass spectral signals for
molecular ions (M+ l) of the compounds using electrospray ionization methods in the
positive mode using LC/MS techniques well known in the field. Reported retention
times refer to observed UV peaks confirmed by NMR methods for the examples below
using the following gradient on a phenomonex C18 reverse phase HPLC column (150
mmX4.6 mm 5 micron). Solvent A = water w/ 0.1% formic acid, solvent B =
acetonitrile w/ 0.1% formic acid. Gradient = 10%B for 1 min, gradient from 10% to
90% B from 1 to 9 min, ramping to 100% B at 9.01 mm and holding at 100% B for 2
mm. In several cases the diastereomers were not separable by the standard HPLC conditions reported above and thus reported as a single retention time. [Table A]
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0003
The present invention further includes the following compounds.
Figure imgf000242_0001
[Table Bj
Figure imgf000242_0002
Experimental Example 1
The HlV inlograso inhibitory activity was investigated based on the following assay method.
(1) Preparation of DNA solution
By the same method as that described in Experimental Example 1 of WO 2004/024693, a substrate DNA solution (2 pmol/μl) and a target DNA solution (5 pmol/μl) were prepared. After each target DNA solution was once boiled, a temperature was slowly lowered to anneal complementary chains, which was used. Each sequence of a substrate DNA and a target DNA is as described in the same Experimental Example.
(2) Measurement of inhibition rate (lCr>o value)
Strep tavidin (manufactured by Vector Laboratories) was dissolved in a 0.1 M carbonate buffer solution (composition: 00 mM Na2CO3, 10 mM NaHCOs) to a concentration of 40 μg/ml, Each 50 μl of this solution was added to a well of an immunoplate (manufactured by NUNC), this is allowed to stand at 4°C overnight to adsorb. Then, each well was washed with a phosphate buffer (composition: 13.7 mM NaCl, 0.27 mM KCl, 0.43 mM NagHPO-i, 0.14 mM KH2PCM) two times, and 300 μl of a phosphate buffer containing 1 % skim milk to block it for 30 minutes. Further, each well was washed with a phosphate buffer two times, 50 μl of a substrate DNA solution (2 pmol/μl) was added to adsorb at room temperature for 30 minutes while shaking, and this was washed with a phosphate buffer two times and, then, distilled water once.
Then, to each well prepared as described above were added 12 μl of a buffer (composition: 150 mM MOPS (pH7 2), 75 mM MnCIa, 50 mM 2-mercaptoethanol, 25% glycerol, 500 μg/ml bovine serum albumin-fraction V), and 51 μl of a reaction solution prepared from 39 μl of distilled water. Then, 9 μl of an integrase solution (30 pmol) was added, and the mixture was mixed well. To a well as a negative control (NC) was added 9 μl of a diluting solution (composition: 20 mM MOPS (pH7 2), 400 mM potassium glutamete, 1 mM EDTA, 0..1% NP-40, 20% glycerol, 1 mM DTT, 4 M urea), and this was mixed well using a plate mixer.
After the plate was incubated at 30°C for 60 minutes, the reaction solution was discarded, followed by washing with 250 μl of a washing buffer (composition: 150 mM MOPS (pH7.2), 50 mM 2-mercaptoothanol, 25% glycerol, 500 μg/ml bovine serum allnimin -fraction V) three times
Then, to each well were added 12 μl of a buffer (composition: 150 mM MOPS (pH7.2), 75 niM MgCh, 50 mM 2-mercaptoothanol, 25% glycerol, 500 μg/ml bovine serum albumin-fraction V), and 53 μl of a reaction solution prepared from 41 pi of distilled water, Further, 6 μl of a solution of a test compound in DMSO was added to each well, and 6 μl of DMSO was added to a well as a positive control (PC), followed by mixing well using a plate mixer. After the plate was incubated at 30°C for 30 minutes, 1 μl of a target DNA (5 pmol/μl) was added, and this was mixed well using a plate mixer.
After each plate was incubated at 30°C for 10 minutes, the reaction solution was discarded, followed by washing with a phosphate buffer two times. Then, an antrdigoxigenin antibody labeled with alkaline phosphatase (sheep Fab fragment: manufactured by Boehringor) was diluted 2000-fold with an antibody diluting solution, 100 μl of the diluent was added to bind at 30°C for 1 hoxir, and this was washed successively with a phosphate buffer containing 0.05 % Tween20 two times, and a phosphate buffer once. Then, 150 μl of an alkaline phosphatase coloring buffer (composition: 10 mM paranitrophenyl phosphate (manufactured by Vector Laboratories), 5 mM MgCIs, 100 mM NaCl, 100 mM Tris-HCl (pli 9.5)) was added to react at 30°C for 2 hours, 50 μl of a T N NaOH solution was added to stop ihe reaction, an absorbance (OD405 nm) of each well was measured, and an inhibition rate (ICπo) was obtained according to the following calculation equation. Inhibition rate (%) = I00LHCC abs.- NC abs.) / (PC abs.- NC abs.)}]
C abs.; absorbance of well of compound
NC abs.: absorbance of NC
PC abs. : absoi"bance of PC
Results arc shown below. [Table lj
Figure imgf000244_0001
The present compound showed the strong integrase inhibitory activity against HTV.
Experimental Example 2 A derivative of 293T cells oxprcssing an attachment factor to improve
adherence to plastic were used for the assay, A VSV-g pseudotyped HlV vector that
expresses luciferase (herein referred to as PHIV) was px'oduced by transfcction of cella
with the pGJ3-Luci vector plasmid (Jarmy, G, et al,, J. Medical Virology, 64:223-231,
2001) and pVSV-g (Clontech). Cells were mixed with the PHIV vector and then
mixed with serially diluted compounds. After incubation at 37°C and 5% CCh for two
days, the plates were read by using Steady GIo luciferase assay reagent (Promega) as
recommended by the manufacturer. To assess non-HIV specific inhibition, a similar
assay was performed, except that coll/PHIV vector mixture was replaced by cells
which had been previously transduced and constitutively expressed luciforase.
[Table 2]
Figure imgf000245_0001
Figure imgf000246_0001
Formulation Example
A term "active ingredient" moans the present compound, a taυtomer thereof, a pharmaceutically acceptable thereof, or a solvate thereof. (Formulation Example 1) A hard gelatin capsule is prepared using the following ingredients; dose
(mg/capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10 Total 460mg
(Formulation Example 2) A tablet is prepared using the following ingredients^ dose
(mg/tablet)
Active ingredient 250
Cellulose (microcrystallino) 400
Silicon dioxide (fumed) 10
Stearic acid 5
Total 665msr
Ingredients are mixed, and compressed to obtain tablets, each weighing 665 mg,

Claims

[Name of Document] Scope of Claims
1 . A compound of the formula :
Figure imgf000248_0001
(wherein,
Z1 is NR4; R4 is hydrogen, oplionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyele lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, S, SO, SO2, NRa (Ra is hydrogen or lower alkyl), -N= and =N-)), O or CH2;
Z2 is optionally substituted lower alkylonc or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from O, S, SO, SO2, NR5 (R5 is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy or optionally substituted amino, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally svibstitutcd phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from CO, O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group as R4), -N= and =N-)), -N= or = JN - |
K.1 is hydrogen or lower alkyli
X is a single bond, a hctcroatom group selected from O, S, SO, SO2 and NH, or lower alkylenc or lower alkenylene each may be intervened by the heteroatom;
R2 is optionally substituted aryl;
"R'5 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkcnyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or op tionally substituted amino;
"R/1 and Za part taken together forms a ring, where the compound (I) is represented by the following formula CM), or CMl) :
)
Figure imgf000249_0001
(wherein, A ring is optionally substituted heterocyclel
R1'1 and Rx are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, op tionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substitutod phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NRr> (Rr> is selected independently from the same substituent group as R'O, -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted hetorocycioox3'- carbonyl or optionally substituted aminocarbonyl; a broken lino represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, Rx is not present;
R1 is hydrogen or lower alkyli
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkcnylenc each may be intervened by the heteroatom group;
IIs is optionally substituted aryl;
R^ is hydrogen, halogen, hydroxy, optionally substitiited lower alkyl, optionally substitu ted cycloalkyl, optionally substituted lower alkcnyl, optionally substituted lower alkoxy, op tionally substituted lower alkenyloxy, optionally substituted aryl, op tionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino)
)
Figure imgf000250_0001
(wherein,
D ring is optionally substituted heterocyclel
R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenyleπe each may be intervened by the heteroatom groxip;
R2 is optionally substituted aryl;
R'5 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, op tionally substitxited cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or op tionally substituted amino)) ; or a pharmaceutically acceptable salt, or solvate thereof.
2. A compound according to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein R1 is hydrogen.
3. A compound according to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein X is lower alkylenei R2 is phenyl or phenyl substituted with at least halogen. ά. A compound according to Claim 1, pharmaceutically acceptable salt, or soivace thereof, wherein R3 is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino,
5. A compound according' to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein R3 is hydrogen,
6. A compound according' to Claim 1, pharmaceutically acceptable salt, or solvate thereof, wherein R1 is hydrogen or lower alkyl; X is lower alkylone; R2 is phenyl or phenyl substituted with at least halogen; Ra is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino.
7 , A compound of the formula ^
Figure imgf000251_0001
(wherein,
A ring is optionally substituted heterocycle;
R1'1 and Rx are independently hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NRD (Rβ is selected independently from the same substituent group as R'O, -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyl; a broken line represents the presence or absence of a bond, provided that when the broken line represents the presence of a bond, Rx is not present; R1 is hydrogen or lower alkyl;
X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocyclooxy or optionally substituted amino); or a pharmaceutically acceptable salt, or solvate thereof
8. A compound according to Claim 7, pharmaceutically acceptable salt, or solvate thereof, wherein R1 is hydrogen or lower alkyl; X is lower alkylene; R2 is phenyl or phenyl substituted with at least halogen; R3 is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionally substituted amino.
9. A compound according to Claim 7, pharmaceutically acceptable salt, or solvate thereof, wherein a broken line represents the absence of a bond.
10. A compound according to Claim 7, pharmaceutically acceptable salt, or solvate thereof, wherein Rx is hydrogen; R14 is hydrogen or optionally substituted lower alkyl.
11. A compound according to Claim 7, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is an optionally substituted and optionally condensed 5- to 7- membered heterocycle containing 1 to 2 hetero atom(s).
12, A compound of the formula:
Figure imgf000252_0001
(wherein,
A ring is an optionally substituted and optionally condensed 5- to 7- membered hetcrocycle containing 1 Io 2 hetero atom(s); the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof; R14 and RX are independently .hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened by a heteroatom group selected from O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group as R4), -N= and =N-), hydroxy, optionally substituted amino, optionally substituted lower alkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkyl carbonyl, optionally substituted lower alkoxy carbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkyl carbonyl, optionally substituted aryloxycarbonyl, optionally substituted hctorocyclecarbonyl, optionally substituted heterocycle lower alkyl carbonyl, optionally substituted heterocycleoxy carbonyl or optionally substituted aminocarbonyll
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino), its pharmaceutically acceptable salt, or
R1 is hydrogen or lower alkyl;
R is independently selected from halogen and Substituent group S1;
Substituent group S1(: optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (wherein the lower alkyl may be intervened with a heteroatom group (s) selected from CO, O, O, S, SO, SO2, NRa (Ra is hydrogen or lower alkyl), -N= and =N-), lower alkoxy lower alkyl, amino lower alkyl optionally substituted with mono- or di- llower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyl optionally substituted with mono- or di- lower alkyl, optionally substituted lower alkyl sulfonyl amino, halogenated lower alkoxy, hydroxy lower alkyl)
m is an integer of 0 to 3); or a pharmaceutically acceptable salt, or solvate thereof.
13. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein Rx and R14 are independently hydrogen or optionally substituted lower alkyl.
14. A compound according to Claim 12, pharmacexitically acceptable salt, or solvate thereof, wherein Rx and R14 are hydrogens.
15. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein R3 is hydrogen,
16. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein in is 0, or 1 to 3 and at least one of R is halogen,
17. A compound according to Claim 7 or 12, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is any one of the followmgs:
Figure imgf000254_0001
(wherein, R20 to R40 are each independently a group selected from Substituent group S2, or any two groups of R20 to R40, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted carbocyle or optionally substituted heterocycle, or each combination of (R20 and R22), (R23 and R2'1), (R25 and R26), (R27 and R29), (R30 and R31), (R32 and R34), (R35 and R36), (R37 and R38), and (R39andR40), taken together with the neighboring atom, may form an optionally substituted carbocyle or optionally substituted hetorocycle.
Substituent group S2: hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted aryl, optionally substituted aryl lower alkyl, optionally substituted aryloxy, optionally substituted heterocycle, optionally substituted heterocycle lower alkyl, optionally substituted heterocycleoxy, hydroxy, optionally substituted amino, optionally substituted lower alkylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted cycloalkyl lower alkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionally substituted arylcarbonyl, optionally substituted aryl lower alkylcarbonyl, optionally substituted aryl oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally substituted heterocycle lower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted phosphoric acid residue, aryl substituted with optionally substituted phosphoric acid residue, aralkyl substituted with optionally substituted phosphoric acid residue, hydroxy substituted with optionally substituted phosphoric acid residue, amino substituted with optionally substituted phosphoric acid residue, or lower alkyl substituted with optionally substituted phosphoric acid residue (the lower alkyl may be intervened with a heteroatom group(s) selected from CO, O, S, SO, SO2, NR5 (R5 is independently selected from the same Substituent group as R4), -N= and =N-)
the stereochemistry of an asymmetric carbon represented by * shows R- or S- configuration, or a mixture thereof)
18. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein R20 to R40 arc each independently hydrogen or substituted lower alkyl, or any two groups of R20 to R40, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally substituted 3- to 7- membered carbocylc or optionally substituted 3- to 7- membored heterocycle, or each combination of (R20 and R22), (R23 and R24), (R25 and R26), (R27 and R29), (R30 and R31), (R32 and R34), (R35 and R36), (R37 and R38), and (R39and R40), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle
19. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1); one of R20 to R25 is optionally substituted lower alkyl and the others are hydrogens.
20. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-I1; one of (R20 and R22), (R23 and R24), and (R25 and R26), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered hetorocycle.
21. A cpmpound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-1); Z=NR26, and R2β and R2e taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocyclc,
22. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); one of R27 to R30 is optionally substituted lower alkyl and the others arc hydrogens.
23. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); one of (R27and Raa) and (R30 and R''1), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocyclc.
24. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-2); Z=NR31, and R30 and R31 taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle.
25. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3)i one of R32 to R3fl is optionally substituted lower alkyl and the others are hydrogens,
26. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A-3); one of (R«2andR3O,(R3l5andR«'),(R37andR38),and(R3aandRio), taken together with the neighboring atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle,
27. A compound according to Claim 17, pharmaceutically acceptable salt, or solvate thereof, wherein A ring is a ring represented by (A- 3); Z=NR40, and R39 and R'U) taken together with the neighboring atom may form an optionally substituted 5- to 7- membered heterocycle.
28. A compound according to Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein Rx is hydrogen; R1'' is hydrogen or optionally substituted lower; R3 is hydrogen; m is 1 to 3 and at least one of Rs is halogen; A ring is a ring described in Claim .17,
29. A compound according Io Claim 12, pharmaceutically acceptable salt, or solvate thereof, wherein Rx is hydrogen; II1'1 is hydrogen; R:i is hydrogen; m is 0, or 1 to 3 and at least one of R is halogen; A ring is a ring described in Claim 17; R20 to R40 are each independently hydrogen or substituted lower alkyl, or any two groups of R2() to R40, which bonds to the same carbon atom, taken together with the carbon atom, may form an optionally svibstituted 3- to 7- membcred carbocyle or optionally substituted 3- to 7- membered heterocycle, or each combination of (R20 and R22), (R23 and R2O, (R2!i and R2G), (R27 and R2"), (R3« and R"), (R82 and R^), (R35 and R^), (R''7 and R»«), and (Rfi9andR40), taken together with the neighboring carbon atom, may form an optionally substituted 5- to 7- membered carbocyle or optionally substituted 5- to 7- membered heterocycle.
30. A compound of the formula"
)
Figure imgf000257_0001
(wherein,
O ring is optionally substituted heterocycle;
R1 is hydrogen or lower alkyl;
X is a single bond, a hctcroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the hetoroatom group;
R2 is optionally substituted aryl;
R3 is hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted lower alkcnyloxy, optionally substituted aryl, optionally substituted aryloxj', optionally substituted heterocyclic group, optionally substituted heterocycleoxy or optionally substituted amino); or a pharmaceutically acceptable salt, or solvate thereof
31. A compound selected from the group consisting of:
(3R, 11aS)-N-[(2,4-Oifluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, l1, 1la -hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide; (4aR,13aS)-N-[(2,4-Difluorophenyl)methyl]-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-carboxamide;
(3aS,13aS)-N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a -decahydropyrido[1',2':4,5]pyrazino[1,2-^pyrrolof1,2-cJpyrimidine-10-carboxamide;
(4aS,13aR)-N-[(2,4-Difluorophenyl)methyl]-αθ-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-carboxamide."
(4aS,13aR)-N-[(4-Fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2, 3,4.1,5,9, 13 ,13, 13a-oct ahydro-1iy-pyrido[1,2-alpyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-S-carboxamide;
(3S,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5, 7,11,3 la-hexahydro[1,3]oxaxolo|3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3aS,13aS)-N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-de cahydropyrido[1',2':4,5]pyrazino[l,2-a]pyrrolo[1,2-clpyrimidine-10-carboxamide,
(3S,,11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1>.S)-1-methylpropyl]-5,7-dioxo -2.S.S.T^lj11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3*Sr,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-carboxamidel
(3S,11aR)-Nr(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-ho xahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-5,7-dioxo-2 ,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide;
(3S, 11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5, 7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S, 11aR)-N- [(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3,5,7, 11-11a -hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.
(3S, 11aR)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7-dioxo-2,3, 5 ,2, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(2S,3R)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2,3,5,7 , 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3R, 11aS)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5, 7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide;
(3R,11aS)-N-[(2,4-Difluorophonyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,7-dioxo-2,3, 5 ,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(5aR, 14aR)-N-[(2,4-Difluorophenyl)methyl]- 11-hydroxy- 10,12-dioxo- 1,2,3,4,5a,6, 10, 12, 14, 14a-decahydropyrido[1,2-a]pyrido[1',2':3,4]imidazo[1,2-d]pyrazine-9-carboxamide; (2S,,3S)-N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3- [(methyloxy)methyn-5,7-dioxo-2-p hcnyl-2.S.β.T. lϊ .11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazino-8-carboxamiclo
(3ώf, 11aR)-3-(Cyclohexylmethyl)-Λ/:[(2,4-difluorop]icnyl)methyl]-6-hydroxy-5,7-dioxo-2, 3,5,7, 1 L, 11a-liexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxaraidc;
(3-S, 11aR)-N-[(2,4- ϋifluorophenyl)methyl]-6-hydroxy-8-(1-methylethyl)-5,7-dioxo-2,3,5, 7, 11 , 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyradne-8-carboxamide;
(5aR, 14aig)-N-[(2,4-D)fluorophenyl)methyl] - 12-hydroxy-11, 13-dioxo-5a,6a,7, 11, 13, 14a- hexahydro-5i7'-indeno[1',2':4,5] [1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazinG- 10-carboxamid
(2S,3R 11a«Sι-N- f(2,4-Diflnorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diplicnyl-2,3,5,7, I1, 1 la-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyra7<ine-8-carboxamide;"
(2S,3R,11a,ffi)-N-[(2,4-difluorop}ienyl)methyl]-6-liydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3R, l1aS>-7^-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5, 7, 11, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazino-8-carboxamide,
(3-S', 11aie)-N-[(2,4-Dιfluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethyl] -5,7-dioxo- 2,3,5,7, H, 11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine -8-carboxamide; (3«S', 11aR)-N- [(2,4-Difluorophenyl)raethyl]-6-hycUOxy-3-l2-(methylsulfonyl)ethyl] -5,7-di oxo-2,3,5.T,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3i5', 11ai:e)-,N-[(2,4-DifJuovophenyl)methyl]-6-hydroxy-3-(1i/-indol-3-.ylmethyI)-5,7-dioxo -2,S,5.T.11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(4R, 12aR)-N-[(4-fluorophenyl)mcihyl]-7-hydroxy-4-methyM-(2-mct,hylpropyl)-6,8-diox 0- 1,2,3,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyrazino[1, 2- a]pyrimidine-9-carboxamid e;
(4R,12aR)-N-[(4-Fhxorophenyl)methyl]-7-hydroxy-4-mot,hyl- 1-(1-mothylel,hyl)-6,8-diox o- 1,2,3,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyra'4ino[1,2-a]pyrimidino-9-carboxamid e;
(4S,12aS)-N-r(2,4-Difluorophenyl)methyl]-7-hydroxy-4-meihyl-1-(2-i--ethylpropyl)-6,8- dioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidinG-9-carboxa midel
(4iS', 12aS)-1*(Cyclopropylmethyl)-iV-[(2,4-difluorophenyl)methyl] -7-hydroxy-4-rαeUiyl-6 ,8*dioxo- 1,2,3,4,6,8,12,12a*octahydropyϊiido[1',2':4,5]pyrazino[1,2-a]py.'imidine-9-carbo x amide;
(4S, 12aS5-N- [(2,4-Difluorophenyl)methyl]- 1-(2-Λuianylmethyl)-7*hydroxy-4-methyl-6,8 -dioxo-1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidιne-9-carbox amide; (4S,12aS)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-thiazol-
2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-c arboxamide;
(4aR,6aR,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a, 7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxa mide;
(4aR,6aR,14aS)-N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11 ,13.14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide
(3S,4aR,6aR,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-3-phenyl-1 ,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzoxazine -10-carboxamide;
(4aS,6aS,14aS)-N-[(2,4-DifluorophenyI)methyl]-12-hydroxy-6-(2-methylpropyl)-11,13-d ioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoli ne-10-carboxamide;
(6a11,7aS,11aS)-N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10, 11,11a, 13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide;
(6aS,7aS,11aS)-N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10, 11, 11a.13-decahydro-6H-pyrido[1',2':4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide; (5aS, 14aS)-N- [(2,4-Difluorophenyl)methyl]- 11-hydroxy-10, 12-dioxo- 1,2,3,<i, 58,6, 10,12, 14,14a-decahydropyridϋl1,2-a]pyrido[1',2':3,4Jimidazo[1,2-d]pyrazine-9-carboxamide)'
(4a R, 14al:l)-N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8, 10-dioxo-2,3,4,4a,5,6,8, 10, 14, l4a-decahydro- 1H-pyrido[1,2-c]pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidinc- 11-carboxam ido;
(4/i;, 12aR)-iV"-[(2,4- Dάfluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbuiyl)-6,8-d ioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidinG-9-carboxa mide>'
(4S, 12aS)-7</-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyM-(1-TOethylethyl)-6,8-di oxo-1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyx-imidine-9-carboxam ide;
(4S,12aS)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyM-(3-methylbxιtyl)-6,8-d ioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyra?;ino[1,2-a]pyrimidine-9-carboxa mide;
(4S, 12aS)-JN-[(2,4-Difluorophcnyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(3-pyridinyl methyl)-1,2,3,4,6,8,12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-sJpyrimidine-9-carbo xamide;
(4S,12aS)-1- Cyclopropyl-N-[(2,4-difluorophenyl)meUiyn-7-hydroxy-4-methyl-6,8-dioxo- 1,2,3,4,6,8,12,12a-octah,ydropyrido[1',2':4,5]pyra/mol1,2-aJpyrimidine-9-carboxamide;
(4S,12aS)-N[(2,4-l)ifluorophenyl)methyl]-7-hydroxy-4-methyl-1-l2-(methyloxy)ethyl]- 6,8-dioxo- 3,2,3, 4,6,8, 12, 12a-ocLahydropyrido[1',2':4,5]pyraz;ino[1.,2-a]pyrimidine-9-carb oxamide;
(3aS,5aS,13aS)-N-[(2,d-DiΩuorophenyl)metlτιyl]-11-hydroxy-5-(2-methylpropyl)-10,12-d ioxo-2,3,3a,4,5,5a,6, 10, 12, 13a-decahydro- 1H-cyclopenta[c]pyrido[1',2':4,5]pyrazino[1,2 -a]pyrimidinew9-carboxamide;
(3R,l1a.≤)-N-[(2,4-ϋifiuorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-h Gxahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4-morpholinyl)ethyl]- l1,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]q uinazoline- 10-carboxamide;
(3aR,5aR,13aS)-N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,3a,4,5a, 6,10,12,13a-decahydrocyclopenta[d]pyrido[1',2':4,5]pyrazino[2,l -b]r1,3]oxazine-9-carbo x amide;
(4aS,6aS,14aS)-N-[(2,4-Diflυorophenyl)methyl]-12-hydroxy-6-rQethyl-11,13-dioxo-1,2,3 ,4,4a,5,6,6a,7,1.l,13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]quinazoline-10-car boxamide;
(4aS,6aS,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(methyloxy)βthyl]-11, id-clioxo- l .i-.Jj,4,4a.5^Oa.T, 1l.13.14a-dodecahydropyrido[1',2':4,5]pyrazinoU,2-a]quin azoline- 10-carboxamide;
(4aS,6aS, 14aS)-6- l2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl] - 12-hydroxy-1 I, 13-dioxo-1,2,3,4,4a,5,6,6a,7, 11, 13,14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]qui nazolinc .0-carboxamide;
(3S, 11a/τ>)-N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7, 11, 11a-h exahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3iS', 11aR)-3-Bulyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7, 11,11a-h exab.ydro|l,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(3S,l1aR)-uN-[(2,4-Diflxiorophenyl)methyl]-6-hydroxy-3- [(4-hydroxyphenyl)methyl] -5,7- dioxo-2,3,5,7, 11, l. a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyra/-ine-8-carboxamide
(4S,12aS)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-X ,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazinol1,2-a]pyrimidine-9-carboxainide;
(4S, 12al5!)-N- [(2,4-Diflx;orophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro- 2.H-thiopyran-4tyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyriinid ine-9-carboxamide;
(4S, 12aS)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo - 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[l,2-a]pyrimidine-O-carboxamide; (4aS,6aS, l'daS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-hydroxyethyl)- 11, 13-d ioxo- 1,2,3,4,4a,5,6,6a,7, 11, 13,14a-dodecahydropyrido[1',2':4,5]pyrazino| 1,2-a]quinazoli ne-30-carboxamide;
(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11, 13-dioxo- 1,2,3,4,-Ia,S,G,Ga,Y,11, 33, 14a-dodecahydropyrido[1',2':4,5]pyrazino-1,2-a]qιιinazoline-1 0-carboxamide)
(4aS,6aS, 14aS)-N- [(2,4-Difluorophenyl)methyl]- 12-hydroxy- 11, 13-dioxo-6-[2-(1-pyrroli dinyl)ethyl]- 1,2,3,4,4a,5,6,6a,7,11, 13, 14a-dodecahydropyrido[1',2':4,5]pyrazino[1,2-a]q uinazoline- 10-carboxamide;
(4aS, 14aS)-N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8, 10-dioxo-2,3,4,4a,5,6,8, 10, 14,l
4a-decahydro- 1H-pyrido[1,2-c]pyridoll',2".4,5]pyrazino[1,2-a]pyrimidine- 11-carboxami de;
(4S, : 2aS)-N-[(4-Fluorophenyl)methyl1-7-hydroxy-4-methyM-[2-(methyloxy)ethyl]-6,8- dioxo-1,2,3,4,6,8,12, 32a-octaliydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxa rnidc;
(4S, 12aS)-1- Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo- 1,2,3 ,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide; (4S, 12aS)-N- |(4-F]uorophenyl)methyl] -7-hydroxy-4-methyl-1- (2-methylpropyl)-6,8-cliox o- 1,2,3,4,6,8, 12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamid
(4S,12aS)-N-[(4-Fluorophenyl)methyl]-7-hydroxy- 1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12 , 12a-oct,ahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidinc-9-carboxamide;
(4S7, 12aΛS)--N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1- (telrahydro-2N -thiopyran-4-yl)- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazinol.1,2-a]pyrimidine -9-carboxamide;
(4S, 12a»≤)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy- 1,4-dimethyl-6,8-dioxo- 1,2,3,4,6,8 , 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-O-carboxamidα;
(4S,12aS)-iV-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo - 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyriraidine-9-carboxamide;
(4S, 12aS)-N-|(4-Fluorophenyl)methyl]-7-hydroxy- 1,4-bis(2-methylpropyl)-6,8-dioxo- 1,2 ,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;
enantiomers thereof; diastereomers ihereof; mixtures of enantiomers thereof; mixtures of diastereomers thereof; mixtures of enantiomers and diastereomers thereof; and pharmaceutically acceptable salts thereof. 02, A compound selected from the group consisting of:
(4a_S; 13a R)-N-[(2,4-Difliioroplicnyl)methyl)-10-hydroxy-9,11-dioxo-2, 3, 4R,S,O,Il,IS, 13a
•octahydro-1J-r-pyrido[1,2-a]pyrrolo[1',2':3,4]imid.azo[1,2-rf]pyrazino-8-carboxaniide;
(4aS,13ait>)-N-[(4-1<Λluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-oct ahydro-1H-pyrido[l ,2- S]PyVrOIo[I1,21IS, 4] limdazo[1,2-d]pyrazine-8-carboxamide J
(3iS;ila-?)--V-f(2,4-Oifluorophenyl)me1.].yl]-6-hydroxy-3-[(1tS)-1-methylpropyl]-5,7-dioxo -2,3,5,7,lI,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxainid.c;
(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;
(3i5',11a/f)-AA-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hc xahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;
(4 S,12aS)-N:[(2,4-Dif[uorophenyl)methyl]-7-hydroxy-4-methyM-(2-methylpropyl)-6,8- dioxo- 1,2,3,4,6,8, 12, 12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyriinidinc-9-carboxa rnidC)
(4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6 ,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1',2':4,5]pyrazino[1,2-a]pyrnnidine-9-carbo xamide.
(4aR,6a/e,14aS)-N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a, 7,11,13,14a-decahydro-2i7-pyrido[1',2':4,5]pyrazino[1,2-a][3,1]benzoxaϋine-10-carboxa mide;
(4a/£,6aR,14a£)-N-[(4-Fluorophenyl)methylM2-hydroxy- 11, 13-dioxo- 1,3, 4,4a, 5,6a,7, - l ,13, 14a-decaliydro-2/r-pyrido[1',2':4,5]pyraziπo[3 ,2-<3ll8, l]benzoxazino-10-carboxamide
4S,9aR)-5Ηydroxy-4-methyl-6, 10-dioxcr3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a, δa-diaza-anthracene^-carboxylic acid 2,4,-difluoro-benylamide;
4R,9aS)-5-Hydroxy-4-methyl-6, lQ-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a, βa-diaza-anthracene^-carboxylic acid 2,4,-difluoro-bonylamide;
2Il,9aS)-5-Hydroxy-2-methyl-6, 10-dioxo-3,4, 6,9,9a, 10-hexahydro-2H-1-oxa-4a, 8a -diaza- anthracene- 7- carboxylic acid 4-fiuoro-benylamide;
enantiomers thereof; diastereomers thereof; mixtures of cnantiomcrs thereof; mixtures of dmstereomers thereof; mixtures of enantiomers and diastereomers thereof; and pharmacexitically acceptable salts thereof.
33. A compound according to claims 31 or 32 wherein the pharmaceutically acceptable salt is a sodium salt,
34. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 33, or a pharmaceutically acceptable salt, or solvate thereof.
35. A pharmaceutical composition according to Claim 34, which is an antrHTV agent.
36. A process for the preparation of a compound of formula (I-20a)
Figure imgf000270_0001
wherein Re is one or two halogen; Jl'- is C1-8alkyl, Ca-i-iarylC1-8alkyl, Cα- uaryl, or alkoxy; and P1 is Ce-narylCj-βalkyli
comprising condensing a compound of the formula
Figure imgf000270_0002
wherein Re is one or two halogen; R00 is C1-8alkyl; and P1 is CcM-iarylC1-8alkyl; with a compound of the formula
Figure imgf000270_0004
wherein R''- is C1-8alkyl, Cβ-i-jarylC1-8alkyl, Cc Maryl, or alkoxy; to form a compound of formula (1-20a),
37. A process for the preparation of a compound of formula (I-20b)
Figure imgf000270_0003
wherein Rl! is one or two halogen; Rκ is C1-8alkyl, Ce-i/jarylC1-8alkyl, Ce-j-jaryl, or alkoxyJ and P1 is Cβ-MarylCi-RalkyL'
comprising condensing a compound of the formula
Figure imgf000271_0001
wherein Rα is one or two halogen; Rδ0 is C1-8alkylJ and P1 is Ce-uarylC1-8alkyl; with a compound of the formula
Figure imgf000271_0002
wherein TC/< is C1-8alkyl, Ca-i-iarylC1-8alkyl, Cβ-i-iaryl, or alkoxyJ to form a compound of formula (I-20b),
38. A process for the preparation of a compound of formula (l-21a)
Figure imgf000271_0003
wherein R0 is one or two halogen; and P1 is Ccs-i<iaryl C1-8alkyl>
comprising condensing a compound of the formula
Figure imgf000271_0004
wherein Re is one or two halogen; Rr>° is C1-8alkyl; and P1 is Cβ-i-iarylCi salkyl; with a compound of the formula
Figure imgf000271_0005
to form a compound of formula (1*2 Ia).
39. A process for the preparation of a compound of formula (I-21b)
Figure imgf000272_0001
wherein R0 is one or two halogen; and P> is Ce-warylC1-8alkyl;
comprising condensing a compound of the formula
Figure imgf000272_0002
wherein R0 is one or two halogen; R50 is Ci galkyl; and P1 is CG i-iarylCi salkyU with a compound of the formula
Figure imgf000272_0004
to form a compound of formula (T-21b).
40, A process for the preparation of a compound of formula (P22a)
Figure imgf000272_0003
wherein Re is one or two halogen; and P1 is Ccj-narylC1-8alkyl; comprising condensing a compound of the formula:
Figure imgf000273_0001
wherein R0 is one or two halogen; Rr>0 is C1-8alkyl; and P1 is Co-MarylC1-8alkyl; with a compound of the formula
Figure imgf000273_0002
to form a compound of formula (l-22a).
41. A process for the preparation of a compound of formula (1-22b)
Figure imgf000273_0003
wherein Rα is one or two halogen; and P1 is Cβ-narylC1-8alkyl; comprising condensing a compound of the formula
Figure imgf000273_0004
wherein Ru is one or two halogen; Rr>" is C1-8alkyl; and P1 is Cc-HarylC1-8alkyl; with a compound of the formula
Figure imgf000273_0005
to form a compound of formula (I-22b),
42. A process for the preparation of a compound of formula (I-23a)
Figure imgf000274_0001
wherein Re is one or two halogen; and P1 is Cβ-narylC1-8alkylJ comprising condensing a compound of the formula
Figure imgf000274_0002
wherein Re is one or two halogen; Ii150 is Ci-Salkyl; and P1 is Ces-MarylCj-galkyL' with a compound of the formula
Figure imgf000274_0003
to form a compound of formula (ϊ-23a).
43. A process for the preparation of a compound of formula (I-23b)
Figure imgf000274_0004
wherein R0 is one or two halogen.; and P 1 is CfM-iarylC1-8alkyl; comprising condensing a compound of the formula
Figure imgf000274_0005
wherein Re is one or two halogen; Rcϋ is C1-8alkyl; and P1 is Ce-i-jarylC1-8alkyl; with a compound of the formula *
Figure imgf000275_0001
to form a compound of formula (J-23b),
44, A process for lhc preparation of a compound of formula (I-24a)
Figure imgf000275_0002
wherein Rα is one or Iwo halogen; Rxl is hydrogen, Oy-ficycloalkyl, lietorocyclo, or C1-8alkyl optionally substituted with hydroxy, Cj-ecycloalkyl, alkoxy, heterocycle, heteroaryl, Cb πaryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci βalkyl or C1-8alkyl.1 and P1 is CG-πarylCi salkyl;
comprising condensing a compound of the formula
Figure imgf000275_0003
wherein Rα is one or two halogen; R150 is C1-8alkyl; and PJ is Cc-HarylC1-8alkyl; with a compound of the formula
Figure imgf000275_0004
wherein R* is C]. βalkyl; RΛl is hydrogen, Cvecycloalkyl, , heterocyclo, or Ci salkyl optionally substituted with hydroxy, C.wscycloalkyl, alkoxy, heterocycle, heteroaryl, Cis-i'iaryl, or amino, wherein said amino may be optionally substituted with -C(O)C] salkyl or C1-8alkyl;
to form a compound of the formula G>24a).
45. A process for the preparation of a compound of formula (I-24b)
Figure imgf000276_0001
wherein Rc is one or two halogen; Rz1 is hydrogen, C3-6cycloalkyl, heterocycle, or C1-8alkyl optionally substituted., with hydroxy, C3-6cycloalkyl, alkoxy, heterocycle, heteroaryl, C6-14aryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8alkyl or C1-8alkyl; and P1 is C6-14arylC1-8alkyl;
comprising condensing a compound of the formula
Figure imgf000276_0002
wherein Rc is one or two halogen; R50 is C1-8alkyl; and P1 is C6-14arylC1-8alkyl; with a compound of the formula
Figure imgf000276_0003
wherein Rz is C1-8alkyl; Rz1 is hydrogen, C3-6cycloalkyl, hotorocycle, or C1-8alkyl optionally substituted with hydroxy, C3-6cycloalkyl, alkoxy, heterocyclo, heteroaryl, C6-14aryl, or amino, wherein said amino may he optionally substituted with -C(O)C1-8alkyl or C1-8alkyl; to form a compound of the formula (I-24b).
46. A process for the preparation of a racemic compound of formula (1-25)
Figure imgf000276_0004
wherein Re is one or two halogen; R/1 is hydrogen, Cs-ocycloalkyl, hetαrocyclo, or Ci-vsalkyl optionally .substituted with hydroxy, Ca-«cycloalkyl, alkoxy, heterocycle, heteroaryl, Co-i-iaryl, or amino, wherein said amino may be optionally substituted with -C(O)C1-8alkyl or C1-8alkyli and P 1 is Co-MarylOj-salkyl;
comprising condensing' a compound of the formula
Figure imgf000277_0001
wherein "R0 is one or two halogen; R50 is Ci-nalkyl; and P1 is Ct-iiiarylC1-8alkyl; with a racemic compound of the formula
Figure imgf000277_0002
whoroin R-1-1 is hydrogen, Cvccycloalkyl, hetorocycle, or Ci-«alkyl optionally substituted with hydroxy, Cs-ocycloalkyl, alkoxy, heterocycle, heteroaryl, Co πaryl, or amino, wherein said amino may be optionally substituted with — C(O)C1-8alkyl or C1-8alkyl;
to form a racemic compound of the formula (1-25),
47, A process for the preparation of a racemic compound of formula (I-26)
Figure imgf000277_0003
wherein R0 is one or two halogen; R7-1 is hydrogen, Ca-βcycloalkyl, heterocycle, or C1-8alkyl optionally substituted with hydroxy, Ca-βcycloalkyl, alkoxy, heterocycle, heteroaryl, Cβ-i<ιaryl, or amino, wherein said amino may be optionally substituted with -C(O)Ci-Salkyl or C1-8alkyli and P1 is Ce-narylC1-8alkyl; comprising condensing a compound of the formula
Figure imgf000278_0001
wherein Ru is one or two halogen; Rr>° is C1-8alkyl; and P1 is Cβ-Maryld-βalkyl; with a raccmic compound of the formula
Figure imgf000278_0002
whoroin Kzl is hydrogen, C3-ecycloalkyl, heterocycle, or C1-8alkyl optionally substituted with hydroxy, Ca-ecycloalkyl, alkoxy, heterocycle, hctcroaryl, CcrHaryl, or amino, wherein said amino may bo optionally substituted with — C(O)C]-salkyl or C1-8alkyl; to form a racemic compound of formula (1-26).
48. A process for the preparation of a racemic compound of formula (I-27)
Figure imgf000278_0003
wherein "R0 is halogen; and P1 is Cβ-HarylC1-8alkyl; comprising condensing a compound of the formula
Figure imgf000278_0004
wherein R0 is one or two halogen; R50 is Cj βalkyl; and P1 is Cft-j-iarylC1-8alkyli with a racemic compound of the formula
Figure imgf000279_0001
to form a raccmic compound of formula (1-27),
49. A method of treatment of an HIV infection in a human comprising administering to said human an antiviral effective amount of a compound according to any of claims J to 33.
50. A compound as claimed in any of claims 1 to 33 for use in medical therapy.
51. Use of a compound as claimed in any of claims 1 to 33 in the manufacture of a medicament for the treatment or prophylaxis of an HlV infection.
52. A compound of formula (1-20a) described m Claim 36. formula (I-20b) described in Claim 37, formula (1-2 I a) described in Claim 38, formula (I-21b) described in Claim 39, formula (I* 22a) described in Claim 40, formula (I -22b) described in Claim 41, formula (l-23a) described in Claim 42, formula (l-23b) described in Claim 43, formula (I -24 a) described in Claim 44, formula (I- 24b) described in Claim 45, formula (1-25) described in Claim 46, formula (I- 26) described in Claim 47, or formula (1-27) described in Claim 48, or a pharmaceutically acceptable salt thereof.
53. A compound of formula (I-20a) described in Claim 36. formula (I-20b) described in Claim 37, formula (I-21a) described in Claim 38, formula (I- 2 Ib) described in Claim 39, formula (I-22a) described in Claim 40, formula (I-22b) described in Claim 41 , formula (I-23a) described in Claim 42, formula (I-23b) described in Claim 43, formula (024a) described in Claim 44, formula (I- 24b) described in Claim 45, formula (1-25) described in Claim 46, formula (1-26) described in Claim 47, or formula (1-27) described in Claim 48, or a pharmaceutically acceptable salt thereof, wherein each P 1 is hydrogen.
54. A pharmaceutical composition according to claim 34 wherein said composition comprises at least one additional therapeutic agent selected from reverse transcriptase inhibitors and protease inhibitors.
55. A method of treatment of an HIV infection in a human comprising administering to said human a composition comprising a compound according to any of claims 1 to 33 and another therapeutic agent.
56, The method according to claim 55 wherein said therapeutic agent is selected from reverse transcriptase inhibitors and protease inhibitors.
PCT/US2006/016604 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity WO2006116764A1 (en)

Priority Applications (59)

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SI200631703T SI1874117T1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
DK06758843.4T DK1874117T3 (en) 2005-04-28 2006-04-28 POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES WITH HIV INTEGRASE INHIBITIVE ACTIVITY
AU2006239177A AU2006239177B8 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
KR1020157036007A KR101848819B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US11/919,386 US8129385B2 (en) 2005-04-28 2006-04-28 Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness
EP06758843.4A EP1874117B8 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
KR1020077027734A KR101363875B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
ES06758843.4T ES2437268T3 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative that has HIV integrase inhibitory activity
EP18166621.5A EP3372281B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
EA200702080A EA014162B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
KR1020137028203A KR101504998B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
CA2606282A CA2606282C (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivatives having hiv integrase inhibitory activity
PL17195280T PL3284520T3 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
KR1020147017235A KR101580310B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
EP17156762.1A EP3187225B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
PL06758843T PL1874117T3 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
EP16154531.4A EP3045206B2 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
JP2008509227A JP4295353B2 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivatives having HIV integrase inhibitory activity
MX2007013351A MX302718B (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity.
NZ562339A NZ562339A (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
CN200680022891.4A CN101212903B (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
PL18166621T PL3372281T3 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
EP17195280.7A EP3284520B1 (en) 2005-04-28 2006-04-28 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
BRPI0610030A BRPI0610030B8 (en) 2005-04-28 2006-04-28 Compound, pharmaceutical composition, and use of a compound
NO20075165A NO339525B1 (en) 2005-04-28 2007-10-10 Polycyclic carbamoyl derivative, pharmaceutical composition comprising this as well as this compound and compositions comprising this for the treatment of disease.
IL186555A IL186555A (en) 2005-04-28 2007-10-10 (4 r,9as)-5-hydroxy-4-methyll-6,1 0-dioxo-3,4,6,9,9a ,10-hexahydro-2h-1-oxa-4a, 8a-diaza-anthracene-7 -carboxylic acid 2,4-difluoro-benzylamide or a pharmaceutically acceptable salt thereof, composition comprising it and uses thereof in the treatment and prophylaxis of hiv
HK08100942.1A HK1107227A1 (en) 2005-04-28 2008-01-24 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
IL215788A IL215788A0 (en) 2005-04-28 2011-10-23 Process for the preparation of polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US13/352,686 US8410103B2 (en) 2005-04-28 2012-01-18 (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
US13/763,174 US8778943B2 (en) 2005-04-28 2013-02-08 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
IL225207A IL225207A (en) 2005-04-28 2013-03-14 Polycyclic carbamoylpyridone derivative, pharmaceutical composition comprising the same, use and process for preparation thereof
IL225206A IL225206A (en) 2005-04-28 2013-03-14 Polycyclic carbamoylpyridone derivative, pharmaceutical composition comprising the same and use thereof
US14/211,364 US9051337B2 (en) 2005-04-28 2014-03-14 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
LU92446C LU92446I2 (en) 2005-04-28 2014-05-07 Dolutegravir or a pharmaceutically acceptable salt or solvate thereof, including sodium dolutegravir
FR14C0041C FR14C0041I2 (en) 2005-04-28 2014-05-19 POLYCYCLIC DERIVATIVE OF CARBAMOYLPYRIDONE WITH INHIBITORY ACTIVITY ON HIV INTEGRASE
CY2014024C CY2014024I2 (en) 2005-04-28 2014-06-25 POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRATED [INTEGRATION] INHIBITING ACTIVITY
NL300676C NL300676I2 (en) 2005-04-28 2014-07-03
HUS1400039C HUS1400039I1 (en) 2005-04-28 2014-07-09 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US14/700,679 US9273065B2 (en) 2005-04-28 2015-04-30 Substituted pyrido[1',2':4,5]pyrazino[1,2-a]pyrimidines as HIV integrase inhibitors
US15/001,336 US20160137666A1 (en) 2005-04-28 2016-01-20 SUBSTITUTED CYCLOPENTA[4,5]OXAZOLO[3,2-a]PYRIDO[1,2-d]PYRAZINES AS HIV INTEGRASE INHIBITORS
US15/086,616 US20160207939A1 (en) 2005-04-28 2016-03-31 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
NO20161315A NO340111B1 (en) 2005-04-28 2016-08-18 Polycyclic carbamoyl derivative, pharmaceutical composition comprising the same as well as such compounds for use in medical therapy
US15/290,094 US20170029438A1 (en) 2005-04-28 2016-10-11 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US15/427,184 US20170145033A1 (en) 2005-04-28 2017-02-08 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
NO2017010C NO2017010I1 (en) 2005-04-28 2017-03-27 (4R, 9aS) -5-hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a, 10-hexahydro-2H-1-oxa-4a, 8a-diazaanthracene-7-carboxylic acid 2 , 4, -difluoro-benzylamide or a pharmaceutically acceptable salt or solvate thereof
US15/482,896 US20170209454A1 (en) 2005-04-28 2017-04-10 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US15/498,684 US20170224695A1 (en) 2005-04-28 2017-04-27 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US15/498,667 US20170224694A1 (en) 2005-04-28 2017-04-27 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US15/597,343 US20170253616A1 (en) 2005-04-28 2017-05-17 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US15/598,655 US20170260203A1 (en) 2005-04-28 2017-05-18 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US15/598,671 US20170267693A1 (en) 2005-04-28 2017-05-18 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US15/697,847 US20170369509A1 (en) 2005-04-28 2017-09-07 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US16/244,441 US20190152990A1 (en) 2005-04-28 2019-01-10 Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
US16/400,373 US10927129B2 (en) 2005-04-28 2019-05-01 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
CY20191100891T CY1122052T1 (en) 2005-04-28 2019-08-20 POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE [INTEGRATION] INHIBITORY ACTIVITY
US16/924,390 US11267823B2 (en) 2005-04-28 2020-07-09 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
NO2021018C NO2021018I1 (en) 2005-04-28 2021-05-10 kabotegravir or a pharmaceutically acceptable salt or solvate thereof
CY20211100866T CY1124601T1 (en) 2005-04-28 2021-10-06 POLYCYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE [INTEGRATION] INHIBITORY ACTIVITY
US17/586,006 US20220213121A1 (en) 2005-04-28 2022-01-27 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

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US13/352,686 Division US8410103B2 (en) 2005-04-28 2012-01-18 (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

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