US20070185007A1 - Aza-quinolinol phosphonate integrase inhibitor compounds - Google Patents

Aza-quinolinol phosphonate integrase inhibitor compounds Download PDF

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US20070185007A1
US20070185007A1 US10/569,655 US56965504A US2007185007A1 US 20070185007 A1 US20070185007 A1 US 20070185007A1 US 56965504 A US56965504 A US 56965504A US 2007185007 A1 US2007185007 A1 US 2007185007A1
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compound
substituted
phosphonate
alkyl
aryl
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Haolun Jin
Choung Kim
Peter Nelson
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    • 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
    • A61K31/4985—Pyrazines or piperazines 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/505—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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
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    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates generally to compounds with antiviral activity and more specifically with HIV-integrase inhibitory properties.
  • HIV infection and related diseases are a major public health problem worldwide.
  • a virally encoded integrase protein mediates specific incorporation and integration of viral DNA into the host genome. Integration is essential for viral replication. Accordingly, inhibition of HIV integrase is an important therapeutic pursuit for treatment of HIV infection and related diseases.
  • HIV-1 Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, etal N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001)410:995-1001).
  • Integrase has emerged as an attractive target, because it is necessary for stable infection and homologous enzymes are lacking in the human host (LaFemina, etal J.
  • integrase The function of integrase is to catalyze integration of proviral DNA, resulting from the reverse transcription of viral RNA, into the host genome, by a stepwise fashion of endonucleolytic processing of proviral DNA within a cytoplasmic preintegration complex (termed 3′-processing or “3′-P”) with specific DNA sequences at the end of the HIV-1 long terminal repeat (LTR) regions, followed by translocation of the complex into the nuclear compartment where integration of 3′-processed proviral DNA into host DNA occurs in a “strand transfer” (ST) reaction (Hazuda, etal Science (2000) 287:646-650; Katztan, etal Adv.
  • ST strand transfer
  • HIV integrase inhibitors which block integration in extracellular assays and exhibit good antiviral effects against HIV-infected cells (Anthony, etal WO 02/30426; Anthony, etal WO 02/30930; Anthony, etal WO 02/30931; WO 02/055079; Zhuang, etal WO 02/36734; U.S. Pat. Nos.
  • HIV integrase inhibitory compounds with improved antiviral and pharmacokinetic properties are desirable, including enhanced activity against development of HIV resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo (Nair, V. “HIV integrase as a target for antiviral chemotherapy” Reviews in Medical Virology (2002) 12(3):179-193; Young (2001) Current Opinion in Drug Discovery & Development, Vol. 4, No. 4, 402-410; Neamati (2002) Expert. Opin. Ther. Patents Vol. 12, No. 5, 709-724). Three-dimensional quantitative structure-activity relationship studies and docking simulations (Buolamwini, etal Jour. Med. Chem .
  • agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., cytotoxic agents and other anti-cancer or anti-viral drugs) that can be administered.
  • a drug e.g., cytotoxic agents and other anti-cancer or anti-viral drugs
  • oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g. blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract.
  • a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.
  • Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside
  • the present invention provides compositions and methods for inhibition of HIV-integrase.
  • the invention provides a compound having the structure:
  • X 1 is CR 1 , NR, or N;
  • X 2 is CR 2 , NR, or N;
  • X 3 is CR 3 , NR, or N;
  • X 4 is CR 4 , NR, or N;
  • X 5 is CR 5 , NR, or N;
  • At least one of X 1 , X 2 , X 3 , X 4 , and X 5 is NR or N;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are, independently selected from H, F, Cl, Br, I, OH, amino (—NH 2 ), ammonium (—NH 3 + ), alkylamino, dialkylamino, trialkylammonium, C 1 -C 8 alkyl, C 1 -C 8 allylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alylthiol, alkylsulfone (—SO 2 R), arylsulfone (—SO 2 Ar), arylsulfoxide (—SOAr), arylthio (—SAr
  • R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
  • L is selected from a bond, O, S, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C( ⁇ O)NH, C( ⁇ O), S( ⁇ O) 2 , C( ⁇ O)NH(CH 2 ) n , and (CH 2 CH 2 O) n , where n may be 1, 2, 3, 4, 5, or 6; and
  • Ar is covalently attached to L and to one or more R 6 and Ar is selected from C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 comprises a phosphonate group.
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • Y is CR 5 , NR or N
  • Z is selected from O, S, NR, CR 2 , CROR, CROC( ⁇ O)R, C( ⁇ O), C( ⁇ S), CRSR, C( ⁇ NR 2 ), C ⁇ CR 2 , CR 2 —CR 2 , CR ⁇ CR, NR—CR 2 , N ⁇ CR, N ⁇ N, SO 2 —NR, C( ⁇ O)CR 2 , S( ⁇ O)CR 2 , SO 2 CR 2 , C( ⁇ O)NR, CR 2 —CR 2 —CR 2 , CR ⁇ CR—CR 2 , CRC( ⁇ O)NR, CR 2 SO 2 CR 2 , CR 2 SO 2 NR, CRC( ⁇ S)NR, CR ⁇ N—CR 2 , CR ⁇ N—NR, or N ⁇ CR—NR.
  • substituted alkylene, substituted alkenylene, substituted alkynylene, substituted aryl, and substituted heteroaryl are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, amino (—NH 2 ), ammonium (—NH 3 + ), alkylamino, dialkylamino, trialkylammonium, C 1 -C 8 allyl, C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkyithiol, alkylsulfone (—SO 2 R), arylsulfone (—SO 2 Ar
  • X 2 is CR 2 and R 2 is selected from H, OH, OC( ⁇ O)OR, OC( ⁇ O)NR 2 , OC( ⁇ O)R, OSO 2 NR 2 (sulfamate), NR 2 , NRSO 2 R, SR, S(O)R, S 0 2 R or SO 2 NR 2 (sulfonamide), lactam having the structures:
  • Also provided in the present invention are compounds of the above formulae wherein L is CH 2 and Ar is substituted phenyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 comprise a prodrug moiety selected from the structures:
  • R 9 is comprised of an ester, an amide, or a carbamate.
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O)— (sulfoxide), —S(O) 2 — (sulfone), —S— (sulfide), or —S—S— (disulfide);
  • M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4 ,5, 6, 7, 8, 9, 10, 11, or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • R y is independently H, alkyl, substituted alkyl, aryl, substituted aryl, or a protecting group, or where taken together at a carbon atom, two vicinal R y groups form a carbocycle or a heterocycle;
  • R x is independently H, alkyl, substituted alkyl, aryl, substituted aryl, or a protecting group, or the formula:
  • M1a, M1c, and M1d are independently 0 or 1
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • W 5 is a carbocycle
  • Y 2c is O, N(R y ) or S.
  • Y 2b is O or N(R x ); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R 1 is H or C 1 -C 6 alkyl; and the phenyl carbocycle is substituted with 0 to 3 R 2 groups where R 2 is C 1 -C 6 alkyl or substituted alkyl.
  • R x is selected from the structures:
  • Also provided in the present invention are compounds of the above formulae wherein x 2 is CR 2 and R 2 comprises a phosphonate prodrug moiety.
  • Also provided in the present invention is a compound of the structure:
  • X 1 is CR 1 , NR, or N;
  • X 2 is CR 2 , NR, or N;
  • X 3 is CR 3 , NR, or N;
  • X 4 is CR 4 , NR, or N;
  • X 5 is CR 5 , NR, or N;
  • At least one of X 1 , X 2 , X 3 , X 4 , and X 5 is NR or N;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from H, F, Cl, Br, I, OH, amino (—NH 2 ), ammonium (—NH 3 + ), alkylamino, dialkylamino, trialkylammonium, C 1 -C 8 alkyl, C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 allcylhydroxyl, C 1 -C 8 allylthiol, alkylsulfone (—SO 2 R), arylsulfone (—SO 2 Ar), arylsulfoxide (—SOAr), arylthio (—SAr), s
  • R is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
  • L is selected from a bond, O, S, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted allylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 allynylene, C 2 -C 12 substituted alkynylene, C( ⁇ O)NH, C( ⁇ O), S( ⁇ O) 2 , C( ⁇ O)NH(CH 2 ) n , and (CH 2 CH 2 O) n , where n may be 1, 2, 3, 4, 5, or 6; and
  • Ar is covalently attached to L and to one or more R 6 and Ar is selected from C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, and C 2 -C 20 substituted heteroaryl;
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 comprises a phosphonate group.
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • the present invention also provides a compound having the formula:
  • Y is CR 5 , NR or N
  • Z is selected from O, S, NR, CR 2 , CROR, CROC( ⁇ O)R, C( ⁇ O), C( ⁇ S), CRSR, C( ⁇ NR 2 ), C ⁇ CR 2 , CR 2 —CR 2 , CR ⁇ CR, NR—CR 2 , N ⁇ CR, N ⁇ N, SO 2 —NR, C( ⁇ O)CR 2 , S( ⁇ O)CR 2 , SO 2 CR 2 , C( ⁇ O)NR, CR 2 —CR 2 —CR 2 , CR ⁇ CR—CR 2 , CRC( ⁇ O)NR, CR 2 SO 2 CR 2 , CR 2 SO 2 NR, CRC( ⁇ S)NR, CR ⁇ N—CR 2 , CR ⁇ N—NR, or N ⁇ CR—NR.
  • substituted alkylene, substituted alkyenylene, substituted allynylene, substituted aryl, and substituted heteroaryl are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, amino (—NH 2 ), ammonium (—NH 3 + ), alkylamino, dialcylamino, trialkylammonium, C 1 - 8 allyl, C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, alkylsulfone (—SO 2 R), arylsulfone (—SO 2
  • X 2 is CR 2 and R 2 is selected from H, OH, OC( ⁇ O)OR, OC( ⁇ O)NR 2 , OC( ⁇ O)R, OSO 2 NR 2 (sulfamate), NR 2 , NRSO 2 R, SR, S(O)R, SO 2 R or SO 2 NR 2 (sulfonamide), lactam having the structures:
  • Also provided in the present invention are compounds of the above formulae wherein L is CH 2 and Ar is substituted phenyl.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 comprise a prodrug moiety selected from the structures:
  • R 9 is comprised of an ester, an amide, or a carbamate.
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O)— (sulfoxide), —S(O) 2 — (sulfone), —S— (sulfide), or —S—S— (disulfide);
  • M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • R y is independently H, alkyl, substituted alkyl, aryl, substituted aryl, or a protecting group, or where taken together at a carbon atom, two vicinal R y groups form a carbocycle or a heterocycle;
  • R x is independently H, alkyl, substituted alkyl, aryl, substituted aryl, or a protecting group, or the formula:
  • M1a, M1c, and M1d are independently 0 or 1
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 2.
  • W 5 is a carbocycle
  • y 2c is O, N(R y ) or S.
  • Y 2b is O or N(R x ); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R 1 is H or C 1 -C 6 alkyl; and the phenyl carbocycle is substituted with 0 to 3 R 2 groups where R 2 is C 1 -C 6 alkyl or substituted alkyl.
  • R x is selected from the structures:
  • Also provided in the present invention are compounds of the above formulae wherein X 2 is CR 2 and R 2 comprises a phosphonate prodrug moiety.
  • composition comprising a therapeutically effective amount of a compound of any of the above formulae and a pharmaceutically acceptable carrier.
  • compositions as above wherein the antiviral agent is an HIV protease inhibitor.
  • compositions made by combining the compound of any of the above formulae and a pharmaceutically acceptable carrier.
  • Also provided in the present invention is a process for making a pharmaceutical composition
  • a process for making a pharmaceutical composition comprising combining a compound of any of the above formulae and a pharmaceutically acceptable carrier.
  • Also provided in the present invention is a method of inhibiting HIV integrase, comprising the administration to a mammal in need of such treatment of a therapeutically effective amount of a compound of any of the above formulae.
  • Also provided in the present invention is a method of treating infection by HIV, or of treating AIDS or ARC, comprising administration to a mammal in need of such treatment of a therapeutically effective amount of a compound of any of the above formulae.
  • the compounds of the invention include at least one phosphonate group covalently attached at any site.
  • the invention also includes a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound selected from the above formulae, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • This invention also includes a method of increasing cellular accumulation and retention of drug compounds, thus improving their therapeutic and diagnostic value.
  • the invention also includes a method of inhibiting HIV, comprising administering to a mammal infected with HIV (HIV positive) an amount of a compound of the above formulae, effective to inhibit the growth of said HIV infected cells.
  • the invention also includes a compound selected from the above formulae for use in medical therapy (preferably for use in treating cancer, e.g. solid tumors), as well as the use of a compound of the above formulae for the manufacture of a medicament useful for the treatment of cancer, e.g. solid tumors.
  • the invention also includes processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the compounds of the above formulae are useful to prepare other compounds of the above formulae.
  • the activity of HIV integrase is inhibited by a method comprising the step of treating a sample suspected of containing HIV virus with a compound or composition of the invention.
  • Another aspect of the invention provides a method for inhibiting the activity of HIV integrase comprising the step of contacting a sample suspected of containing HIV virus with the composition embodiments of the invention.
  • novel methods for the synthesis, analysis, separation, isolation, crystallization, purification, characterization, and testing of the compounds of this invention are provided.
  • phosphonate and “phosphonate group” mean a fumctional group or moiety within a molecule that comprises at least one phosphorus-carbon bond, and at least one phosphorus-oxygen double bond.
  • the phosphorus atom is further substituted with oxygen, sulfur, and nitrogen substituents. These substituents may be part of a prodrug moiety.
  • phosphonate and “phosphonate group” include molecules with phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, phosphondiamidate, and phosphonthioate functional groups.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound.
  • “Pharmaceutically acceptable prodrug” refers to a compound that is metabolized in the host, for example hydrolyzed or oxidized, by either enzymatic action or by general acid or base solvolysis, to form an active ingredient.
  • Typical examples of prodrugs of the compounds of the invention have biologically labile protecting groups on a functional moiety of the compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, photolyzed, hydrolyzed, or other functional group change or conversion involving forming or breaking chemical bonds on the prodrug.
  • Prodrug moiety means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191).
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
  • Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a “prodrug” is thus a covalently modified analog of a therapeutically-active compound.
  • prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters —CH 2 OC( ⁇ O)R 9 and acyloxymethyl carbonates —CH 2 OC( ⁇ O)OR 9 where R 9 is C 1 -C 6 alkyl, C 1 -C 6 substituted alky, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar etal (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
  • a prodrug moiety is part of a phosphonate group.
  • the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
  • An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH 2 OC( ⁇ O)C(CH 3 ) 3 .
  • An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH 2 OC( ⁇ O)OC(CH 3 ) 3 .
  • the phosphonate group may be a phosphonate prodrug moiety.
  • the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group.
  • the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
  • Aryl esters of phosphorus groups are reported to enhance oral bioavailability (DeLambert etal (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g.
  • proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech etal (1993) Antiviral Res., 22: 155-174; Benzaria etal (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion etal, U.S. Pat. No. 6,312,662).
  • Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • the chemical substructure of a protecting group varies widely.
  • One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: “Protective Groups in Organic Chemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion.
  • Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
  • Chemically protected intermediates may themselves be biologically active or inactive.
  • Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
  • Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
  • Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • Alkyl is C 1 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n -propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, —CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH 3 ) 3 ), 1-pentyl (n-pentyl, n
  • Alkenyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond. Examples include, but are not limited to: ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ).
  • Alkynyl is C 2 -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to: acetylenic (—CH ⁇ CH) and propargyl (—CH 2 C ⁇ CH),
  • alkylene and alkyldiyl each refer to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylene radicals include, but are not limited to: methylene (—CH 2 —) 1,2-ethyl (—CH 2 CH 2 —), 1,3-propyl (—CH 2 CH 2 CH 2 —), 1,4-butyl (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene, i.e. double carbon-carbon bond moiety.
  • Typical alkenylene radicals include, but are not limited to: 1,2-ethylene (—CH ⁇ CH—).
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne, i.e. triple carbon-carbon bond moiety.
  • Typical alkynylene radicals include, but are not limited to: acetylene (—C ⁇ C—), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH—).
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Heteroaryl means a monovalent aromatic radical of one or more carbon atoms and one or more atoms selected from N, O, S, or P, derived by the removal of one hydrogen atom from a single atom of a parent aromatic ring system. Heteroaryl groups may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
  • Heteroaryl bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • the heteroaryl group may be bonded to the drug scaffold through a carbon, nitrogen, sulfur, phosphorus or other atom by a stable covalent bond.
  • Heteroaryl groups include, for example: pyridyl, dihydropyridyl isomers, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • Substituted substituents such as “substituted alkyl”, “substituted aryl”, “substituted heteroaryl” and “substituted arylalkyl” mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
  • Typical substituents include, but are not limited to, —X, —R, —O ⁇ , —OR, —SR, —S ⁇ , —NR 2 , —NR 3 , ⁇ NR, —CX 3 , —CN, —OCN, —SCN, —N ⁇ C ⁇ O, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , NC( ⁇ O)R, —C( ⁇ O)R, —C( ⁇ O)NRR —S( ⁇ O) 2 O ⁇ , —S( ⁇ O) 2 OH, —S( ⁇ O) 2 R, —OS( ⁇ O) 2 OR, —S( ⁇ O) 2 NR, —S( ⁇ O)R, —OP( ⁇ O) 2 RR, —P( ⁇ O)O 2 RR —P( ⁇ O)(O ⁇ ) 2 , —P( ⁇ O)(OH) 2
  • Heterocycle means a saturated, unsaturated or aromatic ring system including at least one N, O, S, or P. Heterocycle thus include heteroaryl groups. Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A. “Principles of Modem Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C. W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.
  • heterocycles include by way of example and not limitation pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydropyr
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or , ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Carbocycle means a saturated, unsaturated or aromatic ring system having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • Carbocycle thus includes some aryl groups.
  • Linker or “link” means a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches a phosphonate group to a drug, or between the Formula I scaffold and substituents.
  • Linkers include L interposed between Ar and the nitrogen of Formula I compounds.
  • Linkers may also be interposed between a phosphorus containing A 3 group and the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 positions of Formula I.
  • Linkers include, but are not limited to moieties such as O, S, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -C 12 alkynylene, C 2 -C 12 substituted alkynylene, C( ⁇ O)NH, C( ⁇ O), S( ⁇ O) 2 , C( ⁇ O)NH(CH 2 ) n , and (CH 2 CH 2 O) n , where n may be 1, 2, 3, 4, 5, or 6.
  • Linkers also include repeating units of alkyloxy (e.g.
  • polyethylenoxy, PEG, polymethyleneoxy) and allylamino e.g. polyethyleneamino, JeffamineTM
  • diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral”. refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • d and l or (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • Novel aza-quinolinol phosphonate compounds with inhibitory activity against HIV integrase are described, as embodied in Formula I, including any pharmaceutically acceptable salts thereof.
  • the compounds include an active form for inhibition of nuclear integration of reverse-transcribed HIV DNA.
  • Ring atoms, X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from nitrogen (N), substituted N, or substituted carbon.
  • the compounds of the invention include all enol and tautomeric resonance isomer forms of Formula I.
  • Formula I includes compounds wherein:
  • X 1 is CR 1 , NR, or N;
  • X 2 is CR 2 , NR, or N;
  • X 3 is CR 3 , NR, or N;
  • X 4 is CR 4 , NR, or N;
  • X 5 is CR 5 , NR, or N;
  • At least one of X 1 , X 2 , X 3 , X 4 , and X 5 is NR or N.
  • Exemplary structures within Formula I include the following:
  • CR 1 and CR 2 together may form a ring.
  • X 3 is CR 3 and when X 4 is CR 4 , then CR 3 and CR 4 together may form a ring.
  • X 4 is CR 4 and X 5 is CR 5 , then CR 4 and CR 5 together may form a ring.
  • the ring may be 5, 6, or 7-membered.
  • the ring may be all carbon atoms or it may have one or more heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Exemplary structures when CR 4 and CR 5 form a ring include the following:
  • Z is CR 5 , NR or N.
  • Z is a moiety forming a five, six, or seven membered ring.
  • Z may be O, S, NR, CR 2 , CROR, CROC( ⁇ O)R, C( ⁇ O), C( ⁇ S), CRSR, C( ⁇ NR 2 ), C ⁇ CR 2 , CR 2 —CR 2 , CR ⁇ CR, NR—CR 2 , N ⁇ CR, N ⁇ N, SO 2 —NR, C( ⁇ O)CR 2 , S( ⁇ O)CR 2 , SO 2 CR 2 , C( ⁇ O)NR, CR 2 —CR 2 —CR 2 , CR ⁇ CR—CR 2 , CRC( ⁇ O)NR, CR 2 SO 2 CR 2 , CR 2 SO 2 CR 2 , CR 2 SO 2 CR 2 , CR 2 SO 2 NR, CRC( ⁇ S)NR, CR ⁇ N—CR 2 , CR ⁇ N—NR, or N ⁇
  • L is a bond or any linker which covalently attaches the Ar group to the tricyclic scaffold.
  • L may be a bond, O, S, S( ⁇ O) (sulfoxide), S( ⁇ O) 2 (sulfone), S( ⁇ O) 2 NR (sulfonamide), N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkcylene, C 2 -C 12 alkenylene, C 2 C 12 substituted alkenylene, C 2 12 alkynylene, C 2 -C 12 substituted alkynylene, C( ⁇ O)NH, C( ⁇ O), C( ⁇ O)NH(CH 2 ) n , or (CH 2 CH 2 O) n , where n may be 1, 2, 3, 4, 5, or 6.
  • Ar groups may be any saturated, unsaturated or aromatic ring or ring system comprising a mono- or bicyclic carbocycle or heterocycle, e.g. 3 to 10 ring atoms.
  • the rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
  • Ar may be C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, or C 2 -C 20 substituted heteroaryl.
  • Substituents of Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 may independently include H, F, Cl, Br, I, OH, amino (—NH 2 ), ammonium (—NH 3 + ), alkylamino, dialkylamino, trialkylammonium, C 1 -C 8 alkyl, C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkyithiol, alkylsulfone (—SO 2 R), arylsulfone (—SO 2 Ar), arylsulfoxide (—SOAr), aryl
  • C 6 -C 20 substituted aryl groups include halo-substituted phenyl such as 4-fluorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, and 3,5-difluorophenyl.
  • Ar groups include: where a wavy line in any orientation, indicates the covalent attachment site of the other structural moieties of the compound.
  • substituted phenyl groups include:
  • R 2 may be —H, —OH, —OC( ⁇ O)OR, —OC( ⁇ O)NR 2 , —OC( ⁇ S)NR 2 , —OC( ⁇ O)NRNR 2 , —OC( ⁇ O)R, —C( ⁇ O)OR, —C( ⁇ O)NR 2 , —C( ⁇ O)NRNR 2 , —C( ⁇ O)R, —OSO 2 NR 2 (sulfamate), —NR 2 , —NRSO 2 R, —NRC( ⁇ S)NR 2 , —SR, —S(O)R, —SO 2 R, —SO 2 NR 2 (sulfonamide), —OSO 2 R (sulfonate), —P( ⁇ O)(OR) 2 , —P( ⁇ O)(OR)(NR 2 ), —P( ⁇ O)(NR 2 ) 2 , —P( ⁇ S)(OR) 2 , —P( ⁇ S)(
  • R 2 may include a ring, e.g. 4-7 membered ring lactam or sultam, or piperazinyl sulfamate:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, F, Cl, Br, I, OH, amino (—NH 2 ), ammonium (—NH 3 + ), alkylamino, dialkylamino, trialkylammonium, C 1 -C 8 alkyl C 1 -C 8 alkylhalide (including halomethyl, dihalomethyl, and trihalomethyl such as trifluoromethyl), carboxylate, sulfate, sulfonate, 4-7 membered ring sultam, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, -dialkylarinopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, alkylsulfone (—SO 2 R), arylsulfone (—SO 2 Ar), arylsulfox
  • R may be independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, C 2 -C 20 substituted heteroaryl, a prodrug moiety.
  • a tricyclic integrase inhibitor compound of the invention includes one or more phosphonate group or phosphonate prodrug moiety. At least one of R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 comprises a phosphonate group.
  • the phosphonate group may be a prodrug moiety.
  • the phosphonate group may be directly attached to a ring carbon (CR 1 , CR 2 , CR 3 , CR 4 or CR 5 ) of Formula I.
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R8 may comprise the structure A 3 , where A 3 is:
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x )).
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S( ⁇ O)— (sulfoxide), —S( ⁇ O) 2 — (sulfone), —S— (sulfide), or —S—S— (disulfide).
  • M2 is 0, 1 or 2.
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.
  • R y is independently H, alkyl, substituted alkyl, aryl, substituted aryl, or a protecting group. Alternatively, taken together at a carbon atom, two vicinal R y groups form a ring, i.e. a spiro carbon.
  • the ring may be all carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or alternatively, the ring may contain one or more heteroatoms, for example, piperazinyl, piperidinyl, pyranyl, or tetrahydrofuryl.
  • R x is independently H, alkyl, substituted alkyl, aryl, substituted aryl, or a protecting group, or the formula:
  • M1a, M1c, and M1d are independently 0 or 1.
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • a linker may be interposed between positions R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 and substituent A 3 .
  • the linker may be O, S, NR, N—OR, C 1 -C 12 alkylene, C 1 -C 12 substituted alkylene, C 2 -C 12 alkenylene, C 2 -C 12 substituted alkenylene, C 2 -Cl 2 alkynylene, C 2 -C 12 substituted alkynylene, C( ⁇ O)NH, C( ⁇ O), S( ⁇ O) 2 , C( ⁇ O)NH(CH 2 ) n , and (CH 2 CH 2 O) n , where n may be 1, 2, 3, 4, 5, or 6.
  • Linkers may also be repeating units of alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • the linker may comprise propargyl, urea, or alkoxy groups.
  • Embodiments of A 3 include where M2 is 0, such as: and where M12b is 1, Y 1 is oxygen, and Y 2b is independently oxygen (O) or nitrogen (N(R x )) such as:
  • An embodiment of A 3 includes: where W 5 is a carbocycle such as phenyl or substituted phenyl, and Y 2c is independently O, N(R y ) or S.
  • R 1 may be H and n may be 1.
  • W 5 also includes, but is not limited to, aryl and heteroaryl groups such as:
  • Another embodiment of A 3 includes:
  • Such embodiments include: where Y 2b is O or N(R x ); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R 1 is H or C 1 -C 6 alkyl; and the phenyl carbocycle is substituted with 0 to 3 R 2 groups where R 2 is C 1 -C 6 alkyl or substituted alkyl.
  • Such embodiments of A 3 include phenyl phosphonamidate amino acid, e.g. alanate esters and phenyl phosphonate-lactate esters:
  • Embodiments of R x include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:
  • Embodiments of Formula I include Ia-d where, respectively:
  • the compounds of the invention may also include one or more prodrug moieties located as a covalently-attached substituent at any location of Formula I, e.g. R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , or the 8-hydroxyl.
  • One substituent which may be modified as a prodrug moiety is a phosphonate, phosphate, phosphinate or other phosphoms functionality (Oliyai etal Pharimaceutical Res . (1999) 16:1687-1693; Krise, J. and Stella, V. Adv. Drug Del Reviews (1996) 19:287-310; Bischofberger etal, U.S. Pat. No. 5,798,340).
  • Prodrug moieties of phosphorus functionality serve to mask anionic charges and decrease polarity.
  • the phosphonate prodrug moiety may be an ester (Oliyai, etal Intl. Jour. Phaimaceutics (1999).179:257-265), e.g. POC and POM (pivaloyloxymethyl, Yuan, etal Pharmaceutical Res . (2000) 17:1098-1103), or amidate which separates from the integrase inhibitor compound in vivo or by exposure in vitro to biological conditions, e.g. cells, tissue isolates. The separation may be mediated by general hydrolytic conditions, oxidation, enzymatic action or a combination of steps.
  • Compounds of the invention bearing one or more prodrug moieties may increase or optimize the bioavailability of the compounds as therapeutic agents. For example, bioavailability after oral administration may be preferred and depend on resistance to metabolic degradation in the gastrointestinal tract or circulatory system, and eventual uptake inside cells. Prodrug moieties are considered to confer said resistance by slowing certain hydrolytic or enzymatic metabolic processes. Lipophilic prodrug moieties may also increase active or passive transport of the compounds of the invention across cellular membranes (Darby, G. Antiviral Chem . & Chemotherapy (1995) Supp. 1, 6:54-63).
  • Exemplary embodiments of the invention includes phosphonamidate and phosphoramidate (collectively “amidate”) prodrug compounds.
  • General formulas for phosphonamidate and phosphoramidate prodrug moieties include:
  • the phosphorus atom of the phosphonamidate group is bonded to a carbon atom.
  • the nitrogen substituent R 9 may include an ester, an amide, or a carbamate functional group.
  • R 9 may be —CR 2 C( ⁇ O)OR′ where R′ is H, C 1 -C 6 alky, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heteroaryl, or C 2 -C 20 substituted heteroaryl.
  • the nitrogen atom may comprise an amino acid residue within the prodrug moiety, such as a glycine, alanine, or valine ester (e.g.
  • valacyclovir see: Beauchamp, etal Antiviral Chem. Chemotherapy (1992) 3:157-164), such as the general structure: where R′ is the amino acid side-chain, e.g. H, CH 3 , CH(CH 3 ) 2 , etc.
  • the compounds have pre-organized binding modes which optimize the binding affinity of designed inhibitors.
  • the inhibitor may attain a preferred, low energy conformation (also called bound conformation) in order to interact within an active site.
  • a preferred, low energy conformation also called bound conformation
  • ligands of molecules with multiple rotational bonds exist in many potential conformational states, most of which are not able to bind to the active site. The greater the number of possible ligand conformations typically results in a greater decrease in efficiency of the entropy contribution to the free energy of binding, and will result in less favorable binding affinities.
  • One aspect of designing pre-organized binding features in an integrase inhibitor compound is incorporating conformational constraints that reduces the total number of conformational states and places the inhibitor into a correct binding conformation (Lam, P. Y. S. et al. J Med. Chem , (1996) 39:3514-3525; Chen, J. M. et al. Biochemistry (1998) 37:17735-17744; Chen, J. M. et al. Jour. Amer. Chem. Soc . (2000) 122:9648-9654; Chen, J. M. et al U.S. Pat. No. 6,187,907; Chen, et al Bio. Org. Med. Chem. Letters (2002) 12:1195-1198). Knowledge of one or more preferred binding conformations is important for rational structure design and avoid inactive lead compounds.
  • the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state--any and all protonated forms of the compounds are intended to fall within the scope of the invention.
  • the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na 30 , Li + , K 30 , Ca +2 and Mg +2 .
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion. Moreover, as the compounds can exists in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
  • counter ions e.g., dry salts
  • counter ions e.g., aqueous or organic solutions
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 or organic sulfonic acids, to basic centers, typically amines, or to acidic groups.
  • the compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the salts of the parental compounds with one or more amino acids are included within the scope of this invention.
  • the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the compounds of the invention can also exist as tautomeric, resonance isomers in certain cases.
  • the structures shown herein exemplify only one tautomeric or resonance- form of the compounds.
  • hydrazine, oxime, hydrazone groups may be shown in either the syn or anti configurations.
  • the corresponding alternative configuration is contemplated as well. All possible tautomeric and resonance forms are within the scope of the invention.
  • One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Separation of diastereomers formed from the racemic mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers. Alternatively, enantiomers can be separated directly under chiral conditions, method (3).
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, ⁇ -methoxy- ⁇ -(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers can be separated by chromatography using a chiral stationary phase
  • a chiral stationary phase “Chiral Liquid Chromatography” (1989) W. J Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) “Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase”, J. of Chromatogr. 513:375-378).
  • Enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • the compounds of the invention may be prepared by a variety of synthetic routes and methods known to those skilled in the art.
  • the invention also relates to methods of making the compounds of the invention.
  • the compounds are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in: “Compendium of Organic Synthetic Methods”, John Wiley & Sons, New York, Vol. 1 Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
  • protecting groups to mask reactive functionality and direct reactions regioselectively (Greene, etal (1991) “Protective Groups in Organic Synthesis”, 2nd Ed., John Wiley & Sons).
  • useful protecting groups for the 8-hydroxyl group and other hydroxyl substituents include methyl, MOM (methoxymethyl), trialkylsilyl, benzyl, benzoyl, trityl, and tetrahydropyranyl. Certain aryl positions may be blocked from substitution, such as the 2-position as fluorine.
  • Aza-quinolinol compounds have been prepared, including naphthyridine compounds (US 2003/0119823 A1; WO 03/016315 A1; WO 03/016309 A1; WO 02/30930 A2; WO 02/055079 A2; WO 02/30931 A2; WO 02/30426 A1; WO 02/36734 A2).
  • Quinoline derivatives have been reported (WO 03/031413 A1; US 2002/0103220 A1; US 2002/0055636 A1; U.S. Pat. Nos. 6,211,376; 6,114,349; 6,090,821; 5,88,3255; 5,739,148; 5,639,881; 3,113,135).
  • the intermediate compounds 1-9 incorporate a phosphonate group (R 1 O) 2 P(O) connected to the nucleus by means of a variable linking group, designated as “link” in the attached structures.
  • Charts 2 and 3 illustrates examples of the linking groups present in the structures 1-9.
  • Schemes 1-31 illustrate the syntheses of the intermediate phosphonate compounds of this invention, 1-9, and of the intermediate compounds necessary for their synthesis.
  • reaction sequences which produce the phosphonates 1 are, with appropriate modifications, applicable to the preparation of the phosphonates 2-9.
  • Methods described below for the attachment of phosphonate groups by means of reactive substituents such as OH, Br, NH 2 , CH 3 , CH 2 Br, COOH, CHO etc are applicable to each of the scaffolds 1-9.
  • Scheme 32 illustrates methods for the interconversion of phosphonate diesters, monoesters and acids
  • Scheme 33 illustrates methods for the preparation of carbamates. Protection of Reactive Substituents.
  • Scheme 1 illustrates the preparation of bicyclic hydroxyesters 1.2 from the corresponding anhydrides 1.1, in which at least one of the groups X is C—R 3 .
  • the conversion is effected by means of one or more of the methods described in WO 0230930 A2, Schemes 2, 3, 3A and 5.
  • the resultant ester is then converted into the carboxylic acid 1.3, for example by means of basic hydrolysis using sodium hydroxide, as described in WO 0230930 A2 Scheme 2.
  • furo[3,4-c]pyridazine-5,7-dione 1.4 (WO 994492) is converted, as described above, into 8-hydroxy-pyrido[4,3-c]pyridazine-7-carboxylic acid methyl ester 1.5, and the ester is hydrolyzed with sodium hydroxide to give 8-hydroxy-pyrido[4,3-c]pyridazine-7-carboxylic acid 1.6.
  • furo[3,4-b]pyrazine-5,7-dione 1.7 (Aldrich) and furo[3,4-e][1,2,4]triazine-5,7-dione 1.10 J. Org. Chem., 1958, 23, 1931
  • Scheme 1A illustrates the preparation of bicyclic hydroxyesters 1A.3 in which a substituent Nu is introduced at the 5-position.
  • the bicyclic hydroxyester 1A.1 prepared as described in Scheme 1
  • the halogenation reaction is performed, for example, as described in WO 0230930 A2, p. 159, by reaction of the phenolic ester with N-bromosuccinimide in chloroform, to give the product 1A.2 in which Ha is Br.
  • the hydroxyester 1A.1 is reacted with N-iodosuccinimide, as described in WO 0230930 A2 p.
  • nucleophiles include hydroxy, mercapto or amino compounds, or cyclic or acyclic sulfonamides.
  • the displacement reaction is performed in a polar organic solvent such as pyridine, dimethylformamide, DMPU, dimethylsulfoxide and the like, for example as described in WO 0230930 A2, Examples 57-78.
  • the phenolic hydroxyl group is protected prior to the displacement reaction, and deprotected afterwards.
  • 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid methyl ester 1A.4 (WO 0230930 A2, p. 171) is reacted with one molar equivalent of N-bromosuccinimide in dichloromethane, to yield 5-bromo-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid methyl ester, 1A.5.
  • the phenol is then reacted with p-toluenesulfonyl chloride and triethylamine in chloroform, for example as described in WO 02 30931 A2 p.
  • the hydroxyester 2.1 prepared as described above, is transformed, using the procedures described below, (Schemes 3-31) into the phosphonate ester 2.2.
  • the ester, or the corresponding carboxylic acid is then converted, using, for example, the procedures described in WO 0230930 A2, Schemes 1, 2, 3 and 5, into the phosphonate amide 2.4.
  • the ester 2.1, or the corresponding carboxylic acid is transformed, as described above, into the amide 2.3, and the latter compound is then converted, using the procedures described below, (Schemes 3-31) into the phosphonate amide 2.4.
  • the selection of a suitable stage in the synthetic sequence for the introduction of the phosphonate group is made by one skilled in the art, depending on the reactivities and stabilities of the substrates in a given reaction sequence.
  • Preparation of the Intermediate Phosphonate Esters 1 is made by one skilled in the art, depending on the reactivities and stabilities of the substrates in a given reaction sequence.
  • Schemes 3-7 illustrate methods for the preparation of the phosphonate esters 1.
  • Scheme 3 depicts the preparation of phosphonate esters 1 in which the phosphonate group is directly attached to the group Ar.
  • a bromo-substituted amine 3.1 in which Ar is an aromatic or heteroaromatic group, is reacted, in the presence of a palladium catalyst, with a dialkyl phosphite 3.2 to yield the aryl phosphonate 3.3.
  • the preparation of arylphosphonates by means of a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Med. Chem., 35, 1371, 1992.
  • This reaction is performed in an inert solvent such as toluene, in the presence of a base such as triethylamine and a palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium(0).
  • a base such as triethylamine
  • a palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium(0).
  • the amine group is protected prior to the coupling reaction, and deprotected afterwards.
  • the amine is then reacted with the ester 3.4 to afford the amide 3.5.
  • the conversion of esters into amides is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 987.
  • the reactants are combined in a solvent such as toluene or xylene, in the presence of a base such as sodium methoxide under azeotropic conditions, or of a dialkyl aluminum or trialkyl tin derivative of the amine.
  • a base such as sodium methoxide under azeotropic conditions
  • a dialkyl aluminum or trialkyl tin derivative of the amine is described in J. Med. Chem. Chim. Ther., 34, 1999, 1995, and Syn. Comm., 25, 1401, 1995.
  • the reaction is conducted in an inert solvent such as dichloromethane or toluene.
  • the conversion of bicyclic esters such as 3.4, or the corresponding carboxylic acids, into amides is described in WO 0230930 A2, Schemes 1, 2, 3 and 6.
  • the phenolic hydroxyl group of the bicyclic ester 3.4 is protected, for example as a p-toluenesulfonyl derivative, as described in WO 0230930 A2, Example 1, prior to reaction with the amine component 3.3.
  • 3-bromo-4-fluorobenzylamine 3.6 (Lancaster) is reacted in toluene solution at ca. 100°, with one molar equivalent of a dialkyl phosphite 3.7, triethylamine and 3 mol % of tetrakis(triphenylphosphine)palladium(0), to give the phosphonate product 3.8.
  • Scheme 4 depicts the preparation of phosphonate esters 1 in which the phosphonate group is attached by means of a saturated or unsaturated alkylene chain.
  • a bromo-substituted amine 4.1 in which Ar is an aryl or heteroaryl group, is subjected to a Heck coupling reaction, in the presence of a palladium catalyst, with a dialkyl alkenyl phosphonate 4.2, in which R 5 is a direct bond, an alkyl, alkenyl, cycloalkyl or cycloalkenyl group, optionally incorporating a heteroatom O, S or N, or a functional group such as an amide, ester, oxime, sulfoxide or sulfone etc, or an optionally substituted aryl, heteroaryl or aralkyl group, to give the amine 4.3.
  • the aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a palladium(II) catalyst such as palladium(II) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate.
  • a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a palladium(II) catalyst such as palladium(II) acetate
  • a base such as triethylamine or potassium carbonate.
  • the amine substituent is protected prior to the coupling reaction, and deprotected afterwards.
  • the phosphonate amine 4.3 is then coupled, as described above, with the ester 4.4, or the corresponding carboxylic acid, to produce the amide 4.5.
  • the double bond is reduced to give the saturated analog 4.6.
  • the reduction of olefinic bonds is described in Comprehensive Organic Transformations, by R C. Larock, VCH, 1989, p. 6ff.
  • The-transformation is effected by means of catalytic hydrogenation, for example using a palladium on carbon catalyst and hydrogen or a hydrogen donor, or by the use of diimide or diborane.
  • 3-bromo-4-methoxybenzylamine 4.7 (Lancaster) is reacted in dioxan solution with one molar equivalent of a dialkyl vinyl phosphonate 4.8 (Aldrich) and potassium carbonate, to yield the olefinic phosphonate 4.9.
  • the product is then reacted, as described above, with 5-(1,l-dioxo-isothiazolidin-2-yl)-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid methyl ester 4.10, prepared as described in Scheme 1A, and by methods described in WO 0230930 A2, to give the amide 4.11.
  • the latter compound is reacted with diimide, prepared by basic hydrolysis of diethyl azodicarboxylate, as described in Angew. Chem. Int. Ed., 4, 271, 1965, to yield the saturated product 4.12.
  • Scheme 5 depicts the preparation of phosphonate esters 1 in which the phosphonate group is attached by means of an amide linkage.
  • the, amine group of a carboxy-substituted amine 5.1 is protected to afford the derivative 5.2.
  • the protection of amino groups is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 309ff.
  • Amino groups are protected, for example by alkylation, such as by mono or dibenzylation, or by acylation.
  • the carboxylic acid is reacted with the amine in the presence of an activating agent, such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in the presence of, for example, hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in a non-protic solvent such as, for example, pyridine, DMF or dichloromethane, to afford the amide.
  • an activating agent such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide
  • a non-protic solvent such as, for example, pyridine, DMF or dichloromethane
  • the carboxylic acid is first converted into an activated derivative such as the acid chloride, anhydride, mixed anhydride, imidazolide and the like, and then reacted with the amine, in the presence of an organic base such as, for example, pyridine, to afford the amide.
  • an activated derivative such as the acid chloride, anhydride, mixed anhydride, imidazolide and the like
  • an organic base such as, for example, pyridine
  • the conversion of a carboxylic acid into the corresponding acid chloride is effected by treatment of the carboxylic acid with a reagent such as, for example, thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane, optionally in the presence of a catalytic amount of dimethylformamide.
  • a reagent such as, for example, thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane, optionally in the presence of a catalytic amount of dimethylformamide.
  • the amino-protecting group is then removed from the product 5.4 to give the free amine 5.5.
  • Deprotection of amines is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 309ff.
  • the amine is then coupled with the carboxylic acid 5.6, as described above, to produce the amide 5.7.
  • phthalimido derivative 5.9 4-carboxycyclohexylmethylamine 5.8 (Aldrich) is converted into the phthalimido derivative 5.9.
  • the conversion of amines into phthalimido derivatives is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 358.
  • the conversion is effected by reaction of the amine with an equimolar amount of 2-carbomethoxybenzoyl chloride, N-carboethoxyphthalimide, or preferably, phthalic anhydride.
  • the reaction is performed in an inert solvent such as toluene, dichloromethane or acetonitrile, to prepare the phthalimido derivative 5.9.
  • This material is then reacted with one molar equivalent of a dialkyl aminoethyl phosphonate 5.10, (J. Org. Chem., 2000, 65, 676) and dicyclohexylcarbodiimide in dimethylformamide, to give the amide 5.11.
  • the phthalimido protecting group is then removed, for example by reaction with ethanolic hydrazine at ambient temperature, as described in J. Org. Chem., 43, 2320, 1978, to afford the amine 5.12.
  • Scheme 6 depicts the preparation of phosphonates 1 in which the phosphonate is attached by means of an ether linkage.
  • the amino group of a hydroxy-substituted amine 6.1 is protected, as described above, to give the derivative 6.2.
  • the carbinol is then reacted, with base catalysis, with a diallyl bromomethyl phosphonate 6.3, in which the group R 5 is as defined in Scheme 4.
  • the reaction is conducted in a polar aprotic solvent such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide, in the presence of a base such as potassium carbonate, for cases in which Ar is an aromatic group, or a strong base such as sodium hydride, for cases in which Ar is an aliphatic group.
  • a base such as potassium carbonate
  • Ar is an aromatic group
  • a strong base such as sodium hydride
  • N-methyl 3-hydroxyphenethylamine 6.8 is reacted with one molar equivalent of acetyl chloride in dichloromethane containing pyridine, to give the N-acetyl product 6.9.
  • the product is then reacted at ca. 60° in dimethylformamide solution with one molar equivalent of a dialkyl 3-bromopropenyl phosphonate 6.10 (Aurora) and cesium carbonate, to produce the ether 6.11.
  • the N-acetyl group is then removed, for example by treatment with hog kidney acylase, as described in Tet., 44, 5375, 1988, to give the amine 6.12.
  • Scheme 7 depicts the preparation of phosphonates 1 in which the phosphonate is attached by means of an ether or thioether linkage.
  • a N-protected hydroxyamine 6.2 in which Ar is an aromatic moiety, is subjected to a Mitsunobu reaction with a hydroxy or mercapto-substituted dialkyl phosphonate 7.1, in which R 5 is as defined in Scheme 4, to prepare the ether or thioether product 7.2.
  • the preparation of aromatic ethers and thioethers by means of the Mitsunobu reaction is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 448, and in Advanced Organic Chemistry, Part B, by F. A.
  • N-acetyl 3,5-dichloro-4-hydroxybenzylamine 7.4 is reacted tetrahydrofuran solution with one molar equivalent of a dialkyl mercaptoethyl phosphonate 7.5, (Zh. Obschei. Khim., 1973, 43, 2364) diethyl azodicarboxylate and tri-o-tolylphosphine, to afford the thioether product 7.6.
  • Schemes 8-10 illustrate methods for the preparation of the phosphonate esters 2.
  • Scheme 8 depicts the preparation of phosphonates 2 in which the phosphonate is attached by means of an alkylene chain incorporating an amide linkage.
  • an amine 8.1 is reacted with a bromoalkyl ester 8.2, in which R 5 is as defined in Scheme 4, to yield the alkylated amine 8.3.
  • R 5 is as defined in Scheme 4, to yield the alkylated amine 8.3.
  • the preparation of substituted amines by the reaction of amnines with alkyl halides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 397.
  • 4-trifluoromethylbenzylamine 8.9 is reacted in dimethylformamide with one molar equivalent of methyl bromoacetate 8.10 and potassium carbonate to give the ester 8.11.
  • Hydrolysis employing one molar equivalent of lithium hydroxide in aqueous dimethoxyethane, affords the carboxylic acid 8.12, and this compound is coupled in tetrahydrofuran solution with a dialkyl aminomethyl phosphonate 8.13 (Aurora), in the presence of dicyclohexylcarbodiimide, to give the aminoamide 8.14.
  • Scheme 9 depicts the preparation of phosphonates 2 in which the phosphonate is attached by means of a variable carbon chain.
  • a primary amine 9.1 is subjected to a reductive amination reaction with a dialkyl formyl-substituted phosphonate 9.2, in which R 5 is as defined in Scheme 4, to afford the alkylated amine 9.3.
  • R 5 is as defined in Scheme 4, to afford the alkylated amine 9.3.
  • the preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421, and in Advanced Organic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 269.
  • the amine component and the aldehyde or ketone component are reacted together in a polar solvent in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990.
  • a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride
  • a Lewis acid such as titanium tetraisopropoxide
  • Scheme 10 depicts an alternative method for the preparation of phosphonates 2 in which the phosphonate is attached by means of a variable carbon chain.
  • the phenolic group of a bicyclic amide 10.1 prepared as described above, and in WO 0230930 A2, is protected to give the product 10.2.
  • the protection of phenolic hydroxyl groups is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 10ff.
  • hydroxyl substituents are protected as trialkylsilyloxy ethers.
  • Trialkylsilyl groups are introduced by the reaction of the phenol with a chlorotrialkylsilane and a base such as imidazole, for example as described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M. Wuts, Wiley, Second Edition 1990, p. 10, p. 68-86.
  • phenolic hydroxyl groups are protected as benzyl or substituted benzyl ethers, or as acetal ethers such as methoxymethyl or tetrahydropyranyl.
  • the O-protected amide 10.2 is then reacted with the phosphonate-substituted trifluoromethanesulfonate 10.3, in which R 5 is as defined in Scheme 4, to produce the alkylated amide 10.4.
  • the alkylation reaction is conducted between equimolar amounts of the reactants in an aprotic organic solvent such as dimethylformamide or dioxan, in the presence of a strong base such as lithium hexamethyl disilylazide or sodium hydride, at from ambient temperature to about 90°.
  • the hydroxyl group is then deprotected to give the phenol 10.5.
  • Deprotection of phenolic hydroxyl groups is described in Protective Groups in Organic Synthesis, by T. W. Greene and P. G. M.
  • silyl protecting groups are removed by reaction with tetrabutylammonium fluoride, benzyl groups are removed by catalytic hydrogenation and acetal ethers are removed by treatment with acids.
  • furo[3,4-b]pyrazine-5,7-dione 10.6 (J. Org. Chem., 1964, 29, 2128) is converted, as described above, (Schemes 1, 1A and 2) and in WO 0230930 A2, into 5-(1,1-dioxo-1,2]thiazinan-2-yl)-8-hydroxy-pyrido[3,4b]pyrazine-7-carboxylic acid (naphthalen-2-ylmethyl)-amide 10.7.
  • the product is then reacted with one molar equivalent of tert-butyl chlorodimethylsilane and imidazole in dichloromethane, to give the silyl ether 10.8.
  • Schemes 11-15 illustrate methods for the preparation of the phosphonate esters 3.
  • Scheme 11 depicts the preparation of phosphonates 3 in which the phosphonate is attached by means of a heteroatom O, S or N, and a variable carbon chain.
  • a bicyclic amide 11.1 prepared as previously described, is reacted in an aprotic solvent such as dichloromethane, hexachloroethane or ethyl acetate with a free radical brominating agent such as N-bromosuccinimide or N-bromoacetamide, to yield the 5-bromo product 11.2.
  • This compound is then reacted with a dialkyl hydroxy, mercapto or amino-substituted phosphonate 11.3, in which R 5 is as defined as in Scheme 4, to give the ether, thioether or amine product 11.4.
  • the displacement reaction is conducted in a polar aprotic organic solvent such as dimethylformamide or DMPU, at from 100° to about 150°, in the presence of a base such as triethylamine or cesium carbonate, for example as described in WO 0230930 A2, Examples 57-69.
  • furo[3,4-d]pyrimidine-5,7-dione 11.5 (J. Het. Chem., 1993, 30, 1597) is converted, as described above, into 8-hydroxy-pyrido[4,3-d]pyrimidine-7-carboxylic acid cyclohexylmethyl-amide 11.6.
  • the product is reacted with one molar equivalent of N-bromosuccinimide in dichloromethane to yield the 5-bromo product 11.7.
  • This material is then reacted with a dialkyl mercaptoethyl phosphonate 11.8 (Zh. Obschei. Khim., 1973, 43, 2364) and triethylamine at ca 100° in a pressure vessel, to produce the thioether 11.9.
  • Example 2 the anhydride 11.10 is converted, as described previously, into 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 3,5-dichloro-benzylamide 11.11. Bromination with N-bromosuccinimide in ethyl acetate at reflux temperature then yields the bromo compound 11.12 which is reacted with a dialkyl 3-aminophenyl phosphonate 11.13 (J. Med. Chem., 1984, 27, 654) in dimethylformamide at ca. 130°, using the procedure described in WO 0230930 A2 Example 63, to give the phosphonate 11.14. The product is then reacted with N, N-dimethyloxamide 11.15, (Japanese Patent 540467 18) and dicyclohexylcarbodiimide in dimethylformamide, to yield the amide product 11.16.
  • N, N-dimethyloxamide 11.15 Japanese Patent 540467 18
  • Scheme 12 depicts the preparation of phosphonates 3 in which the phosphonate is attached by means of a carbamate linkage.
  • a protected bromophenol 12.1 is reacted, as described in Scheme 11, with an amine 12.2 to give the displacement product 12.3.
  • This compound is then reacted with phosgene, triphosgene, carbonyl diimidazole or a functional equivalent thereof, and a dialkyl hydroxyalkyl phosphonate 12.4, in which R 5 is as defined in Scheme 4, to yield, after deprotection of the phenol, the carbamate 12.5.
  • R 5 is as defined in Scheme 4
  • the hydroxyester 12.6 is converted, as described previously, into the amide 12.7.
  • This material is then reacted, in dimethylformamide solution at 100°, with ethylamine and cesium carbonate in dimethylformamide, to afford 8-(tert-butyl-dimethyl-silanyloxy)-5-ethylamino-[1,6]naphthyridine-7-carboxylic acid [2-(4fluoro-phenyl)-cyclopropyl]-amide 12.9.
  • the amine is treated with equimolar amounts of a dialkyl hydroxypropyl phosphonate 12.10 (Zh. Obschei. Khim., 1974, 44, 1834) and carbonyldiimidazole in dichloromethane, to prepare, after desilylation, the carbamate 12.11.
  • Scheme 13 depicts the preparation of phosphonates 3 in which the phosphonate is attached by means of an arylvinyl or arylethyl linkage.
  • a bromophenol 13.1 is protected to give the product 13.2.
  • This compound is then coupled with tributylvinyltin to yield the 5-vinyl product 13.3.
  • the coupling reaction is effected in dimethylformamide solution at ca. 80° in the presence of a palladium(0) catalyst, such as tris(dibenzylideneacetone)palladium(0), a triarylphosphine such as tri(2-furyl)phosphine and copper(I) iodide, for example as described in WO 0230930A2, Example 176.
  • the vinyl-substituted product is subjected to a palladium-catalyzed Heck coupling reaction, as described in Scheme 4, with a dibromoaromatic or heteroaromatic compound 13.4, to give the bromoaryl product 13.5.
  • the latter compound is then coupled, as described in Scheme 3, with a dialkyl phosphite 13.6, in the presence of a palladium catalyst, to give the aryl phosphonate 13.7. Deprotection then affords the phenol 13.8.
  • the double bond is reduced, for example as described in Scheme 4, to give the saturated analog 13.9.
  • furo[3,4-c]pyridazine-5,7-dione 13.10 (WO9944992) is converted, using the methods described above, into the silyl-protected bromophenol 13.11.
  • the product is coupled, as described above, with tri(n-butyl)vinyltin to produce the 5-vinyl compound 13.12.
  • the product is coupled, in the presence of a palladium(0) catalyst and triethylamine, with a dialkyl phosphite 13.15, to afford the phosphonate 13.16.
  • Deprotection for example by reaction with tetrabutylammonium fluoride in tetrahydrofuran, then yields the phenol 13.17, and hydrogenation of the latter compound in methanol, using 5% palladium on carbon as catalyst, produces the saturated analog 13.18.
  • Scheme 14 depicts the preparation of phosphonates 3 in which the phosphonate is attached by means of an acetylenic bond.
  • a phenol 14.1 is reacted, as described in WO 0230930 A2 p. 166 and Example 112, with N-iodosuccinimide in dichloromethane-dimethylformamide, to give the 5-iodo product; protection of the phenolic hydroxyl group then affords the compound 14.2.
  • furo[3,4-e][1,2,4]triazine-5,7-dione 14.5, (J. Org. Chem., 1958, 23, 1931) is converted, as described previously, into the hydroxyester 14.6.
  • This material is then converted into 5-iodo-8-(tert-butyl-dimethyl-silanyloxy)-pyrido[3,4-e][1,2,4]triazine-7-carboxylic acid (cyclopent-3-enylmethyl)-amide 14.7, as described above.
  • the product is coupled, as described above, with a dialkyl propynyl phosphonate 14.8, (Syn., 1999, 2027) to yield, after deprotection, the acetylenic phosphonate 14.9.
  • Scheme 15 depicts the preparation of phosphonates 3 in which the phosphonate is directly attached to the bicyclic nucleus.
  • a protected bicyclic bromophenol 15.1 is coupled, in the presence of a palladium catalyst, as described in Scheme 3, with a dialkyl phosphite 15.2, to give after deprotection the aryl phosphonate 15.3.
  • 3-methyl-furo[3,4-b]pyridine-5,7-dione 15.4 (German Patent DE 3707530) is converted, using the procedures described above,.into 5-bromo-8-(tert-butyl-dimethyl-silanyloxy)3-methyl-:[1,6]naphthyridine-7-carboxylic acid [1-(3-chloro-4-fluoro-phenyl)-1-methyl-ethyl]-amide 15.5.
  • Schemes 16-18 illustrate methods for the preparation of the phosphonate esters 4.
  • Scheme 16 depicts the preparation of phosphonate esters 4 in which the phosphonate group is attached by means of a variable carbon chain.
  • the phosphonate 16.1 in which the phenolic hydroxyl group is protected, prepared as described in Scheme 11, is reacted with the sulfonyl chloride 16.2 or the sulfonic acid 16.3 to afford after deprotection the sulfonamide 16.4.
  • the reaction between an amine and a sulfonyl chloride, to produce the sulfonamide is conducted at ambient temperature in an inert solvent such as dichloromethane, in the presence of a tertiary base such as triethylamine.
  • reaction between a sulfonic acid and an amine to afford a sulfonamide is conducted in a polar solvent such as dimethylformamide, in the presence of a carbodiimide such as dicyclohexyl carbodiimide, for example as described in Syn., 1976, 339.
  • a polar solvent such as dimethylformamide
  • the protected amine phosphonate 16.5 prepared by the methods described above, is reacted in dichloromethane solution with one molar equivalent of ethyl sulfonyl chloride 16.6 and triethylamine, to produce, after desilylation, the sulfonamide 16.7.
  • Scheme 17 depicts an alternative method for the preparation of phosphonate esters 4 in which the phosphonate group is attached by means of a variable carbon chain.
  • a dialkyl amino-substituted phosphonate 17.1 in which the group R 5 is as defined in Scheme 4
  • a sulfonyl chloride 17.2 or sulfonic acid 17.3, as described in Scheme 16 to yield the sulfonamide 17.4.
  • the product is then reacted with a bromoamide 17.5, to prepare the displacement product 17.6.
  • the displacement reaction is performed in a basic solvent such as pyridine or quinoline, at from about 80° to reflux temperature, optionally in the presence of a promoter such as copper oxide, as described in WO 0230930 A2 Example 154.
  • a dialkyl 4-aminophenyl phosphonate 17.7 (Epsilon) is reacted in dichloromethane solution with one molar equivalent of methanesulfonyl chloride 17.8 and triethylamine, to give the sulfonamide 17.9.
  • the product is then reacted in pyridine solution at reflux temperature with 5-bromo-8-hydroxy-pyrido[3,4b]pyrazine-7-carboxylic acid 4-fluoro-benzylamide 17.10, prepared by the methods described above, and copper oxide, to yield the sulfonamide 17.11.
  • Scheme 18 depicts an alternative method for the preparation of phosphonate esters 4 in which the phosphonate group is attached by means of a variable carbon chain.
  • a phenol-protected 5-bromo substituted amide 18.1 is reacted, as described in Scheme 17, with a sulfonamide 18.2, to give the displacement product 18.3.
  • the product is then reacted with a dialkyl bromoalkyl phosphonate 18.4 to afford, after deprotection of the phenol, the alkylated compound 18.5.
  • the alkylation reaction is performed in a polar aprotic solvent such as dimethylformamide or DMPU, at from ambient temperature to about 100°, in the presence of a base such as sodium hydride or lithium hexamethyl disilylazide.
  • the product is then reacted in dimethylformamide solution with one molar equivalent of a dialkyl bromoethyl phosphonate 18.9 (Aldrich) and lithium hexamethyl disilylazide, to give after debenzoylation, the sulfonamide phosphonate 18.10.
  • the benzoyl protecting group is removed, for example, by reaction with 1% methanolic sodium hydroxide at ambient temperature, as described in Tet., 26, 803, 1970.
  • Schemes 19-21 illustrate methods for the preparation of the phosphonate esters 5.
  • Scheme 19 illustrates the preparation of phosphonates 5 in which the phosphonate group is attached by means of a variable carbon chain.
  • a bromo-substituted sulfonic acid 19.1 is subjected to an Arbuzov reaction with a trialkyl phosphite 19.2 to give the phosphonate 19.3.
  • the Arbuzov reaction is performed by heating the bromo compound with an excess of the trialkyl phosphite at from 100° to 150°, as described in Handb. Organophosphorus Chem., 1992, 115-72.
  • the resulting phosphonate is then reacted with an amine 19.4, either directly, in the presence of a carbodiimide, or by initial conversion to the sulfonyl chloride, as described in Scheme 16, to afford, after deprotection of the phenolic hydroxyl group, the sulfonamide 19.5.
  • 3-bromopropanesulfonic acid 19.6 (Sigma) is heated at 130° with a trialkyl phosphite 19.7 to give the phosphonate 19.8.
  • the product is then reacted in DMPU solution with 8-(tert-butyl-dimethyl-silanyloxy)-5-ethylamino-[1,6]naphthyridine-7-carboxylic acid 4fluoro-benzylamide 19.9, prepared by the methods described above, in the presence of dicyclohexylcarbodiimide, to give, after desilylation, by reaction with tetrabutylammonium fluoride in tetrahydrofuran, the sulfonamide 19.10.
  • Scheme 20 illustrates the preparation of phosphonates 5 in which the phosphonate group is attached by means of a saturated or unsaturated carbon chain and an aromatic or heteroaromatic group.
  • a vinyl-substituted sulfonic acid 20.1 is coupled, in a palladium-catalyzed Heck reaction, as described in Scheme 4, with a dibromoaromatic or heteroaromatic compound 20.2, to yield the sulfonic acid 20.3.
  • the product is then coupled, in the presence of a palladium catalyst, as described in Scheme 3, with a dialkyl phosphite HP(O)(OR 1 ) 2 , to give the phosphonate 20.4.
  • vinylsulfonic acid 20.8 (Sigma) is coupled, in dioxan solution, in the presence of tetrakis(triphenylphosphine)palladium (0) and potassium carbonate, with 2,5-dibromothiophene 20.9, to form the coupled product 20.10.
  • the product is then reacted in toluene solution at 100° with a dialkyl phosphite 20.11, triethylamine and a catalytic amount of tetrakis(triphenylphosphine)palladium (0), to produce the phosphonate 20.12.
  • This material is then reacted, in dimethylformamide solution at ambient temperature, as described above, with 8-(tert-butyl-dimethyl-silanyloxy)-5-cyclopropylamino-pyrido[4,3-d]pyrimidine-7-carboxylic acid 4-fluoro-benzylamide 20.13, prepared by the methods described above, in the presence of dicyclohexylcarbodiimide, to give, after desilylation, using tetrabutylammonium fluoride, the sulfonamide 20.14. Hydrogenation of the double bond, for example using 5% palladium on carbon as catalyst, then yields the saturated analog 20.15.
  • Scheme 21 illustrates the preparation of phosphonates 5 in which the phosphonate group is attached by means of a variable carbon chain.
  • an aliphatic bromo-substituted sulfonic acid 21.1 is subjected to an Arbuzov reaction with a trialkyl phosphite, as described in Scheme 19, to give the phosphonate 21.2.
  • an aryl bromosulfonic acid 21.1 is coupled, as described in Scheme 3, with a dialkyl phosphite, to give the phosphonate 21.2.
  • the product is then reacted with an amine 21.3 to afford the sulfonamide 21.4.
  • the latter compound is then reacted, as described in Scheme 17, with a bromoamide 21.5, to give the displacement product 21.6.
  • Schemes 22-24 illustrate methods for the preparation of the phosphonate esters 6.
  • Scheme 22 depicts the preparation of phosphonates 6 in which the phosphonate group is attached by means of an amide linkage and a variable carbon chain.
  • a cyclic sulfonamide 22.1 incorporating a secondary amine, is coupled, as described in Scheme 5, with a dialkyl carboxy-substituted phosphonate 22.2 to produce the amide 22.3.
  • the product is then reacted with a bromoamide 22.4 to afford the displacement product 22.5.
  • the cyclic sulfonamide 22.1 is protected to give the analog 22.6.
  • Sulfonamides are protected, for example, by conversion into the N-acyloxymethyl derivatives, such as the pivaloyloxymethyl derivative or the benzoyloxymethyl derivative, by reaction with the corresponding acyloxymethyl chloride in the presence of dimethylaminopyridine, as described in Bioorg. Med. Chem. Lett., 1995, 5, 937, or by conversion into the carbamate derivative, for example the tert. butyl carbamate, by reaction with an alkyl, aryl or aralkyl chloroformate, in the presence of a base such as triethylamine, as described in Tet.
  • Sulfonamide carbamates for example the tert. butyl carbamate, are deprotected by treatment with trifluoroacetic acid.
  • the sulfonamide 22.9 is then reacted with the bromoamide 22.10 to give the displacement product 22.11.
  • [1,2,5]thiadiazepane 1,1-dioxide 22.11A (WO 0230930 A2 p. 321) is reacted in dioxan solution with equimolar amounts of a dialkyl 3-carboxypropyl phosphonate 23.12, (Epsilon) and dicyclohexyl carbodiimide, to produce the amide 22.13.
  • This material is reacted in pyridine solution at reflux temperature with 5-bromo-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 4-fluoro-benzylamide 22.14, prepared by the methods described above, and copper oxide, to afford the displacement product 22.15.
  • the sulfonamide 22.11A is reacted in dichloromethane with one molar equivalent of t-Boc anhydride, triethylamine and dimethylaminopyridine, to give 1,1-dioxo-[1,2,5]thiadiazepane-2-carboxylic acid tert-butyl ester 22.16.
  • the product is then reacted at ambient temperature in dimethylformamide solution with a dialkyl 4-bromomethyl benzyl phosphonate 22.17, (Tet., 1998, 54, 9341) and potassium carbonate, to yield the alkylation product 22.18.
  • the BOC group is removed by treatment with trifluoroacetic acid to give the sulfonamide 22.19, and this material is reacted, as described above, with 5-bromo-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 3-fluoro-benzylamide 22.20, prepared by the methods described above, to afford the displacement product 22.21.
  • Scheme 23 depicts the preparation of phosphonates 6 in which the phosphonate group is attached by means of an aryl or heteroaryl group.
  • a bromoaryl-substituted cyclic sulfonamide prepared as described in J. Org. Chem., 1991, 56, 3549, from the corresponding bromoaryl or bromoheteroaryl acetic acid and a vinyl sulfonic ester, is coupled, as described in Scheme 3, with a dialkyl phosphite to afford the phosphonate 23.2.
  • the product is then reacted, as described above, with a bromoamide 23.3 to yield the displacement product 23.4.
  • 4-(4-bromo-phenyl)-[1,2]thiazinane 1,1-dioxide 23.5 (J. Org. Chem., 1991, 56, 3549) is reacted in dimethylformamide solution with a dialkyl phosphite 23.6 and tetrakis(triphenylphosphine)palladium(0), to give the phosphonate 23.7.
  • the product is then reacted with 5-bromo-8-hydroxy-[1,6]naphthyridine-7-carboxylic acid (5-fluoro-indan-1-yl)-amide 23.8, prepared by the methods described above, to give the phosphonate 23.9.
  • Scheme 24 depicts the preparation of phosphonates 6 in which the phosphonate group is attached by means of an amide linkage.
  • a carboxy-substituted cyclic sulfonamide 24.1 is coupled with an amino-substituted dialkyl phosphonate 24.2, as described in Scheme 5, to give the amide 24.3.
  • the product is then reacted with the bromoamide 24.4 to afford the displacement product 24.5.
  • 1,1-dioxo-[1,2]thiazinane-3-carboxylic acid 24.6 is reacted in dimethylformamide solution with equimolar amounts of an amino-substituted butyl phosphonate 24.7 (Acros) and dicyclohexylcarbodiimide, to afford the amide 24.8.
  • Schemes 25-27 illustrate methods for the preparation of the phosphonate esters 7.
  • Scheme 25 illustrates the preparation of phosphonate esters 7 in which the phosphonate is attached by means of a carbon link or a variable carbon chain incorporating a heteroatom.
  • a methyl-substituted cyclic anhydride 25.1 is converted, as described in Schemes 1 and 2, into the bicyclic amide 25.2, in which the phenolic hydroxyl group is protected.
  • the compound is reacted with a free radical brominating agent such as N-bromosuccinimide to prepare the bromomethyl derivative 25.3.
  • the benzylic bromination reaction is performed at reflux temperature in an inert organic solvent such as hexachloroethane or ethyl acetate, optionally in the presence of an initiator such as dibenzoyl peroxide.
  • the bromomethyl compound 25.3 is then reacted with a trialkyl phosphite in an Arbuzov reaction, as described in Scheme 19, to give, after deprotection of the phenolic hydroxyl group, the phosphonate 25.4.
  • the benzylic bromide 25.3 is reacted with a dialkyl hydroxy, mercapto or amino-substituted phosphonate 25.5, to afford, after deprotection of the phenolic hydroxyl group, the displacement product 25.6.
  • the displacement reaction is effected at from ambient temperature to about 100°, in a polar organic solvent such as dimethylformamide or DMPU, in the presence of a suitable base such as sodium hydride or lithium hexamethyldisilazide, for instances in which Y is O, or cesium carbonate or triethylamine for instances in which Y is S or N.
  • This product is reacted with a dialkyl hydroxyethyl phosphonate 25.11 (Epsilon) and sodium hydride in dimethylformamide at 80°, to yield, after desilylation, the phosphonate 25.12.
  • a dialkyl hydroxyethyl phosphonate 25.11 Epsilon
  • sodium hydride in dimethylformamide at 80°
  • the bromomethyl compound 25.9 is reacted at 120° with a trialkyl phosphite, to obtain, after desilylation, the phosphonate 25.10.
  • Scheme 26 illustrates the preparation of phosphonate esters 7 in which the phosphonate is attached by means of an aminomethyl linkage.
  • a bromomethyl-substituted bicyclic amide 25.3, prepared as described in Scheme 25, is oxidized to the corresponding aldehyde 26.1.
  • the oxidation of halomethyl compounds to aldehydes is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 599ff.
  • the transformation is effected by treatment with dimethylsulfoxide and base, optionally in the presence of a silver salt, or by reaction with trimethylamine N-oxide or hexamethylene tetramine.
  • the aldehyde 26.1 is then reacted with a dialkyl amino-substituted phosphonate 26.2 in a reductive amination reaction, as described in Scheme 9, to yield, after deprotection of the phenolic hydroxyl group, the aminomethyl product 26.3.
  • Scheme 27 illustrates the preparation of phosphonate esters 7 in which the phosphonate is attached by means of an amide linkage.
  • an aldehyde 26.1 (Scheme 26) is oxidized to the corresponding carboxylic acid 27.1.
  • the conversion of aldehydes to the corresponding carboxylic acids is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 838.
  • the reaction is effected by the use of various oxidizing agents such as, for example, potassium permanganate, ruthenium tetroxide, silver oxide or sodium chlorite.
  • the resultant carboxylic acid 27.1 is then coupled, as described in Scheme 5, with a dialkyl amino-substituted phosphonate 27.2, to yield, after deprotection of the phenolic hydroxyl group, the amide 27.3.
  • the anhydride 27.4 is converted, as described above, and in Schemes 25 and 26, into N-[7-(2-cyclohex-3-enyl-ethylcarbamoyl)-4-formyl-8-triisopropylsilanyloxy-[1,6]naphthyridin-5-yl]-N,N′,N′-trimethyl-oxalamide 27.5.
  • the aldehyde is then reacted with silver oxide in aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 4, 919, 1963, to afford the carboxylic acid 27.6.
  • Schemes 28 and 29 illustrate methods for the preparation of the phosphonate esters 8.
  • Scheme 28 illustrates the preparation of phosphonate esters 8 in which the phosphonate is attached by means of a heteroatom O or S and a variable carbon link
  • the hydroxyl group of a hydroxy-substituted cyclic anhydride 28.1 is protected to afford the compound 28.2.
  • the product is then converted, as described in Scheme 1, into the bicyclic ester 28.3, in which the phenol protecting groups are different.
  • the original phenolic hydroxyl group is then deprotected to yield the phenol 28.4, and the product is subjected to a Mitsunobu reaction, as described in Scheme 7, with a dialkyl hydroxy or mercapto-substituted phQsphonate 28.8, to produce the ether or thioether phosphonate 28.9.
  • This material is then reacted, as described in Scheme 3, with the amine ArLNR 2 H, to give after deprotection of the phenolic hydroxyl group, the amide 28.10.
  • the phenol 28.4 is reacted with a dialkyl bromoalkyl-substituted phosphonate 28.5, as described in Scheme 6, to yield the ether 28.6.
  • the latter compound is then transformed, as described above, into the amide 28.7.
  • 3-hydroxy-furo[3,4-b]pyridine-5,7-dione 28.11 (German Patent 4343923) is reacted in tetrahydrofuran solution at 50° with 4-methoxybenzyl bromide and potassium carbonate, to give the 4-methoxybenzyl ether 28.12.
  • the product is then converted, as described above, into the silyl-protected bicyclic ester 28.13.
  • the 4-methoxybenzyl ether is then removed by reaction with dichlorodicyanobenzoquinone in dichloromethane at ambient temperature, as described in Tet. Lett., 27, 3651, 1986, to give the phenol 28.14.
  • the product is then reacted in tetrahydrofuran solution with a dialkyl bromomethyl phosphonate 29.15 (Lancaster) and potassium carbonate, to produce the phosphonate 28.16; the product is then converted, by desilylation, amide formation, bromination, reaction with methylamine and carbamate formation, using the procedures described above, into the hydroxyamide 28.17.
  • the phenol 28.14 is reacted in tetrahydrofuran solution with one molar equivalent of a dialkyl 2-mercaptoethyl phosphonate 28.18 (Zh. Obschei. Khiim., 1973, 43, 2364), diethylazodicarboxylate and triphenylphosphine, to prepare the thioether phosphonate 28.19.
  • the product is then converted, as described above, into the amide 28.20.
  • Scheme 29 illustrates the preparation of phosphonate esters 8 in which the phosphonate is attached either directly, or by means of a saturated or unsaturated carbon chain.
  • a bromo-substituted anhydride 29.1 is converted, as described above, into the phenol-protected amide 29.2.
  • the product is then subjected to a Heck coupling reaction, in the presence of a palladium (0) catalyst, as described in Scheme 4, with a dialkyl alkenyl phosphonate 29.3, to afford, after deprotection of the phenol, the phosphonate 29.4.
  • the olefinic bond is reduced, as described in Scheme 4, to yield the saturated analog 29.5.
  • the bromo-substituted amide 29.2 is coupled, as described in Scheme 3, with a dialkyl phosphite, in the presence of a palladium (0) catalyst, to generate, after deprotection of the phenolic hydroxyl group, the amide phosphonate 29.6.
  • 3-bromo-faro[3,4-b]pyridine-5,7-dione 29.7 (Bioconjugate Chem., 2003, 14, 629) is converted, using the methods described above, into 3-bromo-5-(1,1-dioxo-[1,2]thiazinan-2-yl)-8-triisopropylsilanyloxy-[1,6]naphthyridine-7-carboxylic acid 4-trifluoromethyl-benzylamide 29.8.
  • This compound is then reacted, in dimethylformamide solution at 80°, with one molar equivalent of a dialkyl vinyl phosphonate 29.9, (Aldrich), triethylarrine and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) to yield, after desilylation, the unsaturated phosphonate 29.10.
  • the product is then reacted with diimide, prepared by basic hydrolysis of diethyl azodicarboxylate, as described in Angew. Chem. it. Ed., 4, 271, 1965, to yield the saturated product 29.11.
  • the bromo compound 29.8 is reacted in toluene solution at ca. 100°, with one molar equivalent of a dialkyl phosphite 29.2, triethylamine and 3 mol % tetrakis(triphenylphosphine)palladium(0), to give, after desilylation, the phosphonate product 29.12.
  • Schemes 30 and 31 illustrate methods for the preparation of the phosphonate esters 9.
  • Scheme 30 illustrates the preparation of phosphonate esters 9 in which the phosphonate is attached by means of a saturated or unsaturated carbon link.
  • a methyl-substituted bicyclic anhydride 30.1 is converted, using the methods described above, into the amide 30.2.
  • the product is then condensed, under basic conditions, with a dialkyl formyl-substituted phosphonate 30.3, to afford the unsaturated phosphonate 30.4.
  • the reaction is conducted at from ambient temperature to about 100°, in a polar aprotic solvent such as dimethylformamide or dioxan, in the presence of a base such as sodium hydride, potassium tert. butoxide or lithium hexamethyldisilazide.
  • the product 30.4 is reduced, as described in Scheme 4, to afford the saturated analog 30.5.
  • 2-methyl-furo[3,4-b]pyrazine-5,7-dione 30.6 (Nippon Noyalca Gakk., 1989, 14, 75) is converted, using the methods described above, into 5-(ethanesulfonyl-methyl-amino)-2-methyl-8-triisopropylsilanyloxy-pyrido[3,4-b]pyrazine-7-carboxylic acid (3,5-dichloro-benzyl)-ethyl-amide 30.7.
  • the product is then reacted, in dimethylformamide solution at 60°, with one molar equivalent of a dialkyl formylmethyl phosphonate 30.8 (Aurora) and sodium hydride, to give, after desilylation, the unsaturated phosphonate 30.9.
  • the product is then reacted with diimide, prepared by basic hydrolysis of diethyl azodicarboxylate, as described in Angew. Cherm Int. Ed., 4, 271, 1965, to yield the saturated product 30.10.
  • Scheme 31 illustrates the preparation of phosphonate esters 9 in which the phosphonate is attached by means of an oxime linkage.
  • a methyl-substituted bicyclic anhydride 31.1 is converted, using the methods described above, into the methyl-substituted amide 31.2.
  • Benzylic bromination, as described in Scheme 25, then gives the bromomethyl analog 31.3, and oxidation, as described in Scheme 26 affords the corresponding aldehyde.
  • the aldehyde is then converted, by reaction with hydroxylamine, into the oxime 31.5.
  • the latter compound is then reacted, in a polar solvent such as tetrahydrofuran or dimethylformamide, in the presence of a base such as sodium hydroxide or potassium carbonate, with a dialkyl bromomethyl-substituted phosphonate 31.6, to prepare, after deprotection of the phenolic hydroxyl group, the oxime derivative 31.7.
  • a polar solvent such as tetrahydrofuran or dimethylformamide
  • a base such as sodium hydroxide or potassium carbonate
  • 2-methyl-furo[3,4-b]pyrazine-5,7-dione 30.6 (Nippon Noyaku Gakk., 1989, 14, 75) is converted, using the methods described above, into 5-(ethenesulfonyl-methyl-amino)-2-formyl-8-triisopropylsilanyloxy-pyrido[3,4-b]pyrazine-7-carboxylic acid 4-fluoro-benzylamide 31.9.
  • the aldehyde is then reacted in tetrahydrofiran solution with three molar equivalents of hydroxylamine hydrochloride and sodium acetate, to produce the oxime 31.10.
  • Schemes 1-31 described the preparation of phosphonate esters of the general structure R-link-P(O)(OR 1 ) 2 , in which the groups R 1 may be the same or different.
  • the R 1 groups attached to a phosphonate ester 1-9, or to precursors thereto, may be changed using established chemical transformations.
  • the interconversions reactions of phosphonates are illustrated in Scheme 32.
  • the group R in Scheme 32 represents the substructure to which the substituent link-P(O)(OR 1 ) 2 is attached, either in the compounds 1-9 or in precursors thereto.
  • the R 1 group may be changed, using the procedures described below, either in the precursor compounds, or in the esters 1-9.
  • the conversion of a phosphonate diester 32.1 into the corresponding phosphonate monoester 32.2 is accomplished by a number of methods.
  • the ester 32.1 in which R 1 is an aralkyl group such as benzyl is converted into the monoester compound 32.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem., 1995, 60, 2946.
  • DABCO diazabicyclooctane
  • the reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110°.
  • the conversion of the diester 32.1 in which R 1 is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester 32.2 is effected by treatment of the ester 32.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofaran.
  • Phosphonate diesters 32.1 in which one of the groups R 1 is aralkyl, such as benzyl, and the other is alkyl is converted into the monoesters 32.2 in which R 1 is alkyl by hydrogenation, for example using a palladium on carbon catalyst.
  • Phosphonate diesters in which both of the groups R 1 are alkenyl, such as allyl, is converted into the monoester 32.2 in which R 1 is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem., 38, 3224, 1973 for the cleavage of allyl carboxylates.
  • Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigmay, in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • PYBOP (benzotriazol-1-yloxy)tripyrrolidinophospho
  • the conversion of the phosphonate monoester 32.2 to the diester 32.1 is effected by the use of the Mitsunobu reaction, as described above (Scheme 7).
  • the substrate is reacted with the hydroxy compound RI OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine.
  • the phosphonate monoester 32.2 is transformed into the phosphonate diester 32.1, in which the introduced RI group is alkenyl or aralkyl, by reaction of thermonoester with the halide R 1 Br, in which R 1 is as alkenyl or aralkyl.
  • the alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate.
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • a base such as cesium carbonate.
  • the phosphonate monoester is transformed into the phosphonate diester in a two step procedure.
  • the phosphonate monoester 32.2 is transformed into the chloro analog RP(O)(OR 1 )C1 by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.
  • a phosphonic acid R-lil(c-P(O)(OH) 2 is transformed into a phosphonate monoester RP(O)(OR 1 )(OH) (Scheme 32, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-linkc-P(O)(OR 1 ) 2 32.1, except that only one molar proportion of the component R 1 OH or R 1 Br is employed.
  • a phosphonic acid R-link-P(O)(OH) 2 32.3 is transformed into a phosphonate diester R-link-P(O)(OR 1 ) 2 32.1 (Scheme 32, Reaction 6) by a coupling reaction with the hydroxy compound R 1 OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.
  • the reaction is conducted in a basic solvent such as pyridine.
  • phosphonic acids 32.3 is transformed into phosphonic esters 32.1 in which R 1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70°.
  • phosphonic acids 32.3 is transformed into phosphonic esters 32.1 in which R 1 is alkenyl, by means of an alkylation reaction.
  • the phosphonic acid is reacted with the alkenyl bromide R 1 Br in a polar organic solvent such as acetonitrle solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester 32.1.
  • a polar organic solvent such as acetonitrle solution at reflux temperature
  • a base such as cesium carbonate
  • the phosphonate esters 1-9 may contain a carbamate linkage.
  • the preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzlcy, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p. 260ff.
  • Scheme 33 illustrates various methods by which the carbamate linkage is synthesized.
  • a carbinol 33.1 in the general reaction generating carbamates, a carbinol 33.1, is converted into the activated derivative 33.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described herein.
  • the activated derivative 33.2 is then reacted with an amine 33.3, to afford the carbamate product 33.4.
  • Examples 1-7 in Scheme 33 depict methods by which the general reaction is effected.
  • Examples 8-10 illustrate alternative methods for the preparation of carbamates.
  • Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the carbinol 33.5.
  • the carbinol 33.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0°, as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate 33.6.
  • the latter compound is then reacted with the amine component 33.3, in the presence of an organic or inorganic base, to afford the carbamate 33.7.
  • the chloroformyl compound 33.6 is reacted with the amine 33.3 in a water-miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate 33.7.
  • the reaction is performed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.
  • Example 2 depicts the reaction of the chloroformate compound 33.6 with imidazole to produce the imidazolide 33.8.
  • the imidazolide product is then reacted with the amine 33.3 to yield the carbamate 33.7.
  • the preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0°, and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357.
  • Example 3 depicts the reaction of the chloroformate 33.6 with an activated hydroxyl compound R′′OH, to yield the mixed carbonate ester 33.10.
  • the reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine.
  • the hydroxyl component R′′OH is selected from the group of compounds 33.19-33.24 shown in Scheme 33, and similar compounds.
  • the mixed carbonate 33.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976.
  • Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole 33.8 is employed.
  • a carbinol 33.5 is reacted with an equimolar amount of carbonyl diimidazole 33.11 to prepare the intermediate 33.8.
  • the reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran.
  • the acyloxyimidazole 33.8 is then reacted with an equimolar amount of the amine R′NH 2 to afford the carbamate 33.7.
  • the reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate 33.7.
  • Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole 33.13.
  • a carbinol ROH is reacted at ambient temperature with an equiinolar amount of benztriazole carbonyl chloride 33.12, to afford the alkoxycarbonyl product 33.13.
  • the reaction is performed in an organic solvent. such as benzene or toluene, in the presence of a tertiary organic amine such as triethylarnine, as described in Syn., 1977, 704.
  • the product is then reacted with the amine R′NH 2 to afford the carbamate 33.7.
  • the reaction is conducted in toluene or ethanol, at from ambient temperature to about 80° as described in Syn., 1977, 704.
  • Example 6 illustrates the preparation of carbamates in which a carbonate (R′′O) 2 CO, 33.14, is reacted with a carbinol 33.5 to afford the intermediate alkyloxycarbonyl intermediate 33.15.
  • the latter reagent is then reacted with the amine R′NH 2 to afford the carbamate 33.7.
  • the procedure in which the reagent 33.15 is derived from hydroxybenztriazole 33.19 is described in Synthesis, 1993, 908; the procedure in which the reagent 33.15 is derived from N-hydroxysuccinimide 33.20 is described in Tet. Lett., 1992, 2781; the procedure in which the reagent 33.15 is derived from 2-hydroxypyridine 33.23 is described in Tet.
  • Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides 33.16.
  • an alkyl chloroformate 33.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide 33.16.
  • the latter compound is then reacted with an equimolar amount of the amine R′NH 2 to afford the carbamate 33.7.
  • the reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Syn., 1982, 404.
  • Example 8 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and the chloroformyl derivative of an amine 33.17.
  • the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate 33.7.
  • Example 9 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an isocyanate 33.18.
  • the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate 33.7.
  • Example 10 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an amine R′NH 2 .
  • the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium.
  • a tertiary base such as triethylamine, and selenium.
  • Carbon monoxide is passed through the solution and the reaction proceeds to afford the carbamate 33.7.
  • Scheme A26 illustrates the preparation of phosphonate esters of Formula 1a in which the phosphonate is attached by means of an amide group and a variable carbon linkage.
  • a protected dihydroxyapiiline A26.1 is reacted with a 2-halo heterocyclic aldehyde A26.2, in which Y is C or N, to afford the displacement product A26.3.
  • the nucleophilic displacement reaction of 2-halo heterocycles is described, for example, in Heterocyclic Chemistry, by T. L., Gilchrist, Longman, 1992, p.143.
  • the reaction is catalyzed by acid or base, and is conducted in an inert solvent such as pyridine.
  • the product is cyclized to give the tricyclic ester A26.4.
  • methyl 3-amino-2,5-dihydroxybenzoate A26.10 is reacted sequentially with one molar equivalent of chlorotriisopropylsilane and imidazole in dichloromethane, and then with excess diphenyldiazomethane, to produce the differentially protected compound A26.11.
  • the product is then reacted, as described above, with 4-bromothiazole-5-carboxaldehyde A26.12 (WO 9317681) to give 5-benzhydryloxy-8-triisopropylsilanyloxy-thiazolo[4,5-b]quinoline-6-carboxylic acid methyl ester A26.13.
  • Scheme A27 illustrates the preparation of phosphonate esters of Formula 1b in which the phosphonate is attached by means of a variable carbon linkage optionally incorporating a heteroatom.
  • a protected 3-amino--2-hydroxy benzoate ester A27.1 is reacted, as described in Scheme A26, with a heterocyclic 2-halo ketone A27.2 to afford the amine A27.3.
  • Thermal cyclization of this compound then affords the tricyclic product A27.4.
  • the compound is then subjected to benzylic bromination to yield the bromomethyl product A27.5.
  • the latter compound is then reacted with a trialkyl phosphite at 120° C. to produce the phosphonate A27.6.
  • the phosphonate is then reacted with the amine ArBNHR A27.7 and trimethylalurninum to give after deprotection the amide A27.8.
  • the bromomethyl compound A27.5 is reacted, as described in Scheme A17, with a hydroxy, mercapto or amino-substituted phosphonate A27.9, in which the group R a is an acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroaryl moiety.
  • the ether, thioether or amine product is then reacted, as described above, with the amine ArBNHR to prepare after deprotection the phosphonate A27.11.
  • methyl 3-amino-2-diphenylmethoxybenzoate A27.12 is reacted with 5-acetyl-4-bromothiazole A27.13 (WO 9317681) to afford after cyclization of the initial displacement product, 5-benzhydryloxy-9-methyl-thiazolo[4,5-b]quinoline-6-carboxylic acid methyl ester A27.14.
  • Reaction with N-bromosuccinimide in hexachloroethane then yields the bromomethyl analog A27.15, and this material is reacted with a trialkyl phosphite in an Arbuzov reaction to give the phosphonate A27.16.
  • the product is then reacted with 3,5-dichlorobenzyl methylamine A27.17 and trimethyl aluminum to afford after deprotection the phosphonate A27.18.
  • the bromomethyl compound A27.15 is reacted in acetonitrile solution with a dialkyl 3-hydroxyphenyl phosphonate A27.19 (Epsilon) and potassium carbonate, to obtain the ether product A27.20.
  • This compound is then reacted with cyclopentylmethylamine and trimethylaluminum to give after deprotection the phosphonate A27.21.
  • Scheme A28 illustrates the preparation of phosphonate esters of Formula 1c in which the phosphonate is attached by means of carbon linkage optionally incorporating a heteroatom.
  • a substituted aniline A28.1 is reacted, using the procedures described in Scheme A26, with a methyl-substituted 2-bromoheterocyclic aldehyde A28.2 to produce the methyl-substituted tricyclic product A28.3.
  • the compound is then subjected to benzylic bromination to give the bromomethyl analog A28.4.
  • the bromomethyl compound A28.4 is reacted in an Arbuzov reaction with a trialkyl phosphite to yield after deprotection the phosphonate A28.7.
  • methyl 3-amino-2-diphenylmethoxybenzoate A28.8 is reacted, as described above, with 2-bromo-4-methylpyridine-3-carboxaldehyde A28.9 (Arkivoc, 2000, 1, 52) to produce after cyclization, the tricyclic ester A28.10.
  • the ester is then reacted with trimethylaluminum and N-methylcyclobutylmethylamine A28.11 to give 9-benzhydryloxy-4methyl-benzo[b][1,8]naphthyridine-8-carboxylic acid cyclobutylmethyl-methyl-amide A28.12.
  • Benzylic bromination then gives the bromomethyl analog A28.13.
  • the latter compound is heated at 120° C. with excess of a trialkyl phosphite to produce after deprotection the phosphonate A28.14.
  • the bromomethyl compound A28.13 is reacted in acetonitrile solution with a dialkyl mercaptomethyl phosphonate A28.15 (Tet., 1994, 50, 10277) and diisopropylamine to produce after deprotection the thioether phosphonate A28.16.
  • a number of methods are available for the conversion of phosphonic acids into amidates and esters.
  • the phosphonic acid is either converted into an isolated activated intermediate such as a phosphoryl chloride, or the phosphonic acid is activated in situ for reaction with an amine or a hydroxy compound.
  • the conversion of phosphonic acids into phosphoryl chlorides is accomplished by reaction with thionyl chloride, for example as described in J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063, or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride, as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem., 1994, 59, 6144, or by reaction with phosphorus pentachloride, as described in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995, 38, 1372.
  • the resultant phosphoryl chlorides are then reacted with amines or hydroxy compounds in the presence of a base to afford the amidate or ester products.
  • Phosphonic acids are converted into activated imidazolyl derivatives by reaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem. Comm., 1991, 312, or Nucleosides Nucleotides 2000, 19, 1885.
  • Activated sulfonyloxy derivatives are obtained by the reaction of phosphonic acids with trichloromethylsulfonyl chloride, as described in J. Med. Chem. 1995, 38, 4958, or with triisopropylbenzenesulfonyl chloride, as described in Tet. Lett., 1996, 7857, or Bioorg. Med. Chem. Lett., 1998, 8, 663.
  • the activated sulfonyloxy derivatives are then reacted with amines or hydroxy compounds to afford amidates or esters.
  • the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a diimide coupling agent.
  • a diimide coupling agent The preparation of phosphonic amidates and esters by means of coupling reactions in the presence of dicyclohexyl carbodiimide is described, for example, in J. Chem. Soc., Chem. Comm., 1991, 312, or J. Med. Chem., 1980, 23, 1299 or Coll. Czech. Chem. Comm., 1987, 52, 2792.
  • the use of ethyl dimethylaminopropyl carbodiimide for activation and coupling of phosphonic acids is described in Tet. Lett., 2001, 42, 8841, or Nucleosides Nucleotides, 2000, 19, 1885.
  • the agents include Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem., 1995, 60, 5214, and J. Med. Chem., 1997, 40, 3842, mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J. Med Chem., 1996, 39, 4958, diphenylphosphoryl azide, as described in J. Org.
  • Phosphonic acids are converted into amidates and esters by means of the Mitsunobu reaction, in which the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a triaryl phosphine and a dialkyl azodicarboxylate.
  • the procedure is described in Org. Lett., 2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.
  • Phosphonic esters are also obtained by the reaction between phosphonic acids and halo compounds, in the presence of a suitable base.
  • the method is described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem. Soc. Perkin Trans., I, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372, or Tet. Lett., 2002, 43, 1161.
  • Schemes 1-5 illustrate the conversion of phosphonate esters and phosphonic acids into carboalkoxy-substituted phosphorobisamidates (Scheme 1), phosphoroamidates (Scheme 2), phosphonate monoesters (Scheme 3) and phosphonate diesters, (Scheme 4)
  • Scheme 1 illustrates various methods for the conversion of phosphonate diesters 1.1 into phosphorobisamidates 1.5.
  • the diester 1.1 prepared as described previously, is hydrolyzed, either to the monoester 1.2 or to the phosphonic acid 1.6. The methods employed for these transformations are described above.
  • the monoester 1.2 is converted into the monoamidate 1.3 by reaction with an aminoester 1.9, in which the group R 2 is H or alkyl, the group R 4 is an alkylene moiety such as, for example, CHCH 3 , CHPr I , CH(CH 2 Ph), CH 2 CH(CH 3 ) and the like, or a group present in natural or modified aminoacids, and the group R 5 is alkyl.
  • the reactants are combined in the presence of a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc., 1957, 79, 3575, optionally in the presence of an activating agent such as hydroxybenztriazole, to yield the amidate product 1.3.
  • a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc., 1957, 79, 3575
  • an activating agent such as hydroxybenztriazole
  • the amidate-forming reaction is also effected in the presence of coupling agents such as BOP, as described in J. Org. Chem., 1995, 60, 5214, Aldrithiol, PYBOP and similar coupling agents used for the preparation of amides and esters.
  • the reactants 1.2 and 1.9 are transformed into the monoamidate 1.3 by means of a Mits
  • the phosphonic acid 1.6 is converted into the bisamidate 1.5 by use of the coupling reactions described above.
  • the reaction is perfoirmed in one step, in which case the nitrogen-related substituents present in the product 1.5 are the same, or in two steps, in which case the nitrogen-related substituents can be different.
  • the phosphonic acid 1.6 is converted into the mono or bis-activated derivative 1.7, in which Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.
  • Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.
  • the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride, as described in Nucleosides and Nucleotides, 2000, 10, 1885.
  • the activated product is then reacted with the aminoester 1.9, in the presence of a base, to give the bisamidate 1.5.
  • the reaction is performed in one step, in which case the nitrogen substituents present in the product 1.5 are the same, or in two steps, via the intermediate 1.11, in which case the nitrogen substituents can be different.
  • Example 5 the phosphonic acid 1.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991, 312, with carbonyl diimidazole to give the imidazolide 1.32.
  • the product is then reacted in acetonitrile solution at ambient temperature, with one molar equivalent of ethyl alaninate 1.33 to yield the monodisplacement product 1.34.
  • the latter compound is then reacted with carbonyl diimidazole to produce the activated intermediate 1.35, and the product is then reacted, under the same conditions, with ethyl N-methylalaninate 1.33a to give the bisamidate product 1.36.
  • the intermediate monoamidate 1.3 is also prepared from the monoester 1.2 by first converting the monoester into the activated derivative 1.8 in which Lv is a leaving group such as halo, imidazolyl etc, using the procedures described above.
  • the product 1.8 is then reacted with an aminoester 1.9 in the presence of a base such as pyridine, to give an intermediate monoamidate product 1.3.
  • the latter compound is then converted, by removal of the R 1 group and coupling of the product with the aminoester 1.9, as described above, into the bisamidate 1.5.
  • the product is subjected to a Mitsunobu coupling procedure, with equimolar amounts of butyl alaninate 1.30, triphenyl phosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran, to give the bisamidate product 1.31.
  • the activated phosphonic; acid derivative 1.7 is also converted into the bisamidate 1.5 via the diamino compound 1.10.
  • the conversion of activated phosphonic acid derivatives such as phosphoryl chlorides into the corresponding amino analogs 1.10, by reaction with ammonia, is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976.
  • the diamino compound 1.10 is then reacted at elevated temperature with a haloester 1.12, in a polar organic solvent such as dimnethylformamide, in the presence of a base such as dimethylaminopyridine or potassium carbonate, to yield the bisamidate 1.5.
  • Scheme 1 illustrates the preparation of bisamidates derived from tyrosine.
  • the monoimidazolide 1.32 is reacted with propyl tyrosinate 1.40, as described in Example 5, to yield the monoamidate 1.41.
  • the product is reacted with carbonyl diimidazole to give the imidazolide 1.42, and this material is reacted with a further molar equivalent of propyl tyrosinate to produce the bisamidate product 1.43.
  • aminoesters 1.9 Using the above procedures, but employing, in place of propyl tyrosinate 1.40, different aminoesters 1.9, the corresponding products 1.5 are obtained.
  • the aminoesters employed in the two stages of the above procedure can be the same or different, so that bisamidates with the same or different amino substituents are prepared.
  • Scheme 2 illustrates methods for the preparation of phosphonate monoamidates.
  • a phosphonate monoester 1.1 is converted, as described in Scheme 1, into the activated derivative 1.8. This compound is then reacted, as described above, with an aminoester 1.9, in the presence of a base, to afford the monoamidate product 2.1.
  • the phosphonate monoester 1.1 is coupled, as described in Scheme 1, with an aminoester 1.9 to produce the amidate 2.1. If necessary, the R 1 substituent is then altered, by initial cleavage to afford the phosphonic acid 2.2. The procedures for this transformation depend on the nature of the R 1 group, and are described above.
  • the phosphonic acid is then transformed into the ester amidate product 2.3, by reaction with the hydroxy compound R 3 OH, in which the group R 3 is aryl, heteroaryl, allcyl, cycloalkyl, haloalkyl etc, using the same coupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobu reaction etc) described in Scheme 1 for the coupling of amines and phosphonic acids.
  • Example 3 the monoamidate 2.13 is coupled, in tetrahydrofuran solution at ambient temperature, with equimolar amounts of dicyclohexyl carbodiimide and 4hydroxy-N-methylpiperidine 2.16, to produce the amidate ester product 2.17.
  • the activated phosphonate ester 1.8 is reacted with ammonia to yield the amidate 2.4.
  • the product is then reacted, as described in Scheme 1, with a haloester 2.5, in the presence of a base, to produce the amidate product 2.6.
  • the nature of the R 1 group is changed, using the procedures described above, to give the product 2.3.
  • the method is illustrated in Scheme 2, Example 4.
  • the monophenyl phosphoryl chloride 2.18 is reacted, as described in Scheme 1, with ammonia, to yield the amino product 2.19.
  • This material is then reacted in N-methylpyrrolidinone solution at 170° with butyl 2-bromo-3-phenylpropionate 2.20 and potassium carbonate, to afford the amidate product 2.21.
  • the monoamidate products 2.3 are also prepared from the doubly activated phosphonate derivatives 1.7.
  • the intermediate 1.7 is reacted with a limited amount of the aminoester 1.9 to give the mono-displacement product 1.11.
  • the latter compound is then reacted with the hydroxy compound R 3 OH in a polar organic solvent such as dimethylformamide, in the presence of a base such as diisopropylethylamine, to yield the monoamidate ester 2.3.
  • Scheme 3 illustrates methods for the preparation of carboalkoxy-substituted phosphonate diesters in which one of the ester groups incorporates a carboalkoxy substituent.
  • a phosphonate monoester 1.1 is coupled, using one of the methods described above, with a hydroxyester 3.1, in which the groups R 4 and R 5 are as described in Scheme 1.
  • equimolar amounts of the reactants are coupled in the presence of a carbodiimide such as dicyclohexyl carbodiimide, as described in Aust. J. Chem., 1963, 609, optionally in the presence of dimethylaminopyridine, as described in Tet., 1999, 55, 12997.
  • the reaction is conducted in an inert solvent at ambient temperature.
  • the conversion of a phosphonate monoester 1.1 into a mixed diester 3.2 is also accomplished by means of a Mitsunobu coupling reaction with the hydroxyester 3.1, as described in Org. Lett., 2001, 643.
  • the reactants 1.1 and 3.1 are combined in a polar solvent such as tetrahydrofuran, in the presence of a triarylphosphine and a dialkyl azodicarboxylate, to give the mixed diester 3.2.
  • the R 1 substituent is varied by cleavage, using the methods described previously, to afford the monoacid product 3.3.
  • the product is then coupled, for example using methods described above, with the hydroxy compound R 3 OH, to give the diester product 3.4.
  • the mixed diesters 3.2 are also obtained from the monoesters 1.1 via the intermediacy of the activated monoesters 3.5.
  • the resultant activated monoester is then reacted with the hydroxyester 3.1, as described above, to yield the mixed diester 3.2.
  • the mixed phosphonate diesters are also obtained by an alternative route for incorporation of the R 3 O group into intermediates 3.3 in which the hydroxyester moiety is already incorporated.
  • the monoacid intermediate 3.3 is converted into the activated derivative 3.6 in which Lv is a leaving group such as chloro, imidazole, and the like, as previously described.
  • the activated intermediate is then reacted with the hydroxy compound R 3 OH, in the presence of a base, to yield the mixed diester product 3.4.
  • the phosphonate esters 3.4 are also obtained by means of alkylation reactions performed on the monoesters 1.1.
  • the reaction between the monoacid 1.1 and the haloester 3.7 is performed in a polar solvent in the presence of a base such as diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in the presence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.
  • a base such as diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372
  • a non-polar solvent such as benzene
  • Scheme 4 illustrates methods for the preparation of phosphonate diesters in which both the ester substituents incorporate carboalkoxy groups.
  • the compounds are prepared directly or indirectly from the phosphonic acids 1.6.
  • the phosphonic acid is coupled with the hydroxyester 4.2, using the conditions described previously in Schemes 1-3, such as coupling reactions using dicyclohexyl carbodiimide or similar reagents, or under the conditions of the Mitsunobu reaction, to afford the diester product 4.3 in which the ester substituents are identical.
  • the diesters 4.3 are obtained by alkylation of the phosphonic acid 1.6 with a haloester 4.1.
  • the alkylation reaction is performed as described in Scheme 3 for the preparation of the esters 3.4.
  • the diesters 4.3 are also obtained by displacement reactions of activated derivatives 1.7 of the phosphonic acid with the hydroxyesters 4.2.
  • the displacement reaction is performed in a polar solvent in the presence of a suitable base, as described in Scheme 3.
  • the displacement reaction is performed in the presence of an excess of the hydroxyester, to afford the diester product 4.3 in which the ester substituents are identical, or sequentially with limited amounts of different hydroxyesters, to prepare diesters 4.3 in which the ester substituents are different.
  • Example 4 depicts the displacement reaction between equimolar amounts of the phosphoryl dichloride 2.22 and ethyl 2-methyl-3-hydroxypropionate 4.11, to yield the monoester product 4.12.
  • the reaction is conducted in acetonitrile at 70° in the presence of diisopropylethylamine.
  • the product 4.12 is then reacted, under the same conditions, with one molar equivalent of ethyl lactate 4.13, to give the diester product 4.14.
  • 2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be prepared by the route in Scheme 5.
  • Condensation of 2-methyl-2-propanesulfinamide with acetone give sulfinyl imine 11 ( J. Org. Chem. 1999, 64, 12).
  • Addition of dimethyl methylphosphonate lithium to 11 afford 12.
  • Acidic methanolysis of 12 provide amine 13. Protection of amine with Cbz group and removal of methyl groups yield phosphonic acid 14, which can be converted to desired 15 (Scheme 5a) using methods reported earlier on.
  • An alternative synthesis of compound 14 is also shown in Scheme Sb.
  • Commercially available 2-amino-2-methyl-1-propanol is converted to aziridines 16 according to literature methods ( J. Org.
  • Representative compounds of the invention are tested for biological activity by methods including anti-HIV assay, measuring inhibition of HIV-integrase strand transfer catalysis, and cytotoxicity.
  • methods including anti-HIV assay, measuring inhibition of HIV-integrase strand transfer catalysis, and cytotoxicity.
  • Wolfe etal J Virol . (1996) 70:14241432; Hazuda, etal Nucleic Acids Res . (1994) 22:1121-22; Hazuda, etal J. Virol (1997) 71:7005-7011; Hazuda, etal Drug Desigin and Discovery (1997) 15:17-24; and Hazuda, etal Science (2000) 287:646-650.
  • the antiviral activity of a compound of the invention can be determined using pharmacological models which are well known in the art.
  • the compounds of the present invention demonstrate inhibition of integration of HIV reverse-transcribed DNA, there may be other mechanisms of action whereby HIV replication or proliferation is affected.
  • the compounds of the invention may be active via inhibition of HIV-integrase or other enzymes associated with HIV infection, AIDS, or ARC.
  • the compounds of the invention may have significant activity against other viral diseases.
  • the specific assays embodied in Examples x-y are not meant to limit the present invention to a specific mechanism of action.
  • the compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • compositions of the invention and their physiologically acceptable salts hereafter collectively referred to as the active ingredients may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration may vary with for example the condition of the recipient.
  • the active ingredients While it is possible for the active ingredients to be administered alone it is preferably to present them as pharmaceutical formulations.
  • the formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above defined, together with one or more pharmaceutically acceptable carriers therefor and optionally other. therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the formulations are preferably applied as a topical ointment or cream containing the active 15 ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include TweenTM 60, SpanTM 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as pentamidine for treatment of pneumocystis pneumonia.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
  • Controlled release formulations may be employed for the treatment or prophylaxis of various microbial infections particularly human bacterial, human parasitic protozoan or human viral infections caused by microbial species including Plasmodium, Pneumocystis, herpes viruses (CMV, HSV 1, HSV 2, VZV, and the like), retroviruses, adenoviruses and the like.
  • the controlled release formulations can be used to treat HIV infections and related conditions such as tuberculosis, malaria, pneumocystis pneumonia, CMV retinitis, AIDS, AIDS-related complex (ARC) and progressive generalized lymphadeopathy (PGL), and AIDS-related neurological conditions such as multiple sclerosis, and tropical spastic paraparesis.
  • human retroviral infections that may be treated with the controlled release formulations according to the invention include Human T-cell Lymphotropic virus (HTLV)-I and IV and HIV-2 infections.
  • HTLV Human T-cell Lymphotropic virus
  • the invention accordingly provides pharmaceutical formulations for use in the treatment or prophylaxis of the above-mentioned human or veterinary conditions and microbial infections.
  • the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of the infections or conditions indicated above.
  • further therapeutic agents include agents that are effective for the treatment or prophylaxis of viral, parasitic or bacterial infections or associated conditions or for treatment of tumors or related conditions include 3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′-deoxy-3′-thiacytidine (3TC), 2′,3′-dideoxy-2′3′-didehydroadenosine (D4A), 2′3′-dideoxy-2′3′-didehydrothymidine (D4T), carbovir (carbocyclic 2′3′-dideoxy-2′3′-didehydroguanosine), 3′-azido-2′3′-dideoxyuridine, 5-fluorothymidine, (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU), 2-chloro
  • IC50 (also referred to as CC50, CD50, TC50, TD50 or cytotoxicity) is the inhibitory concentration that reduces cellular growth or viability of uninfected cells by 50%.
  • HIV Integrase assay is carried out in Reacti-Bind High Binding Capacity Streptavidin coated plates (Pierce # 15502) in 100 ⁇ l reactions. The wells of the plate are rinsed once with PBS. Each well is then coated at room temperature for 1 h with 100 PI of 0.14 PM double-stranded, 5′-biotin labelled donor DNA.
  • Integrase/buffer mixture 25 mM HEPES, pH 7.3, 12.5 mM DTT, 93.75 mM NaCl, 12.5 mM MgCl 2 , 1.25% Glycerol, 0.3125 ⁇ M integrase
  • 3′-Processing is allowed to proceed for 30 min at 37° C., after which, 10 ⁇ l of test compound and 10 ⁇ l of 2.5 ⁇ M 3′-DIG (digitoxigenin)-labeled, double-stranded Target DNA are added to each well to allow strand-transfer to proceed for 30 min at 37°.
  • the plate is then washed three times with 2 ⁇ SSC for 5 min and rinsed once with PBS.
  • 100 ⁇ l of a 1/2000 dilution of HRP-conjugated anti-DIG antibody (Pierce #31468) are added to each well and incubated for 1 hour. The plate is then washed three times for 5 min each, with 0.05% Tween-20 in PBS.
  • EC50 (also commonly referred to as ED50 or IC50) is the effective concentration that inhibits 50% of viral production, 50% of viral infectivity, or 50% of the virus-induced cytopathic effect.
  • Anti-HIV assay is carried out in 96-well Clear Bottom Black Assay Plate (Costar # 3603) in 100 ⁇ l of culture medium, using the CellTiter-GloTM Reagent (Promega # G7570) for signal detection.
  • MT-2 cells (1.54 ⁇ 10 4 cells) are infected with wild-type virus at an m.o.i. (multiplicity of infection, i.e. the ratio between the number of infectious viral particles and cells in an assay) of about 0.025, and grown in the presence of various drug concentrations (serial 5-fold dilutions) in 100 ⁇ l of RPMI medium containing 10% FBS, 2% glutamine, 1% HEPES and 1% penicillin/streptomycin for 5 days.
  • Uninfected MT-2 cells (1.54 ⁇ 10 4 cells) are grown in the presence of various drug concentrations (serial 2-fold dilutions) in 100 ⁇ l of RPMI medium containing 10% FBS, 2% glutamine, 1% HEPES and 1% penicillin/streptomycin for 5 days.
  • 100 ⁇ l of CellTiter-GloTM Reagent is added to each well in the assay plate and the chemiluminescence (in relative light units) is measured after 10 mins of incubation with the Wallac Victor 2 1420 MultiLabel Counter.

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Publication number Priority date Publication date Assignee Title
US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
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Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PA8539401A1 (es) * 2001-02-14 2002-10-28 Warner Lambert Co Quinazolinas como inhibidores de mmp-13
WO2005061519A1 (en) * 2003-12-19 2005-07-07 Takeda San Diego, Inc. Kinase inhibitors
BRPI0507628A (pt) 2004-02-11 2007-07-03 Smithkline Beecham Corp composto ou sal farmaceuticamente aceitável do mesmo, método de tratamento de uma infecção viral em um ser humano, uso de um composto composição farmacêutica, e, processo para a preparação de um composto
JP2007533753A (ja) * 2004-04-23 2007-11-22 タケダ サン ディエゴ インコーポレイテッド インドール誘導体及びキナーゼ阻害剤としてのその使用
EP1778669A2 (de) * 2004-08-18 2007-05-02 Takeda San Diego, Inc. Kinase-inhibitoren
DE602005023333D1 (de) * 2004-10-15 2010-10-14 Takeda Pharmaceutical Kinaseinhibitoren
US20080214503A1 (en) * 2005-08-04 2008-09-04 Smithkline Beecham Corporation Hiv Integrase Inhibitors
JP2009503089A (ja) * 2005-08-04 2009-01-29 スミスクライン ビーチャム コーポレーション Ｈｉｖインテグラーゼ阻害薬
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
AU2007221049A1 (en) * 2006-02-28 2007-09-07 Amgen Inc. Cinnoline and quinazoline derivates as phosphodiesterase 10 inhibitors
GEP20135728B (en) 2006-10-09 2013-01-25 Takeda Pharmaceuticals Co Kinase inhibitors
ES2475206T3 (es) 2008-02-01 2014-07-10 Takeda Pharmaceutical Company Limited Derivados de oxima como inhibidores de HSP90
AU2010305805B2 (en) 2009-10-13 2014-04-03 Elanco Animal Health Ireland Limited Macrocyclic integrase inhibitors
JP5739517B2 (ja) 2010-04-02 2015-06-24 ヤンセン・アールアンドデイ・アイルランド 大環状インテグラーゼ阻害剤
JP5605029B2 (ja) * 2010-07-06 2014-10-15 住友化学株式会社 化合物、樹脂及びレジスト組成物
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
CN102885846B (zh) * 2011-07-18 2014-02-19 中国医学科学院医药生物技术研究所 2-硫代-6-氮杂尿苷在制备抗hiv-1病毒的药物中的应用
US8954475B2 (en) * 2011-11-10 2015-02-10 Microsoft Technology Licensing, Llc Deep cloning of objects using binary format
CN104185420B (zh) 2011-11-30 2017-06-09 埃默里大学 用于治疗或预防逆转录病毒和其它病毒感染的抗病毒jak抑制剂
EP2794624B1 (de) 2011-12-22 2019-05-15 Geron Corporation Guanin-analoga als telomerasesubstrate und telomerlängenaffektoren
PT3176170T (pt) 2012-06-13 2019-02-05 Incyte Holdings Corp Compostos tricíclicos substituídos como inibidores de fgfr
WO2014026125A1 (en) 2012-08-10 2014-02-13 Incyte Corporation Pyrazine derivatives as fgfr inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
SG10201708520YA (en) 2013-04-19 2017-12-28 Incyte Corp Bicyclic heterocycles as fgfr inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
KR20230130175A (ko) 2014-12-26 2023-09-11 에모리 유니버시티 Ｎ4-하이드록시시티딘, 이와 관련된 유도체 및 이의 항 바이러스적 용도
TWI712601B (zh) 2015-02-20 2020-12-11 美商英塞特公司 作為fgfr抑制劑之雙環雜環
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
WO2016134294A1 (en) 2015-02-20 2016-08-25 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
CN107325099A (zh) * 2017-06-05 2017-11-07 李芷琪 具有杀虫活性的哌啶并吡啶并4,5‑二氢‑1,2,3‑三氮唑类衍生物的制备方法
AU2018378832B9 (en) 2017-12-07 2021-05-27 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
MA52493A (fr) 2018-05-04 2021-03-10 Incyte Corp Sels d'un inhibiteur de fgfr
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
CA3157361A1 (en) 2019-10-14 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
BR112022010664A2 (pt) 2019-12-04 2022-08-16 Incyte Corp Derivados de um inibidor de fgfr
JP2023505258A (ja) 2019-12-04 2023-02-08 インサイト・コーポレイション Ｆｇｆｒ阻害剤としての三環式複素環
WO2021257857A1 (en) 2020-06-19 2021-12-23 Incyte Corporation Naphthyridinone compounds as jak2 v617f inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
WO2022006456A1 (en) 2020-07-02 2022-01-06 Incyte Corporation Tricyclic pyridone compounds as jak2 v617f inhibitors
AU2021300429A1 (en) 2020-07-02 2023-02-16 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
TW202302589A (zh) 2021-02-25 2023-01-16 美商英塞特公司 作為ｊａｋ２ ｖ６１７ｆ抑制劑之螺環內醯胺
EP4352059A1 (de) 2021-06-09 2024-04-17 Incyte Corporation Tricyclische heterocyclen als fgfr-inhibitoren
WO2023078252A1 (en) 2021-11-02 2023-05-11 Flare Therapeutics Inc. Pparg inverse agonists and uses thereof

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816570A (en) 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
US4968788A (en) 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
ES2083580T3 (es) 1990-06-13 1996-04-16 Arnold Glazier Profarmacos de fosforo.
DK0481214T3 (da) 1990-09-14 1999-02-22 Acad Of Science Czech Republic Prolægemidler af phosphonater
US5883255A (en) 1990-10-31 1999-03-16 Smithkline Beecham Corporation Substituted indolizino 1,2-b!quinolinones
US5639881A (en) 1991-11-08 1997-06-17 Arizona Board Of Regents Acting On Behalf Of Arizona State University Synthesis and elucidation of pyrimido (4,5-Q) quinazoline derivatives
US5326776A (en) 1992-03-02 1994-07-05 Abbott Laboratories Angiotensin II receptor antagonists
US5798340A (en) 1993-09-17 1998-08-25 Gilead Sciences, Inc. Nucleotide analogs
US5543523A (en) 1994-11-15 1996-08-06 Regents Of The University Of Minnesota Method and intermediates for the synthesis of korupensamines
DE19613591A1 (de) 1996-04-04 1997-10-09 Hoechst Ag Substituierte-Chinolin-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung
US6310211B1 (en) 1996-09-10 2001-10-30 Pharmacia & Upjohn Company 8-hydroxy-7-substituted quinolines as anti-viral agents
US6312662B1 (en) 1998-03-06 2001-11-06 Metabasis Therapeutics, Inc. Prodrugs phosphorus-containing compounds
EP1082121A4 (de) 1998-06-03 2003-02-05 Merck & Co Inc Hiv-integraseinhibitoren
JP2002516858A (ja) 1998-06-03 2002-06-11 メルク エンド カムパニー インコーポレーテッド Ｈｉｖインテグラーゼ阻害薬
CA2333643A1 (en) 1998-06-30 2000-01-06 James D. Rodgers Substituted quinolin-2(1h)-ones useful as hiv reverse transcriptase inhibitors
US6187907B1 (en) 1998-08-31 2001-02-13 James Chen Triple helix coil template having a biologically active ligand
WO2000036132A1 (en) 1998-12-14 2000-06-22 Merck & Co., Inc. Hiv integrase inhibitors
CN1367784A (zh) 1999-06-02 2002-09-04 盐野义制药株式会社 新的取代丙烯酮衍生物的制备方法
EP1196384A4 (de) 1999-06-25 2002-10-23 Merck & Co Inc 1-(aromatisch oder heteroaromatisch substituierte)-3-(heteroaromatisch substituiert)-1,3-propandione und ihre anwendungen
US6245806B1 (en) 1999-08-03 2001-06-12 Merck & Co., Inc. HIV integrase inhibitors
WO2001027309A1 (en) 1999-10-13 2001-04-19 Merck & Co., Inc. Hiv integrase inhibitors
US6245402B1 (en) * 1999-12-14 2001-06-12 Xerox Corporation Imageable seam intermediate transfer belt having an overcoat
PE20011349A1 (es) 2000-06-16 2002-01-19 Upjohn Co 1-aril-4-oxo-1,4-dihidro-3-quinolincarboxamidas como agentes antivirales
US6525049B2 (en) 2000-07-05 2003-02-25 Pharmacia & Upjohn Company Pyrroloquinolones as antiviral agents
ES2287170T3 (es) * 2000-10-12 2007-12-16 MERCK & CO., INC. Aza- y poliaza-naftalenil-carboxamidas utilies como inhibidores de la vih integrasa.
CA2425067A1 (en) 2000-10-12 2002-05-10 Merck & Co., Inc. Aza-and polyaza-naphthalenyl ketones useful as hiv integrase inhibitors
DE60138635D1 (de) 2000-10-12 2009-06-18 Merck & Co Inc Aza- und polyaza naphthalenyl karboxamide als inhibitoren der hiv-integrase
CA2425625A1 (en) * 2000-10-12 2002-07-18 Merck & Co., Inc. Aza-and polyaza-naphthalenyl carboxamides useful as hiv integrase inhibitors
US20050014780A1 (en) 2001-08-17 2005-01-20 Maligres Peter E. Process for preparing 5-sulfonamido-8-hydroxy-1,6-naphthyridine-7-carboxamides
AR036256A1 (es) 2001-08-17 2004-08-25 Merck & Co Inc Sal sodica de un inhibidor de integrasa del vih, procesos para su preparacion, composiciones farmaceuticas que lo contienen y su uso para la manufactura de un medicamento
FR2830863B1 (fr) 2001-10-12 2004-01-30 Bioalliance Pharma Derives de quinoleine, procede de synthese, et medicaments renfermant ces derives
JP4494020B2 (ja) 2002-03-15 2010-06-30 メルク・シャープ・エンド・ドーム・コーポレイション Ｈｉｖインテグラーゼ阻害剤として有用なｎ−（置換ベンジル）−８−ヒドロキシ−１，６−ナフチリジン−７−カルボキサミド
WO2004035577A2 (en) 2002-10-16 2004-04-29 Gilead Sciences, Inc. Pre-organized tricyclic integrase inhibitor compounds

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10479772B2 (en) 2015-02-02 2019-11-19 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10829461B2 (en) 2015-02-02 2020-11-10 Valo Early Discovery, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10214501B2 (en) 2015-02-02 2019-02-26 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10214500B2 (en) 2015-02-02 2019-02-26 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10239845B2 (en) 2015-02-02 2019-03-26 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10377726B2 (en) 2015-02-02 2019-08-13 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10407418B2 (en) 2015-02-02 2019-09-10 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10414738B2 (en) 2015-02-02 2019-09-17 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10421731B2 (en) 2015-02-02 2019-09-24 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10428031B2 (en) 2015-02-02 2019-10-01 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10442776B2 (en) 2015-02-02 2019-10-15 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10450284B2 (en) 2015-02-02 2019-10-22 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10450283B2 (en) 2015-02-02 2019-10-22 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10457652B2 (en) 2015-02-02 2019-10-29 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10464910B2 (en) 2015-02-02 2019-11-05 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10464909B2 (en) 2015-02-02 2019-11-05 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10472337B2 (en) 2015-02-02 2019-11-12 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10421732B2 (en) 2015-02-02 2019-09-24 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11891365B2 (en) 2015-02-02 2024-02-06 Valo Health, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494352B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494351B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494353B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10501424B2 (en) 2015-02-02 2019-12-10 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10513501B2 (en) 2015-02-02 2019-12-24 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494354B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10822316B2 (en) 2015-02-02 2020-11-03 Valo Early Discovery, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10829462B2 (en) 2015-02-02 2020-11-10 Valo Early Discovery, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10870645B2 (en) 2015-02-02 2020-12-22 Valo Early Discovery, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US11702412B2 (en) 2015-02-02 2023-07-18 Valo Health, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10988450B2 (en) 2015-02-02 2021-04-27 Valo Early Discovery, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11274085B2 (en) 2015-02-02 2022-03-15 Valo Health, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11274084B2 (en) 2015-02-02 2022-03-15 Valo Health, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11279681B2 (en) 2015-02-02 2022-03-22 Valo Health, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10874649B2 (en) 2016-06-17 2020-12-29 Valo Early Discovery, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US11730721B2 (en) 2016-06-17 2023-08-22 Valo Health, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors

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