US20120027752A1 - Methods and compounds for treating paramyxoviridae virus infections - Google Patents

Methods and compounds for treating paramyxoviridae virus infections Download PDF

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US20120027752A1
US20120027752A1 US13/189,373 US201113189373A US2012027752A1 US 20120027752 A1 US20120027752 A1 US 20120027752A1 US 201113189373 A US201113189373 A US 201113189373A US 2012027752 A1 US2012027752 A1 US 2012027752A1
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alkyl
substituted
independently
alkynyl
alkenyl
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Richard L. Mackman
Jay P. Parrish
Adrian S. Ray
Dorothy Agnes Theodore
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Gilead Sciences Inc
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Gilead Sciences Inc
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Priority to US13/189,373 priority Critical patent/US20120027752A1/en
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PARRISH, JAY P., MACKMAN, RICHARD L., RAY, ADRIAN S., THEODORE, DOROTHY AGNES
Publication of US20120027752A1 publication Critical patent/US20120027752A1/en
Priority to US14/579,348 priority patent/US20150111839A1/en
Priority to US14/613,719 priority patent/US10065958B2/en
Priority to US16/042,085 priority patent/US10696679B2/en
Priority to US16/879,491 priority patent/US11492353B2/en
Priority to US17/854,818 priority patent/US20230125751A1/en
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
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    • 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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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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    • C07H7/06—Heterocyclic radicals
    • 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
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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 methods and compounds for treating Paramyxoviridae virus infections, particularly methods and nucleosides for treating respiratory syncytial virus infections and parainfluenza virus infections.
  • Paramyxoviruses of the Paramyxoviridae family are negative-sense, single-stranded, RNA viruses that are responsible for many prevalent human and animal diseases. These viruses comprise at least two major subfamilies, Paramyxovirinae and Pneumovirinae.
  • the subfamily Paramyxovirina includes the human parainfluenza viruses (HPIV), measles virus and mumps virus.
  • HPIV human parainfluenza viruses
  • measles virus measles virus
  • mumps virus mumps virus.
  • HPIV are the second most common cause of lower respiratory tract infection in younger children and collectively cause about 75% of the cases of Croup (http://www.cdc.gov/ncidod/dvrd/revb/respiratory/hpivfeat.htm). HPIVs can cause repeated infections throughout life including upper respiratory tract illness and even serious lower respiratory tract disease (e.g., pneumonia, bronchitis, and bronchiolitis), the latter being especially of concern among the elderly, and among patients with compromised immune systems (Sable, Infect. Dis. Clin. North Am. 1995, 9, 987-1003). Currently, no vaccines are available to prevent HPIV infections. Therefore there is a need for anti-Paramyxovirina therapeutics.
  • the subfamily Pneumovirinae includes Human respiratory syncytial virus (HRSV). Almost all children will have had an HRSV infection by their second birthday. HRSV is the major cause of lower respiratory tract infections in infancy and childhood with 0.5% to 2% of those infected requiring hospitalization. The elderly and adults with chronic heart, lung disease or those that are immunosuppressed also have a high risk for developing severe HRSV disease (http://www.cdc.gov/rsv/index.html). No vaccine to prevent HRSV infection is currently available. The monoclonal antibody palivizumab is available for infants at high risk, e.g., premature infants or those with either cardiac or lung disease, but the cost for general use is often prohibitive. Ribavirin has also been used to treat HRSV infections but has limited efficacy. Therefore, there is a need for anti-Pneumovirinae therapeutics and anti-Paramyxoviridae therapeutics in general.
  • Ribosides of the nucleobases pyrrolo[1,2-f][1,2,4]triazine, imidazo[1,5-f][1,2,4]triazine, imidazo[1,2-f][1,2,4]triazine, and [1,2,4]triazolo[4,3-f][1,2,4]triazine have been disclosed in Carbohydrate Research 2001, 331(1), 77-82; Nucleosides & Nucleotides (1996), 15(1-3), 793-807; Tetrahedron Letters (1994), 35(30), 5339-42; Heterocycles (1992), 34(3), 569-74; J. Chem. Soc. Perkin Trans.
  • a method for treating a Paramyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I:
  • each R 1 is H or halogen
  • each R 2 , R 3 or R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl;
  • R 2 , R 3 or R 5 on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached form a double bond;
  • R 6 is OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, (C 2 -C 8 )substi
  • each n is independently 0, 1, or 2;
  • each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ;
  • R 7 is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , or
  • each Y or Y 1 is, independently, O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ;
  • W 1 and W 2 when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —; or one of W 1 or W 2 together with either R 3 or R 4 is —Y 3 — and the other of W 1 or W 2 is Formula Ia; or W 1 and W 2 are each, independently, a group of the Formula Ia:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;
  • each Y 3 is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is independently R y or the formula:
  • each M1a, M1c, and M1d is independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • each R y is independently H, F, Cl, Br, I, OH, R, —C( ⁇ Y 1 )R, —C( ⁇ Y 1 )OR, —C( ⁇ Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC( ⁇ Y 1 )R, —OC( ⁇ Y 1 )OR, —OC( ⁇ Y 1 )(N(R) 2 ), —SC( ⁇ Y 1 )R, —SC( ⁇ Y 1 )OR, —SC( ⁇ Y 1 )(N(R) 2 ), —N(R)C( ⁇ Y 1 )R, —N(R)C( ⁇ Y 1 )OR, —N(R)C( ⁇ Y 1 )N(R) 2 , —SO 2 NR 2
  • each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 substituted heterocyclyl, arylalkyl or substituted arylalkyl;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups;
  • each R 8 is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NNHR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C
  • each R 9 or R 10 is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NHNR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , R 11 , OR 11 or SR 11 ;
  • each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —; and wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )
  • the method comprises administering a therapeutically effective amount of a racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate or solvate of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof to a mammal in need thereof.
  • the method comprises treating a Paramyxovirina infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the method comprises treating a parainfluenza, measles or mumps virus infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the method comprises treating a parainfluenza virus infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the method comprises treating a Pneumovirinae infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the method comprises treating a respiratory syncytial virus infection in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I compound, or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an effective amount of a Formula I compound, or a pharmaceutically acceptable salt or ester thereof, in combination with at least one additional therapeutic agent.
  • the method comprises administering a therapeutically effective amount of a combination pharmaceutical agent comprising:
  • a) a first pharmaceutical composition comprising a compound of Formula I; or a pharmaceutically acceptable salt, solvate, or ester thereof, and
  • a second pharmaceutical composition comprising at least one additional therapeutic agent active against infectious Paramyxoviridae viruses.
  • the present application provides for a method of inhibiting a Paramyxoviridae RNA-dependent RNA polymerase, comprising contacting a cell infected with a Paramyxoviridae virus with an effective amount of a compound of Formula I; or a pharmaceutically acceptable salts, solvate, and/or ester thereof.
  • a compound of Formula I or a pharmaceutically acceptable salt, solvate, and/or ester thereof to treat a viral infection caused by a Paramyxoviridae virus.
  • the invention also provides processes and novel intermediates disclosed herein which are useful for preparing Formula I compounds of the invention.
  • novel methods for synthesis, analysis, separation, isolation, purification, characterization, and testing of the compounds of this invention are provided.
  • a method of treating a Paramyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I represented by Formula II:
  • each R 1 is H or halogen
  • each R 2 is OR a or halogen
  • each R 3 or R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl;
  • R 2 , R 3 or R 5 on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached form a double bond;
  • R 6 is OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted
  • each n is independently 0, 1, or 2;
  • each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ;
  • R 7 is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , or
  • each Y or Y 1 is, independently, O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ;
  • W 1 and W 2 when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —; or one of W 1 or W 2 together with either R 3 or R 4 is —Y 3 — and the other of W 1 or W 2 is Formula Ia; or W 1 and W 2 are each, independently, a group of the Formula Ia:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;
  • each Y 3 is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is independently R y or the formula:
  • each M1a, M1c, and M1d is independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • each R y is independently H, F, Cl, Br, I, OH, R, —C( ⁇ Y 1 )R, —C( ⁇ Y 1 )OR, —C( ⁇ Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC( ⁇ Y 1 )R, —OC( ⁇ Y 1 )OR, —OC( ⁇ Y 1 )(N(R) 2 ), —SC( ⁇ Y 1 )R, —SC( ⁇ Y 1 )OR, —SC( ⁇ Y 1 )(N(R) 2 ), —N(R)C( ⁇ Y 1 )R, —N(R)C( ⁇ Y 1 )OR, —N(R)C( ⁇ Y 1 )N(R) 2 , —SO 2 NR 2
  • each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 substituted heterocyclyl, arylalkyl or substituted arylalkyl;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups;
  • each R 8 is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NNHR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C
  • each R 9 is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NHNR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , R 11 , OR 11 or SR 11 ;
  • each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —; and
  • each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 3 , R 5 , R 6 , R 11 or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —.
  • R 1 of Formula II is H.
  • R 6 of Formula II is N 3 , CN, halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl.
  • R 6 of Formula II is CN, methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R 6 of Formula II is CN. In another aspect of this embodiment, R 6 of Formula II is methyl. In another aspect of this embodiment, R 5 of Formula II is H. In another aspect of this embodiment, R 2 of Formula II is OR a . In another aspect of this embodiment, R 2 of Formula II is OH. In another aspect of this embodiment, R 2 of Formula II is F. In another aspect of this embodiment, R 3 of Formula II is OR a . In another aspect of this embodiment, R 3 of Formula II is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 .
  • R 3 of Formula II is OH.
  • R 8 of Formula II is NR 11 R 12 .
  • R 8 of Formula II is NH 2 .
  • R 8 of Formula II is OR 11 .
  • R 8 of Formula II is OH.
  • R 9 of Formula II is H.
  • R 9 of Formula II is NR 11 R 12 .
  • R 9 of Formula II is NH 2 .
  • R 7 of Formula II is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 or
  • R 7 of Formula II is H. In another aspect of this embodiment, R 7 of Formula II is
  • the Paramyxoviridae infection is caused by a Paramyxovirina virus.
  • the Paramyxovirina virus is a parainfluenza, measles or mumps virus.
  • the Paramyxovirina virus is a Respirovirus virus.
  • the Paramyxovirina virus is a type 1 or 3 Human parainfluenza virus.
  • the Paramyxoviridae infection is caused by a Pneumovirinae virus.
  • the Pneumovirinae virus is a respiratory syncytial virus.
  • the Pneumovirinae virus is a Human respiratory syncytial virus.
  • a method of treating a Paramyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I represented by Formula III:
  • each R 2 is OR a or F
  • each R 3 is OR a ;
  • R 6 is OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted
  • each n is independently 0, 1, or 2;
  • each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ;
  • R 7 is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , or
  • each Y or Y 1 is, independently, O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ;
  • W 1 and W 2 when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —; or one of W 1 or W 2 together with either R 3 or R 4 is —Y 3 — and the other of W 1 or W 2 is Formula Ia; or W 1 and W 2 are each, independently, a group of the Formula Ia:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;
  • each Y 3 is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is independently R y or the formula:
  • each M1a, M1c, and M1d is independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • each R y is independently H, F, Cl, Br, I, OH, R, —C( ⁇ Y 1 )R, —C( ⁇ Y 1 )OR, —C( ⁇ Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC( ⁇ Y 1 )R, —OC( ⁇ Y 1 )OR, —OC( ⁇ Y 1 )(N(R) 2 ), —SC( ⁇ Y 1 )R, —SC( ⁇ Y 1 )OR, —SC( ⁇ Y 1 )(N(R) 2 ), —N(R)C( ⁇ Y 1 )R, —N(R)C( ⁇ Y 1 )OR, —N(R)C( ⁇ Y 1 )N(R) 2 , —SO 2 NR 2
  • each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 substituted heterocyclyl, arylalkyl or substituted arylalkyl;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups;
  • each R 8 is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NNHR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C
  • each R 9 is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NHNR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , R 11 , OR 11 or SR 11 ; and
  • each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —; and
  • each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 6 , R 11 or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —.
  • R 6 of Formula III is N 3 , CN, halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl.
  • R 6 of Formula III is CN, methyl, ethenyl, or ethynyl.
  • R 6 of Formula III is CN. In another aspect of this embodiment, R 6 of Formula III is methyl. In another aspect of this embodiment, R 2 of Formula III is OR a . In another aspect of this embodiment, R 2 of Formula III is OH. In another aspect of this embodiment, R 2 of Formula III is F. In another aspect of this embodiment, R 3 of Formula III is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 . In another aspect of this embodiment, R 3 of Formula III is OH. In another aspect of this embodiment, R 8 of Formula III is NR 11 R 12 . In another aspect of this embodiment, R 8 of Formula III is NH 2 . In another aspect of this embodiment, R 8 of Formula III is OR 11 .
  • R 8 of Formula III is OH.
  • R 9 of Formula III is H.
  • R 9 of Formula III is NR 11 R 12 .
  • R 9 of Formula III is NH 2 .
  • R 7 of Formula III is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 or
  • R 7 of Formula III is H. In another aspect of this embodiment, R 7 of Formula III is
  • R 6 of Formula III is N 3 , CN, halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl and R 8 is NH 2 .
  • R 6 of Formula III is CN, methyl, ethenyl, or ethynyl.
  • R 6 of Formula III is CN. In another aspect of this embodiment, R 6 of Formula III is methyl. In another aspect of this embodiment, R 2 of Formula III is OR a . In another aspect of this embodiment, R 2 of Formula III is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 . In another aspect of this embodiment, R 2 of Formula III is OH. In another aspect of this embodiment, R 2 of Formula III is F. In another aspect of this embodiment, R 3 of Formula III is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 . In another aspect of this embodiment, R 3 of Formula III is OH. In another aspect of this embodiment, R 9 of Formula III is H.
  • R 9 of Formula III is NR 11 R 12 . In another aspect of this embodiment, R 9 of Formula III is NH 2 . In another aspect of this embodiment, R 7 of Formula III is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 or
  • R 7 of Formula III is H. In another aspect of this embodiment, R 7 of Formula III is
  • R 6 of Formula III is CN, methyl, ethenyl, or ethynyl, R 8 is NH 2 , and R 9 is H.
  • R 6 of Formula III is CN.
  • R 6 of Formula III is methyl.
  • R 2 of Formula III is OR a .
  • R 2 of Formula III is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 .
  • R 2 of Formula III is OH.
  • R 2 of Formula III is F.
  • R 3 of Formula III is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 .
  • R 3 of Formula III is OH.
  • R 7 of Formula III is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 or
  • R 7 of Formula III is H. In another aspect of this embodiment, R 7 of Formula III is
  • the Paramyxoviridae infection is caused by a Paramyxovirina virus.
  • the Paramyxovirina virus is a parainfluenza, measles or mumps virus.
  • the Paramyxovirina virus is a Respirovirus virus.
  • the Paramyxovirina virus is a type 1 or 3 Human parainfluenza virus.
  • the Paramyxoviridae infection is caused by a Pneumovirinae virus.
  • the Pneumovirinae virus is a respiratory syncytial virus.
  • the Pneumovirinae virus is a Human respiratory syncytial virus.
  • each R 1 is H or halogen
  • each R 3 or R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R a , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl or (C 2 -C 8 )substituted alkynyl;
  • R 6 is OR a , N(R a ) 2 , N 3 , CN, S(O) n R a , —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted
  • each n is independently 0, 1, or 2;
  • each R a is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), or —SO 2 NR 11 R 12 ;
  • R 7 is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 , or
  • each Y or Y 1 is, independently, O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ;
  • W 1 and W 2 when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —; or one of W 1 or W 2 together with either R 3 or R 4 is —Y 3 — and the other of W 1 or W 2 is Formula Ia; or W 1 and W 2 are each, independently, a group of the Formula Ia:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;
  • each Y 3 is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is independently R y or the formula:
  • each M1a, M1c, and M1d is independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • each R y is independently H, F, Cl, Br, I, OH, R, —C( ⁇ Y 1 )R, —C( ⁇ Y 1 )OR, —C( ⁇ Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC( ⁇ Y 1 )R, —OC( ⁇ Y 1 )OR, —OC( ⁇ Y 1 )(N(R) 2 ), —SC( ⁇ Y 1 )R, —SC( ⁇ Y 1 )OR, —SC( ⁇ Y 1 )(N(R) 2 ), —N(R)C( ⁇ Y 1 )R, —N(R)C( ⁇ Y 1 )OR, —N(R)C( ⁇ Y 1 )N(R) 2 , —SO 2 NR 2
  • each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocyclyl, C 2 -C 20 substituted heterocyclyl, arylalkyl or substituted arylalkyl;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups;
  • each R 8 is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NNHR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C
  • each R 9 is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH( ⁇ NR 11 ), —CH ⁇ NHNR 11 , —CH ⁇ N(OR 11 ), —CH(OR 11 ) 2 , —C( ⁇ O)NR 11 R 12 , —C( ⁇ S)NR 11 R 12 , —C( ⁇ O)OR 11 , R 11 , OR 11 or SR 11
  • each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or aryl(C 1 -C 8 )alkyl; or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —; and
  • each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 3 , R 5 , R 6 , R 11 or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —.
  • R 6 is N 3 , CN, halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl.
  • R 6 is CN, methyl, ethenyl, or ethynyl.
  • R 6 is CN.
  • R 6 is methyl.
  • R 1 is H.
  • R 3 is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 .
  • R 3 is OH.
  • R 8 is NR 11 R 12 .
  • R 8 is NH 2 .
  • R 8 is OR 11 .
  • R 8 is OH.
  • R 9 is H.
  • R 9 is NR 11 R 12 .
  • R 9 is NH 2 .
  • R 7 is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 or
  • R 7 is H. In another aspect of this embodiment, R 7 is
  • R 6 is N 3 , CN, halogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, or (C 2 -C 8 )substituted alkynyl and R 8 is NH 2 .
  • R 6 is CN, methyl, ethenyl, or ethynyl.
  • R 6 is CN.
  • R 6 is methyl.
  • R 1 is H.
  • R 3 is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 .
  • R 3 is OH.
  • R 9 is H.
  • R 9 is NR 11 R 12 .
  • R 9 is NH 2 .
  • R 7 is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 or
  • R 7 is H. In another aspect of this embodiment, R 7 is
  • R 6 is CN, methyl, ethenyl, or ethynyl, R 8 is NH 2 , and R 9 is H.
  • R 1 is H.
  • R 6 is CN.
  • R 6 is methyl.
  • R 3 is OH, —OC( ⁇ O)R 11 , or —OC( ⁇ O)OR 11 .
  • R 3 is OH.
  • R 7 is H, —C( ⁇ O)R 11 , —C( ⁇ O)OR 11 or
  • R 7 is H. In another aspect of this embodiment, R 7 is
  • a method of treating a Paramyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formulas I-IV, wherein R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or aryl(C 1 -C 8 )alkyl.
  • R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carb
  • R 11 and R 12 taken together with a nitrogen to which they are both attached, form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —. Therefore, by way of example and not limitation, the moiety —NR 11 R 12 can be represented by the heterocycles:
  • a method of treating a Paramyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I-IV, wherein each R 3 , R 4 , R 5 , R 6 , R 11 or R 12 is, independently, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl, wherein said (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl are, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a .
  • R 3 , R 4 , R 5 , R 6 , R 11 or R 12 could represent moieties such as —CH(NH 2 )CH 3 , —CH(OH)CH2CH3, —CH(NH 2 )CH(CH 3 ) 2 , —CH 2 CF 3 , —(CH 2 ) 2 CH(N 3 )CH 3 , —(CH 2 ) 6 NH 2 and the like.
  • a method of treating a Paramyxoviridae infection in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I-IV, wherein R 3 , R 4 , R 5 , R 6 , R 11 or R 12 is (C 1 -C 8 )alkyl wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —.
  • R 3 , R 4 , R 5 , R 6 , R 11 or R 12 could represent moieties such as —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH(CH 3 ) 2 , —CH 2 SCH 3 , —(CH 2 ) 6 OCH 3 , —(CH 2 ) 6 N(CH 3 ) 2 and the like.
  • a method of treating a Paramyxoviridae infection in a sample comprising administering an effective amount of a compound of Formula I selected from the group consisting of:
  • a compound of the invention or “a compound of Formula I” means a compound of Formula I or a pharmaceutically acceptable salt, thereof.
  • a compound of Formula (number) means a compound of that formula and pharmaceutically acceptable salts, thereof.
  • Alkyl is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • an alkyl group can have 1 to 20 carbon atoms (i.e, C 1 -C 20 alkyl), 1 to 8 carbon atoms (i.e., C 1 -C 8 alkyl), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl).
  • alkyl groups include, but are not limited to, 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, —CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (—CH(CH 3 )
  • Alkoxy means a group having the formula —O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 -C 12 alkoxy), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkoxy).
  • alkoxy groups include, but are not limited to, methoxy (—O—CH 3 or —OMe), ethoxy (—OCH 2 CH 3 or —OEt), t-butoxy (—O—C(CH 3 ) 3 or —OtBu) and the like.
  • Haloalkyl is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
  • the alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C 1 -C 12 haloalkyl), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl).
  • suitable haloalkyl groups include, but are not limited to, —CF 3 , —CHF 2 , —CFH 2 , —CH 2 CF 3 , and the like.
  • Alkenyl is a 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.
  • an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkenyl), 2 to 8 carbon atoms (i.e., C 2 -C 8 alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl).
  • alkenyl groups 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 a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkynyl), 2 to 8 carbon atoms (i.e., C 2 -C 8 alkyne,), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH), and the like.
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical 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.
  • an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (—CH 2 —), 1,1-ethyl (—CH(CH 3 )—), 1,2-ethyl (—CH 2 CH 2 —), 1,1-propyl (—CH(CH 2 CH 3 )—), 1,2-propyl (—CH 2 CH(CH 3 )—), 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 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.
  • alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • 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 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.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkynylene radicals include, but are not limited to, acetylene (—C ⁇ CH), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ C—).
  • Ammonia refers generally to a nitrogen radical which can be considered a derivative of ammonia, having the formula —N(X) 2 , where each “X” is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc.
  • the hybridization of the nitrogen is approximately sp 3 .
  • Nonlimiting types of amino include —NH 2 , —N(alkyl) 2 , —NH(alkyl), —N(carbocyclyl) 2 , —NH(carbocyclyl), —N(heterocyclyl) 2 , —NH(heterocyclyl), —N(aryl) 2 , —NH(aryl), —N(alkyl)(aryl), —N(alkyl)(heterocyclyl), —N(carbocyclyl)(heterocyclyl), —N(aryl)(heteroaryl), —N(alkyl)(heteroaryl), etc.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • Nonlimiting examples of amino groups include —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —NH(CH 2 CH 3 ), —N(CH 2 CH 3 ) 2 , —NH(phenyl), —N(phenyl) 2 , —NH(benzyl), —N(benzyl) 2 , etc.
  • Substituted alkylamino refers generally to alkylamino groups, as defined above, in which at least one substituted alkyl, as defined herein, is attached to the amino nitrogen atom.
  • Non-limiting examples of substituted alkylamino includes —NH(alkylene-C(O)—OH), —NH(alkylene-C(O)—O-alkyl), —N(alkylene-C(O)—OH) 2 , —N(alkylene-C(O)—O-alkyl) 2 , etc.
  • Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • 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, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp 2 carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein.
  • the arylalkenyl group can comprise 8 to 20 carbon atoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein.
  • the arylalkynyl group can comprise 8 to 20 carbon atoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • substituted in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, “substituted alkyl”, “substituted alkylene”, “substituted aryl”, “substituted arylalkyl”, “substituted heterocyclyl”, and “substituted carbocyclyl” means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Typical substituents include, but are not limited to, —X, —R b , —O ⁇ , ⁇ O, —OR b , —SR b , —S ⁇ , —NR b 2 , —N + R b 3 , ⁇ NR b , —CX 3 , —CN, —OCN, —SCN, —N ⁇ C ⁇ O, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , —NHC( ⁇ O)R b , —OC( ⁇ O)R b , —NHC( ⁇ O)NR b 2 , —S( ⁇ O) 2 —, —S( ⁇ O) 2 OH, —S( ⁇ O) 2 R b , —OS( ⁇ O) 2 OR b , —S( ⁇ O) 2 NR b 2 , —S( ⁇ O)R b , —OP
  • Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term “substituted” is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
  • 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.
  • Heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH 3 , etc.), an amine (e.g., —NHCH 3 , —N(CH 3 ) 2 , etc.), or a thioalkyl group (e.g., —SCH 3 ).
  • the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., —CH 2 CH 2 —O—CH 3 , etc.), an alkyl amine (e.g., —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , etc.), or a thioalkyl ether (e.g., —CH 2 —S—CH 3 ).
  • an alkyl ether e.g., —CH 2 CH 2 —O—CH 3 , etc.
  • an alkyl amine e.g., —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , etc.
  • a thioalkyl ether e.g., —CH 2 —S—CH 3
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., —CH 2 CH 2 —OH), an aminoalkyl group (e.g., —CH 2 NH 2 ), or an alkyl thiol group (e.g., —CH 2 CH 2 —SH).
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • a C 1 -C 6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
  • Heterocycle or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern 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; and J. Am. Chem. Soc. (1960) 82:5566.
  • heterocycle includes a “carbocycle” as defined herein, wherein one or more (e.g.
  • heterocycle or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings).
  • Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups.
  • a non-limiting example of a carbonyl substituted heterocyclyl is:
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl
  • 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, 1H-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.
  • Heterocyclylalkyl 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 a heterocyclyl radical (i.e., a heterocyclyl-alkylene-moiety).
  • Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CH 2 —, 2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry .
  • heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkyl group comprises 3 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.
  • heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc.
  • 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl,
  • Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also a sp 2 carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety).
  • the heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry , and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkenyl group comprises 4 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • Heterocyclylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkynylene-moiety).
  • the heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry , and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkynyl group comprises 4 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
  • suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • Non-limiting examples of heteroaryl rings include all of those aromatic rings listed in the definition of “heterocyclyl”, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
  • Carbocycle or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 7 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, or spiro-fused rings.
  • Non-limiting 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, and phenyl.
  • Non-limiting examples of bicyclo carbocycles includes naphthyl, tetrahydronapthalene, and decaline.
  • Carbocyclylalkyl refers to to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein.
  • Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
  • Arylheteroalkyl refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein.
  • the aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety.
  • an arylheteroalkyl group can have the general formulae -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc.
  • any of the alkylene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.
  • Heteroarylalkyl refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein.
  • Non-limiting examples of heteroaryl alkyl include —CH 2 -pyridinyl, —CH 2 -pyrrolyl, —CH 2 -oxazolyl, —CH 2 -indolyl, —CH 2 -isoindolyl, —CH 2 -purinyl, —CH 2 -furanyl, —CH 2 -thienyl, —CH 2 -benzofuranyl, —CH 2 -benzothiophenyl, —CH 2 -carbazolyl, —CH 2 -imidazolyl, —CH 2 -thiazolyl, —CH 2 -isoxazolyl, —CH 2 -pyrazolyl, —CH 2 -isothiazolyl, —CH 2
  • optionally substituted in reference to a particular moiety of the compound of Formula I-III (e.g., an optionally substituted aryl group) refers to a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by substituents such as those listed under the definition of “substituted”.
  • the term “optionally replaced” in reference to a particular moiety of the compound of Formula I-III e.g., the carbon atoms of said (C 1 -C 8 )alkyl may be optionally replaced by —O—, —S—, or NR a —
  • the carbon atoms of said (C 1 -C 8 )alkyl may be optionally replaced by —O—, —S—, or NR a —
  • one or more of the methylene groups of the (C 1 -C 8 )alkyl may be replaced by 0, 1, 2, or more of the groups specified (e.g., —O—, —S—, or NR a —).
  • non-terminal carbon atom(s) in reference to an alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers to the carbon atoms in the moiety that intervene between the first carbon atom of the moiety and the last carbon atom in the moiety. Therefore, by way of example and not limitation, in the alkyl moiety —CH 2 (C*)H 2 (C*)H 2 CH 3 or alkylene moiety —CH 2 (C*)H 2 (C*)H 2 CH 2 — the C* atoms would be considered to be the non-terminal carbon atoms.
  • Certain Y and Y 1 alternatives are nitrogen oxides such as + N(O)(R) or + N(O)(OR). These nitrogen oxides, as shown here attached to a carbon atom, can also be represented by charge separated groups such as
  • Linker or “link” means a chemical moiety comprising a covalent bond or a chain of atoms.
  • Linkers include repeating units of alkyloxy (e.g. polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • oxygen-linked means that if a bond between two moieties can be formed by using more than one type of atom in a moiety, then the bond formed between the moieties is through the atom specified.
  • a nitrogen-linked amino acid would be bonded through a nitrogen atom of the amino acid rather than through an oxygen or carbon atom of the amino acid.
  • one or more of W 1 or W 2 are independently a radical of a nitrogen-linked naturally occurring ⁇ -amino acid ester.
  • naturally occurring amino acids include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, selenocysteine, serine, tyrosine, arginine, histidine, ornithine and taurine.
  • the esters of these amino acids comprise any of those described for the substitutent R, particularly those in which R is optionally substituted (C 1 -C 8 )alkyl.
  • purine or “pyrimidine” base comprises, but is not limited to, adenine, N 6 -alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -allylaminopurine, N 6 -thioallyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C 5
  • Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.
  • the purine and pyrimidine bases of Formula I-III are linked to the ribose sugar, or analog thereof, through a nitrogen atom of the base. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired.
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
  • the carbon atoms of the compounds of Formula I-IV are intended to have a valence of four.
  • the remaining carbon substitutents needed to provide a valence of four should be assumed to be hydrogen.
  • 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 an intermediate 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.
  • 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 moiety may include an active metabolite or drug itself.
  • prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters —CH 2 OC( ⁇ O)R 30 and acyloxymethyl carbonates —CH 2 C( ⁇ O)OR 30 where R 30 is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • R 30 is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • the acyloxyalkyl ester was used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
  • a prodrug moiety is part of a phosphate group.
  • the acyloxyalkyl ester may be used to deliver phosphoric 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 phosphate group may be a phosphate prodrug moiety.
  • the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to those comprising 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 et al (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 et al (1993) Antiviral Res., 22: 155-174; Benzaria et al (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al, U.S. Pat. No. 6,312,662).
  • a compound of Formula I-IV and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs.
  • crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism).
  • crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures.
  • the pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism).
  • the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I-III and their pharmaceutically acceptable salts.
  • a compound of Formula I-IV and its pharmaceutically acceptable salts may also exist as an amorphous solid.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
  • Additives, including solvents, may be used to create the amorphous forms of the instant invention.
  • the instant invention comprises all amorphous forms of the compounds of Formula I-IV and their pharmaceutically acceptable salts.
  • R x comprises a R y substituent.
  • R y can be R.
  • R can be W 3 .
  • W 3 can be W 4 and W 4 can be R or comprise substituents comprising R y .
  • One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • W 3 and R y are recursive substituents in certain embodiments.
  • each recursive substituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment.
  • each recursive substituent can independently occur 12 or fewer times in a given embodiment.
  • each recursive substituent can independently occur 3 or fewer times in a given embodiment.
  • W 3 will occur 0 to 8 times
  • R y will occur 0 to 6 times in a given embodiment.
  • W 3 will occur 0 to 6 times and R y will occur 0 to 4 times in a given embodiment.
  • Recursive substituents are an intended aspect of the invention.
  • One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in an embodiment of the invention, the total number will be determined as set forth above.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • terapéuticaally effective amount is the amount of compound of Formula I-IV present in a composition described herein that is needed to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a subject to be treated to give an anticipated physiological response or desired biological effect when such a composition is administered by the chosen route of administration.
  • the precise amount will depend upon numerous factors, for example the particular compound of Formula I-IV, the specific activity of the composition, the delivery device employed, the physical characteristics of the composition, its intended use, as well as patient considerations such as severity of the disease state, patient cooperation, etc., and can readily be determined by one skilled in the art based upon the information provided herein.
  • normal saline means a water solution containing 0.9% (w/v) NaCl.
  • hypertonic saline means a water solution containing greater than 0.9% (w/v) NaCl.
  • 3% hypertonic saline would contain 3% (w/v) NaCl.
  • the compounds of the Formula I-IV may comprise a phosphate group as R 7 , which may be a prodrug moiety
  • each Y or Y 1 is, independently, O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ;
  • W 1 and W 2 when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —; or one of W 1 or W 2 together with either R 3 or R 4 is —Y 3 — and the other of W 1 or W 2 is Formula Ia; or W 1 and W 2 are each, independently, a group of Formula Ia:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;
  • each Y 3 is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R y is independently H, F, Cl, Br, I, OH, R, —C( ⁇ Y 1 )R, —C( ⁇ Y 1 )OR, —C( ⁇ Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC( ⁇ Y 1 )R, —OC( ⁇ Y 1 )OR, —OC( ⁇ Y 1 )(N(R) 2 ), —SC( ⁇ Y 1 )R, —SC( ⁇ Y 1 )OR, —SC( ⁇ Y 1 )(N(R) 2 ), —N(R)C( ⁇ Y 1 )R, —N(R)C( ⁇ Y 1 )OR, or —N(R)C( ⁇ Y 1 )N(R) 2 , —SO 2 NR 2
  • each R x is independently R y , 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;
  • each R is H, halogen, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 2 -C 20 heterocycle, C 2 -C 20 substituted heterocyclyl, arylalkyl, substituted arylalkyl or a protecting group;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
  • W 5 carbocycles and W 5 heterocycles may be independently substituted with 0 to 3 R y groups.
  • W 5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
  • W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.
  • the W 5 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.
  • a W 5 heterocycle 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).
  • W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 heterocyclic 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 W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
  • W 5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
  • W 5 also includes, but is not limited to, examples such as:
  • W 5 carbocycles and heterocycles may be independently substituted with 0 to 3 R groups, as defined above.
  • substituted W 5 carbocycles include:
  • substituted phenyl carbocycles include:
  • Formula I-IV compounds include substructures such as:
  • each Y 2b is, independently, O or N(R).
  • each Y 2b is O and each R x is independently:
  • M12c is 1, 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S.
  • one Y 2b —R x is NH(R) and the other Y 2b —R x is O—R x wherein R x is:
  • each Y 2b is O and each R x is independently:
  • each Y 2b is O and each R x is independently:
  • M12c is 1 and Y 2 is a bond, O, or CR 2 .
  • Formulas I-IV compounds include substructures such as:
  • each Y 3 is, independently, O or N(R). In another aspect of this embodiment, each Y 3 is O. In another aspect of this embodiment, the substructure is:
  • R y is W 5 as defined herein.
  • each Y 2c is, independently, O, N(R y ) or S.
  • Formula I-IV compounds includes the substructures wherein one of W 1 or W 2 together with either R 3 or R 4 is —Y 3 — and the other of W 1 or W 2 is Formula Ia.
  • Such an embodiment is represented by a compound of Formula Ib selected from:
  • each Y and Y 3 is O.
  • W 1 or W 2 is Y 2b —R x ; each Y, Y 3 and Y 2b is O and R x is:
  • M12c is 1, 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S.
  • W 1 or W 2 is Y 2b —R x ; each Y, Y 3 and Y 2b is O and R x is:
  • W 1 or W 2 is Y 2b —R x ; each Y, Y 3 and Y 2b is O and R x is:
  • M12c is 1 and Y 2 is a bond, O, or CR 2 .
  • W 5 is a carbocycle such as phenyl or substituted phenyl.
  • the substructure is:
  • R x is:
  • M12c is 1, 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S.
  • the chiral carbon of the amino acid and lactate moieties may be either the R or S configuration or the racemic mixture.
  • R y is (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl or (C 2 -C 8 ) substituted alkynyl.
  • R y is (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl or (C 2 -C 8 ) substituted alkynyl; and R is CH 3 .
  • R y is (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl or (C 2 -C 8 ) substituted alkynyl; R is CH 3 ; and each Y 2 is —NH—.
  • W 1 and W 2 are, independently, nitrogen-linked, naturally occurring amino acids or naturally occurring amino acid esters.
  • W 1 and W 2 are, independently, naturally-occurring 2-hydroxy carboxylic acids or naturally-occurring 2-hydroxy carboxylic acid esters wherein the acid or ester is linked to P through the 2-hydroxy group.
  • each R x is, independently, (C 1 -C 8 ) alkyl. In another aspect of this embodiment, each R x is, independently, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • W 1 and W 2 are independently selected from one of the formulas in Tables 20.1-20.37 and Table 30.1 below.
  • the variables used in Tables 20.1-20.37 e.g., W 23 , R 21 , etc.
  • Tables 20.1-20.37 pertain only to Tables 20.1-20.37, unless otherwise indicated.
  • each R 21 is independently H or (C 1 -C 8 )alkyl
  • each R 22 is independently H, R 21 , R 23 or R 24 wherein each R 24 is independently substituted with 0 to 3 R 23 ;
  • each R 23 is independently R 23a , R 23b , R 23c R 23d , provided that when R 23 is bound to a heteroatom, then R 23 is R 23c or R 23d ;
  • each R 23a is independently F, Cl, Br, I, —CN, N 3 or —NO 2 ;
  • each R 23b is independently Y 21 ;
  • each R 23c is independently —R 2x , —N(R 2x )(R 2x ), —SR 2x , —S(O)R 2x , —S(O) 2 R 2x , —S(O)(OR 2x ), —S(O) 2 (OR 2x ), —OC( ⁇ Y 21 )R 2x , —OC( ⁇ Y 21 )OR 2x , —OC( ⁇ Y 21 )(N(R 2x )(R 2x )), —SC( ⁇ Y 21 )R 2x , —SC( ⁇ Y 21 )OR 2x , —SC( ⁇ Y 21 )(N(R 2x )(R 2x )), —N(R 2x )C( ⁇ Y 21 )R 2x , —N(R 2x )C( ⁇ Y 21 )OR 2x , or —N(R 2x )C( ⁇ Y 21 )(N(R 2x )
  • each R 23d is independently —C( ⁇ Y 21 )R 2x , —C( ⁇ Y 21 )OR 2x or —C( ⁇ Y 21 )(N(R 2x )(R 2x ));
  • each R 2x is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heteroaryl; or two R 2x taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR 21 —; and wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR 21 —;
  • each R 24 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;
  • each R 25 is independently R 24 wherein each R 24 is substituted with 0 to 3 R 23 groups;
  • each R 25a is independently (C 1 -C 8 )alkylene, (C 2 -C 8 )alkenylene, or (C 2 -C 8 )alkynylene any one of which said (C 1 -C 8 )alkylene, (C 2 -C 8 )alkenylene, or (C 2 -C 8 )alkynylene is substituted with 0-3 R 23 groups;
  • each W 23 is independently W 24 or W 25 ;
  • each W 24 is independently R 25 , —C( ⁇ Y 21 )R 25 , —C( ⁇ Y 21 )W 25 ; —SO 2 R 25 , or —SO 2 W 25 ;
  • each W 25 is independently carbocycle or heterocycle wherein W 25 is independently substituted with 0 to 3 R 22 groups;
  • each Y 21 is independently O or S.
  • Embodiments of R x include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:
  • any reference to the compounds of the invention described heerein 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 or an alkaline earth (for example, Na + , Li + , K + , Ca +2 and Mg +2 ), ammonium and NR 4 + (wherein R is defined herein).
  • Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid
  • 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.
  • compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the compounds of the invention may have chiral centers, e.g. chiral carbon or phosphorus atoms.
  • the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic and diastereomeric mixtures are all within the scope of the invention.
  • the racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases followed by conversion back to the optically active substances.
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • 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, reactivities and biological properties. For example, the compounds of Formula I-IV may have a chiral phosphorus atom when R 7 is
  • W 1 and W 2 are different.
  • W 1 or W 2 also has a chiral center, for example with W 1 or W 2 is a nitrogen-linked, chiral, naturally occurring ⁇ -amino acid ester, then the compound of Formula I-IV will exists as diastereomers because there are two centers of chirality in the molecule. All such diastereomers and their uses described herein are encompassed by the instant invention. Mixtures of diastereomers may be separate under high resolution analytical procedures such as electrophoresis, crystallization and/or chromatography. Diastereomeres may have different physical attributes such as, but not limited to, solubility, chemical stabilities and crystallinity and may also have different biological properties such as, but not limited to, enzymatic stability, absorption and metabolic stability.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • racemic 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.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the compounds of the invention can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • Another aspect of the invention relates to methods of inhibiting the activity of Paramyxoviridae polymerase comprising the step of treating a sample suspected of containing Paramyxoviridae with a composition of the invention.
  • compositions of the invention may act as inhibitors of Paramyxoviridae polymerase, as intermediates for such inhibitors or have other utilities as described below.
  • the inhibitors will bind to locations on the surface or in a cavity of Paramyxoviridae polymerase having a geometry unique to Paramyxoviridae polymerase.
  • Compositions binding Paramyxoviridae polymerase may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of Paramyxoviridae polymerase.
  • the invention relates to methods of detecting Paramyxoviridae polymerase in a sample suspected of containing Paramyxoviridae polymerase comprising the steps of: treating a sample suspected of containing Paramyxoviridae polymerase with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label.
  • Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.
  • the compounds herein are labeled in conventional fashion using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino.
  • samples suspected of containing Paramyxoviridae polymerase include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • the sample will be suspected of containing an organism which produces Paramyxoviridae polymerase, frequently a pathogenic organism such as a Paramyxoviridae virus.
  • Samples can be contained in any medium including water and organic solvent ⁇ water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
  • the treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample.
  • the addition step comprises any method of administration as described above.
  • the activity of Paramyxoviridae polymerase after application of the composition can be observed by any method including direct and indirect methods of detecting Paramyxoviridae polymerase activity. Quantitative, qualitative, and semiquantitative methods of determining Paramyxoviridae polymerase activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • Organisms that contain Paramyxoviridae polymerase include the Paramyxoviridae virus.
  • the compounds of this invention are useful in the treatment or prophylaxis of Paramyxoviridae infections in animals or in man.
  • compositions of the invention are screened for inhibitory activity against Paramyxoviridae polymerase by any of the conventional techniques for evaluating enzyme activity.
  • typically compositions are first screened for inhibition of Paramyxoviridae polymerase in vitro and compositions showing inhibitory activity are then screened for activity in vivo.
  • Compositions having in vitro Ki (inhibitory constants) of less then about 5 ⁇ 10 ⁇ 6 M and preferably less than about 1 ⁇ 10 ⁇ 7 M are preferred for in vivo use.
  • the compounds of this invention are 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. All formulations will optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipients” (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, particularly those additional therapeutic ingredients as discussed herein.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • 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. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is 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 active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) 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 dimethyl sulphoxide 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 invention include Tween® 60, Span® 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.
  • 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 are used.
  • compositions according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium tartrate
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • 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%, and 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 intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of Paramyxoviridae infections as described below.
  • the invention is a novel, efficacious, safe, nonirritating and physiologically compatible inhalable composition
  • a compound of Formula I-IV or a pharmaceutically acceptable salt thereof, suitable for treating Paramyxoviridae infections and potentially associated bronchiolitis.
  • Preferred pharmaceutically acceptable salts are inorganic acid salts including hydrochloride, hydrobromide, sulfate or phosphate salts as they may cause less pulmonary irritation.
  • the inhalable formulation is delivered to the endobronchial space in an aerosol comprising particles with a mass median aerodynamic diameter (MMAD) between about 1 and about 5 ⁇ m.
  • MMAD mass median aerodynamic diameter
  • the compound of Formula I-IV is formulated for aerosol delivery using a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).
  • Non-limiting examples of nebulizers include atomizing, jet, ultrasonic, pressurized, vibrating porous plate, or equivalent nebulizers including those nebulizers utilizing adaptive aerosol delivery technology (Denyer, J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10).
  • a jet nebulizer utilizes air pressure to break a liquid solution into aerosol droplets.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a pressurized nebulization system forces solution under pressure through small pores to generate aerosol droplets.
  • a vibrating porous plate device utilizes rapid vibration to shear a stream of liquid into appropriate droplet sizes.
  • the formulation for nebulization is delivered to the endobronchial space in an aerosol comprising particles with a MMAD predominantly between about 1 ⁇ m and about 5 ⁇ m using a nebulizer able to aerosolize the formulation of the compound of Formula I-IV into particles of the required MMAD.
  • the majority of aerosolized particles should not have a MMAD greater than about 5 ⁇ m. If an aerosol contains a large number of particles with a MMAD larger than 5 ⁇ m, the particles are deposited in the upper airways decreasing the amount of drug delivered to the site of inflammation and bronchoconstriction in the lower respiratory tract. If the MMAD of the aerosol is smaller than about 1 ⁇ m, then the particles have a tendency to remain suspended in the inhaled air and are subsequently exhaled during expiration.
  • the aerosol formulation for nebulization delivers a therapeutically efficacious dose of the compound of Formula I-IV to the site of Paramyxoviridae infection sufficient to treat the Paramyxoviridae infection.
  • the amount of drug administered must be adjusted to reflect the efficiency of the delivery of a therapeutically efficacious dose of the compound of Formula I-IV.
  • a combination of the aqueous aerosol formulation with the atomizing, jet, pressurized, vibrating porous plate, or ultrasonic nebulizer permits, depending on the nebulizer, about, at least, 20, to about 90%, typically about 70% delivery of the administered dose of the compound of Formula I-IV into the airways.
  • at least about 30 to about 50% of the active compound is delivered. More preferably, about 70 to about 90% of the active compound is delivered.
  • a compound of Formula I-IV or a pharmaceutically acceptable salt thereof is delivered as a dry inhalable powder.
  • the compounds of the invention are administered endobronchially as a dry powder formulation to efficacious deliver fine particles of compound into the endobronchial space using dry powder or metered dose inhalers.
  • the compound of Formula I-IV is processed into particles with, predominantly, MMAD between about 1 ⁇ m and about 5 ⁇ m by milling spray drying, critical fluid processing, or precipitation from solution. Media milling, jet milling and spray-drying devices and procedures capable of producing the particle sizes with a MMAD between about 1 ⁇ m and about 5 ⁇ m are well know in the art.
  • excipients are added to the compound of Formula I-IV before processing into particles of the required sizes.
  • excipients are blended with the particles of the required size to aid in dispersion of the drug particles, for example by using lactose as an excipient.
  • Particle size determinations are made using devices well known in the art.
  • a multi-stage Anderson cascade impactor or other suitable method such as those specifically cited within the US Pharmacopoeia Chapter 601 as characterizing devices for aerosols within metered-dose and dry powder inhalers.
  • a compound of Formula I-IV is delivered as a dry powder using a device such as a dry powder inhaler or other dry powder dispersion devices.
  • dry powder inhalers and devices include those disclosed in U.S. Pat. No. 5,458,135; U.S. Pat. No. 5,740,794; U.S. Pat. No. 5,775,320; U.S. Pat. No. 5,785,049; U.S. Pat. No. 3,906,950; U.S. Pat. No. 4,013,075; U.S. Pat. No. 4,069,819; U.S. Pat. No. 4,995,385; U.S. Pat. No. 5,522,385; U.S. Pat. No.
  • Drug powder is placed in the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity.
  • Non-laminar flow characteristics of the powder path cause the excipient-drug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs.
  • a compound of Formula I-IV, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using either type of dry powder inhaler as described herein, wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of 1 ⁇ m to about 5 ⁇ m.
  • a compound of Formula I-IV is delivered as a dry powder using a metered dose inhaler.
  • metered dose inhalers and devices include those disclosed in U.S. Pat. No. 5,261,538; U.S. Pat. No. 5,544,647; U.S. Pat. No. 5,622,163; U.S. Pat. No. 4,955,371; U.S. Pat. No. 3,565,070; U.S. Pat. No. 3,361,306 and U.S. Pat. No. 6,116,234.
  • a compound of Formula I-IV, or a pharmaceutically acceptable salt thereof is delivered as a dry powder using a metered dose inhaler wherein the MMAD of the dry powder, exclusive of any excipients, is predominantly in the range of about 1-5 ⁇ m.
  • 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 are 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 injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are 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 the 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 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 in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about 0.01 to about 5 mg/kg body weight per day; most typically, from about 0.05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • compositions of the invention are also used in combination with other active ingredients.
  • the other active therapeutic agent is active against Paramyxoviridae virus infections, particularly respiratory syncytial virus infections and/or parainfluenza virus infections.
  • Non-limiting examples of these other active therapeutic agents are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, and mixtures thereof.
  • additional active therapeutics used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds of Formula I-IV.
  • the additional agents are preferrably administered orally or by direct inhalation.
  • other preferred additional therapeutic agents in combination with the compounds of Formula I-IV for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.
  • Glucocorticoids which were first introduced as an asthma therapy in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin Immunol., 75 (1 Pt) 1-13, 1985).
  • oral glucocorticoid therapies are associated with profound undesirable side effects such as truncal obesity, hypertension, glaucoma, glucose intolerance, acceleration of cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001).
  • a solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation.
  • corticosteroids Inhaled corticosteroids (ICS) have been developed to mitigate the severe adverse effects of oral steroids.
  • corticosteroids that may be used in combinations with the compounds of Formula I-IV are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisones, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butylate, flumethasone, flumetasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone propionate, cicl
  • anti-inflammatory signal transduction modulators like phosphodiesterase inhibitors (e.g. PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g. blocking NF ⁇ B through IKK inhibition), or kinase inhibitors (e.g.
  • P38 MAP, JNK, PI3K, EGFR or Syk is a logical approach to switching off inflammation as these small molecules target a limited number of common intracellular pathways—those signal transduction pathways that are critical points for the anti-inflammatory therapeutic intervention (see review by P. J. Barnes, 2006).
  • non-limiting additional therapeutic agents include: 5-(2,4-Difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797); 3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluorormethoxy-benzamide (PDE-4 inhibitor Roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-Dichloro-pyridin
  • Combinations comprising inhaled ⁇ 2-adrenoreceptor agonist bronchodilators such as formoterol, albuterol or salmeterol with the compounds of Formula I-IV are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.
  • Combinations of inhaled ⁇ 2-adrenoreceptor agonist bronchodilators such as formoterol or salmeterol with ICS's are also used to treat both the bronchoconstriction and the inflammation (Symbicort® and Advair®, respectively).
  • the combinations comprising these ICS and ⁇ 2-adrenoreceptor agonist combinations along with the compounds of Formula I-IV are also suitable, but non-limiting, combinations useful for the treatment of respiratory viral infections.
  • anticholinergics are of potential use and, therefore, useful as an additional therapeutic agents in combination with the compounds of Formula I-IV for the treatment of viral respiratory infections.
  • anticholinergics include, but are not limited to, antagonists of the muscarinic receptor (particularly of the M3 subtype) which have shown therapeutic efficacy in man for the control of cholinergic tone in COPD (Witek, 1999); 1- ⁇ 4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl ⁇ -pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide; 3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (Ipratropium-N
  • the compounds of Formula I-IV may also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections.
  • a non-limiting example of a mucolytic agent is ambroxol.
  • the compounds of Formula I-IV may be combined with expectorants to treat both the infection and symptoms of respiratory infections.
  • a non-limiting example of an expectorant is guaifenesin.
  • Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung diseases (Kuzik, J. Pediatrics 2007, 266).
  • the compounds of Formula I-IV may also be combined with nebulized hypertonic saline particularly when the Paramyxoviridae virus infection is complicated with bronchiolitis.
  • the combination of the compounds of Formula I-IV with hypertonic saline may also comprise any of the additional agents discussed above.
  • nebulized about 3% hypertonic saline is used.
  • any compound of the invention with one or more additional active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination When administered sequentially, the combination may be administered in two or more administrations.
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
  • a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
  • a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
  • a unit dose of a compound of the invention may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.
  • the combination therapy may provide “synergy” and “synergistic”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially
  • effective dosages of two or more active ingredients are administered together.
  • a synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
  • the present application provides for methods of inhibiting Paramyxoviridae polymerase in a cell, comprising: contacting a cell infected with HCV with an effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, whereby Paramyxoviridae polymerase is inhibited.
  • the present application provides for methods of inhibiting Paramyxoviridae polymerase in a cell, comprising: contacting a cell infected with HCV with an effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent, whereby Paramyxoviridae polymerase is inhibited.
  • the present application provides for methods of inhibiting Paramyxoviridae polymerase in a cell, comprising: contacting a cell infected with Paramyxoviridae virus with an effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent selected
  • the present application provides for methods of treating Paramyxoviridae virus infection in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.
  • the present application provides for methods of treating Paramyxoviridae virus infection in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent, whereby Paramyxoviridae polymerase is inhibited.
  • the present application provides for methods of treating Paramyxoviridae virus infection in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent.
  • the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabelled (e.g. 14 C or 3 H) compound of the invention, administering it parenterally in a detectable dose (e.g.
  • metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HCV polymerase inhibitory activity of their own.
  • compositions and methods for determining stability of compounds in surrogate gastrointestinal secretions are known.
  • Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37° C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo.
  • the prodrugs of the invention typically will be stable in the digestive system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.
  • the 2-ethylbutyl alanine chlorophosphoramidate ester B was prepared using the same procedure as chloridate A except substituting 2-ethylbutyl alanine ester for ethyl alanine ester.
  • the material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.
  • the isopropyl alanine chlorophosphoramidate ester C was prepared using the same procedure as chloridate A except substituting isopropyl alanine ester for the ethyl alanine ester. The material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.
  • the commercially available lactol (10 g, 23.8 mmol) was dissolved in anhydrous DMSO (30 mL) under N 2 (g). Ac 2 O (20 mL) was added and the resultant reaction mixture stirred at RT for 48 h. The reaction mixture was poured onto ice H 2 O (500 mL) and the mixture stirred for 20 min. The mixture was extracted with EtOAc (3 ⁇ 200 mL) and the combined organic extracts were then washed with H 2 O (3 ⁇ 200 mL). The organic extract was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 and subjected to silica gel chromatography eluting with 25% EtOAc in hexanes to provide the lactone (9.55 g, 96%).
  • the bromopyrazole (prepared according to WO2009/132135) (0.5 g, 2.4 mmol) was suspended in anhydrous THF (10 mL) under N 2 (g). The suspension was stirred and TMSCl (0.67 mL, 5.28 mmol) was added. The mixture was stirred for 20 min. at RT and then cooled to ⁇ 78° C. after which time a solution of n-BuLi (6 mL, 1.6 N in hexanes, 9.6 mmol) was added slowly. The reaction mixture was stirred for 10 min. at ⁇ 78° C. and then the lactone (1 g, 2.4 mmol) was added via syringe.
  • the hydroxy nucleoside (1.1 g, 2.0 mmol) was dissolved in anhydrous CH 2 Cl 2 (40 mL) and the solution cooled with stirring to 0° C. under N 2 (g).
  • TMSCN (0.931 mL, 7 mmol) was added and the mixture stirred for a further 10 min.
  • TMSOTf (1.63 mL, 9.0 mmol) was slowly added to the reaction and the mixture stirred for 1 h.
  • the reaction mixture was then diluted with CH 2 Cl 2 (120 mL) and aqueous NaHCO 3 (120 mL) was added to quench the reaction. The reaction mixture was stirred for a further 10 min and the organic layer separated.
  • the tribenzyl cyano nucleoside (70 mg, 0.124 mmol) was dissolved in anhydrous CH 2 Cl 2 (2 mL) and cooled to ⁇ 78° C. under N 2 (g). A solution of BCl 3 (1N in CH 2 Cl 2 , 0.506 mL, 0.506 mmol) was added and the reaction mixture stirred for 1 h. at ⁇ 78° C. When the reaction was complete by LC/MS, MeOH was added to quench the reaction. The reaction mixture was allowed to warm to room RT and the solvent removed under reduced pressure.
  • the reaction mixture was treated with BCl 3 (1.0 M in CH 2 Cl 2 , 766 ⁇ L, 0.77 mmol) and stirred for 2 h. The mixture was then cooled to ⁇ 78° C. and treated with Et 3 N (340 ⁇ L, 2.44 mmol) followed by MeOH (2 mL) before allowing to warm to RT. The reaction was concentrated under reduced pressure and then co-evaporated with MeOH (3 ⁇ 5 mL). The residue was then suspended in H 2 O (5 mL) and treated with NaHCO 3 (1 g). The solution was stirred for 10 min and then concentrated under reduced pressure.
  • BCl 3 1.0 M in CH 2 Cl 2 , 766 ⁇ L, 0.77 mmol
  • the starting nucleoside (prepared as described in the synthesis of compound 2) (0.355 g, 0.765 mmol) was dissolved in anhydrous THF (35 mL) and cooled to 0° C. with stirring under N 2 (g). A solution of methyl magnesium chloride (2 mL, 6 mmol) (3N in THF) was added and the resultant mixture stirred overnight. Acetic acid (7 mmol) was added to quench the reaction and then the solvents were removed by rotory under reduced pressure. The residue was re-dissolved in CH 2 Cl 2 and the solution subjected to a plug of silica gel to isolate the product (0.355 g) as a crude mixture. LC/MS (m/z: 480, M +1 ).
  • the crude material was dissolved in anhydrous CH 2 Cl 2 (20 mL) and placed under N 2 (g). The solution was stirred and treated with methanesulfonic acid (0.2 mL, 2.74 mmol). The reaction mixture was stirred for 12 h at RT and then quenched by the addition of Et 3 N (3.5 mmol). The mixture was concentrated under reduced pressure and the residue subjected to silica gel chromatography to provide the methyl substituted nucleoside (0.174 g, 0.377 mmol, 44% yield) as a 4:1 mixture of beta- and alpha-anomers respectively.
  • the benzylated nucleoside material (0.134 g, 0.290 mmol), Degussa catalyst (0.268 g) and AcOH (30 mL) were mixed together.
  • the reaction atmosphere was charged with H 2 (g) and the reaction stirred for 2 h.
  • the catalyst was removed by filtration and the mixture concentrated under reduced pressure.
  • the residue was dissolved in a minimal amount of H 2 O and subjected to reverse phase HPLC(C 18 hydro RP column) to isolate the ⁇ -anomer 3 (0.086 g, 0.217 mmol, 57% yield).
  • the nucleoside 3 (0.011 g, 0.04 mmol) was dissolved in trimethylphosphate (2 mL) and cooled to 0° C. The mixture was stirred under an atmosphere of N 2 (g) and 1-Methylimidazole (0.320 mL, 5 mmol) followed by the alaninylmonoisopropyl, monophenol phosphorchloridate C (0.240 mL, 4.4 mmol) was added. The reaction mixture was stirred for 2 h. at 0° C. and then allowed to warm slowly to RT. while monitoring by LC/MS. When complete by LCMS, the reaction mixture was treated with H 2 O (5 mL) and then concentrated under reduced pressure.
  • the nucleoside 3 (0.026 g, 0.092 mmol) was dissolved in trimethylphosphate (2 mL) and cooled to 0° C. The mixture was stirred under N 2 (g) and 1-methylimidazole (0.062 mL, 0.763 mmol) followed by the chloridate A (0.160 g, 0.552 mmol) were added. The reaction mixture was stirred for 2 h. at 0° C. and then allowed to warm slowly to RT. H 2 O (5 mL) was added to quench the reaction and then the mixture concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 and subjected to silica gel chromatography eluting with 0-100% EtOAc in hexanes.
  • the nucleoside 3 (0.022 g, 0.056 mmol) was dissolved in trimethylphosphate (1 mL) and stirred under N 2 (g). Phosphorous oxychloride (0.067 mL, 0.73 mmol) was added and the mixture stirred for 2 h. Monitoring by analytical ion-exchange column determined the time at which >80 percent of monophosphate was formed. A solution of tributylamine (0.44 mL, 1.85 mmol) and triethylammonium pyrophosphate (0.327 g, 0.72 mmol) dissolved in anhydrous DMF (1 mL) was added.
  • the acetate material (1.2 g, 5.5 mmol) (J. Org. Chem. 1985, 50, 3547, De Bernardo et al) was dissolved in a 1:1 mixture MeOH and THF (10 mL). A 1N solution of NaOH(aq) (10 mL) was added until the pH was 13. The reaction mixture was stirred for 2 h and then neutralized to pH 8-9 by the addition of AcOH. The mixture was extracted with EtOAc (10 ⁇ 30 mL) and the combined organic extracts dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-70% EtOAc in hexanes to give the desired product (866 mg, 90%).
  • the nucleoside 1 (45 mg, 0.15 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and the solution stirred under N 2 (g) at 0° C. Methyl imidazole (36 ⁇ L, 0.45 mmol) was added to the solution. Chlorophosphoramidate C (69 mg, 0.225 mmol) was dissolved in anhydrous THF (0.25 mL) and added dropwise to the nucleoside mixture. When the reaction was complete by LCMS, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO 3 solution, saturated NaCl, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-5% MeOH in CH 2 Cl 2 followed by preparative HPLC to give the product (20.9 mg, 25%).
  • Compound 11 was prepared from Compound 2 and chloridate A using same method as for the preparation of compound 8.
  • the nucleoside 1 (14.6 mg, 0.05 mmol) was dissolved in anhydrous trimethyl phosphate (0.5 mL) and stirred under N 2 (g) at RT.
  • POCl 3 (9.2 ⁇ L, 0.1 mmol) was added and the mixture stirred for 60 min.
  • Alanine ethyl ester hydrochloride (61 mg, 0.4 mmol) and then Et 3 N (70 ⁇ L, 0.5 mmol) was added.
  • the resultant mixture was stirred for 15 min. and then additional Et 3 N (70 ⁇ L, 0.5 mmol) was added to give a solution pH of 9-10.
  • the mixture was stirred for 2 h.
  • the nucleoside alcohol (0.6 g, 1.08 mmol) (prepared as described in Compound 1 synthesis) was dissolved in anhydrous THF (8 mL) and placed under N 2 (g). The reaction mixture was stirred and cooled to 0° C. and then treated with a 0.5N solution of ethynyl magnesium bromide in THF (17.2 mL, 17.2 mmol). The reaction mixture was stirred overnight at RT. AcOH (1.5 mL) was added to quench the reaction. The mixture was concentrated under reduced pressure and the residue redissolved in CH 2 Cl 2 . The solution subjected to a plug of silca gel eluting with 0 to 80% EtOAc in Hexanes to provide the title product as a crude mixture.
  • the tribenzyl nucleoside (0.650 g, 1.16 mmol) was dissolved in anhydrous CH 2 Cl 2 (30 mL) and cooled to ⁇ 78° C. under N 2 (g).
  • a solution of boron tribromide (1 N in CH 2 Cl 2 , 5.5 mL) was added and the reaction mixture stirred for 1 h. at ⁇ 78° C.
  • a solution of MeOH (10 mL) and pyridine (2 mL) was added to quench the reaction and the mixture was allowed to rise to RT.
  • the mixture was concentrated under reduced pressure and subjected to preparative HPLC to provide the a-anomer (20 mg) and ⁇ -anomer 13 (110 mg)
  • the tribenzyl alcohol from Compound 1 synthesis (0.250 g, 0.453 mmol) was dissolved in anhydrous THF (25 mL) and stirred under N 2 (g). The reaction mixture was cooled to 0° C. and then a 3.0 N solution of methyl magnesium chloride in THF (1.2 mL, 3.62 mmol) was added. The reaction mixture was stirred overnight at RT. Acetic acid (1.5 mL) was added to quench the reaction and then the mixture was concentrated under reduced pressure. The residue was redissoved in CH 2 Cl 2 and subjected to a plug of silca gel eluting with 0 to 80% EtOAc in hexanes. The crude product (0.452 g) was then used in the next reaction without further purification.
  • the tribenzyl nucleoside (0.20 g, 0.364 mmol) was dissolved in AcOH (30 mL). and charged with Pd/C (Degussa) (400 mg). The stirred mixture was flushed with N 2 (g) three times and then H 2 (g) was introduced, The reaction was stirred under H 2 (g) for 2 h. and then the catalyst removed by filtration. The solution was concentrated under reduced pressure and under the residue was re-dissolved in H 2 O. The solution was subjected to preparative HPLC under neutral conditions to provide the ⁇ -anomer and ⁇ -anomer 14 in 81% yield.
  • the nucleoside 1 (0.028 g, 0.096 mmol) was dissolved in trimethylphosphate (1 mL). The reaction was stirred under N 2 (g) and then treated with 1H-tetrazole (0.021 g, 0.29 mmol). The reaction mixture was cooled to 0° C. and the phosphane (Nucleoside Nucleotides, Nucleic acids; 14; 3-5; 1995; 763-766. Lefebvre, Isabelle; Pompon, Alain; Perigaud, Christian; Girardet, Jean-Luc; Gosselin, Gilles; et al.) (87 mg, 0.192 mmol) was added. The reaction was stirred for 2 h.
  • Compound 16 was prepared using the same method as compound 15 except substituting compound 13 as the starting nucleoside.
  • Another aspect of the invention relates to methods of inhibiting viral infections, comprising the step of treating a sample or subject suspected of needing such inhibition with a composition of the invention.
  • samples suspected of containing a virus include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • biological material samples blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like
  • laboratory samples food, water, or air samples
  • bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • samples will be suspected of containing an organism which induces a viral infection, frequently a pathogenic organism such as a tumor virus.
  • Samples can be contained in any medium including water and organic solvent ⁇ water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
  • the anti-virus activity of a compound of the invention after application of the composition can be observed by any method including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semiquantitative methods of determining such activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • the antiviral activity of a compound of the invention can be measured using standard screening protocols that are known.
  • the antiviral activity of a compound can be measured using the following general protocols.
  • Antiviral activity against RSV is determined using an in vitro cytoprotection assay in Hep2 cells.
  • compounds inhibiting the virus replication exhibit cytoprotective effect against the virus-induced cell killing that can be quantified using a cell viability reagent.
  • the method used is similar to methods previously described in published literature (Chapman et al., Antimicrob Agents Chemother. 2007, 51(9):3346-53.)
  • Hep2 cells are obtained from ATCC (Manassas, Va.) and maintained in MEM media supplemented with 10% fetal bovine serum and penicillin/streptomycin. Cells are passaged twice a week and kept at subconfluent stage. Commercial stock of RSV strain A2 (Advanced Biotechnologies, Columbia, Md.) is titered before compound testing to determine the appropriate dilution of the virus stock that generates desirable cytopathic effect in Hep2 cells.
  • Hep2 cells are seeded into 96-well plates 24 hours before the assay at a density of 3,000 cells/well.
  • compounds to be tested are serially diluted in cell culture media. Eight concentrations in 3-fold serial dilution increments are prepared for each tested compound and 100 uL/well of each dilution is transferred in duplicate onto plates with seeded Hep2 cells. Subsequently, appropriate dilution of virus stock previously determined by titration is prepared in cell culture media and 100 uL/well is added to test plates containing cells and serially diluted compounds.
  • Each plate includes three wells of infected untreated cells and three wells of uninfected cells that served as 0% and 100% virus inhibition control, respectively.
  • RSV-induced cytopathic effect is determined using a Cell TiterGlo reagent (Promega, Madison, Wis.) followed by a luminescence read-out. The percentage inhibition is calculated for each tested concentration relative to the 0% and 100% inhibition controls and the EC50 value for each compound is determined by non-linear regression as a concentration inhibiting the RSV-induced cytopathic effect by 50%.
  • Ribavirin purchased from Sigma, St. Louis, Mo. is used as a positive control for antiviral activity.
  • Cytotoxicity of tested compounds is determined in uninfected Hep2 cells in parallel with the antiviral activity using the cell viability reagent in a similar fashion as described before for other cell types (Cihlar et al., Antimicrob Agents Chemother. 2008,52(2):655-65.). The same protocol as for the determination of antiviral activity is used for the measurement of compound cytotoxicity except that the cells are not infected with RSV. Instead, fresh cell culture media (100 uL/well) without the virus is added to tested plates with cells and prediluted compounds. Cells are then incubated for 4 days followed by a cell viability test using CellTiter Glo reagent and a luminescence read-out.
  • Untreated cell and cells treated with 50 ug/mL puromycin (Sigma, St. Louis, Mo.) are used as 100% and 0% cell viability control, respectively.
  • the percent of cell viability is calculated for each tested compound concentration relative to the 0% and 100% controls and the CC50 value is determined by non-linear regression as a compound concentration reducing the cell viability by 50%.
  • RSV ribonucleoprotein (RNP) complexes were prepared from a method modified from Mason et al (1).
  • HEp-2 cells were plated at a density of 7.1 ⁇ 10 4 cells/cm 2 in MEM+10% fetal bovine serum (FBS) and allowed to attach overnight at 37° C. (5% CO 2 ).
  • FBS fetal bovine serum
  • the media was replaced with MEM+2% FBS supplemented with 2 ⁇ g/mL actinomycin D and returned to 37° C. for one hour.
  • the cells were then washed once with PBS and treated with 35 mL of PBS+250 ⁇ g/mL lyso-lecithin for one minute, after which all liquid was aspirated.
  • the cells were harvested by scrapping them into 1.2 mL of buffer A [50 mM TRIS acetate (pH 8.0), 100 mM potassium acetate, 1 mM DTT and 2 ⁇ g/mL actinomycin D] and lysed by repeated passage through an 18 gauge needle (10 times).
  • the cell lysate was placed in ice for 10 minutes and then centrifuged at 2400 g for 10 minutes at 4° C.
  • the supernatant (S1) was removed and the pellet (P1) was disrupted in 600 uL of Buffer B [10 mM TRIS acetate (pH 8.0), 10 mM potassium acetate and 1.5 mM MgCl 2 ] supplemented with 1% Triton X-100 by repeated passage through an 18 gauge needle (10 times).
  • the resuspended pellet was placed in ice for 10 minutes and then centrifuged at 2400 g for 10 minutes at 4° C.
  • the supernatant (S2) was removed and the pellet (P2) was disrupted in 600 uL of Buffer B supplemented with 0.5% deoxycholate and 0.1% Tween 40.
  • the resuspended pellet was placed in ice for 10 minutes and then centrifuged at 2400 g for 10 minutes at 4° C.
  • the supernatant (S3) fraction containing the enriched RSV RNP complexes, was collected and the protein concentration determined by UV absorbance at 280 nm. Aliquoted RSV RNP S3 fractions were stored at ⁇ 80° C.
  • Transcription reactions contained 25 ⁇ g of crude RSV RNP complexes in 30 ⁇ L of reaction buffer [50 mM TRIS-acetate (pH 8.0), 120 mM potassium acetate, 5% glycerol, 4.5 mM MgCl 2 , 3 mM DTT, 2 mM ethyleneglycol-bis(2-aminoethylether)-tetraacetic acid (EGTA), 50 ⁇ g/mL BSA, 2.5 U RNasin (Promega), ATP, GTP, UTP, CTP and 1.5 uCi [ ⁇ - 32 P] NTP (3000 Ci/mmol)].
  • reaction buffer [50 mM TRIS-acetate (pH 8.0), 120 mM potassium acetate, 5% glycerol, 4.5 mM MgCl 2 , 3 mM DTT, 2 mM ethyleneglycol-bis(2-aminoethylether)-tetraacetic acid (EGTA
  • the radiolabeled nucleotide used in the transcription assay was selected to match the nucleotide analog being evaluated for inhibition of RSV RNP transcription.
  • the three remaining nucleotides were added at a final concentration of 100 ⁇ M.
  • RNA sample loading buffer Sigma
  • agarose/MOPS gel containing 2M formaldehyde
  • the Parainfluenza Cytoprotection assay uses Vero cells and Parainfluenza 3 strain C 243. Briefly virus and cells are mixed in the presence of test compound and incubated for 7 days. The virus is pre-titered such that control wells exhibit 85 to 95% loss of cell viability due to virus replication. Therefore, antiviral effect or cytoprotection is observed when compounds prevent virus replication.
  • Each assay plate contains cell control wells (cells only), virus control wells (cells plus virus), compound toxicity control wells (cells plus compound only), compound colorimetric control wells (compound only), as well as experimental wells (compound plus cells plus virus).
  • Cytoprotection and compound cytotoxicity are assessed by MTS (CellTiter®96 Reagent, Promega, Madison Wis.) dye reduction. The % reduction in viral cytopathic effects (CPE) is determined and reported; IC 50 (concentration inhibiting virus replication by 50%), TC 50 (concentration resulting in 50% cell death) and a calculated TI (therapeutic index TC 50/ IC 50 ) are provided along with a graphical representation of the antiviral activity and compound cytotoxicity when compounds are tested in dose-response. Each assay includes ribavirin as a positive control.
  • Vero cells (Kidney, African green monkey, Cercopithecus aethiops ) were obtained from the American Type Culture Collection (ATCC, Rockville, Md.) and are grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2.0 mM L-Glutamine, 100 units/ml Penicillin and 100 ug/ml Streptomycin (“growth medium”). Cells are sub-cultured twice a week at a split ratio of 1:10 using standard cell culture techniques. Total cell number and percent viability determinations are performed using a hemacytometer and trypan blue exclusion. Cell viability must be greater than 95% for the cells to be utilized in the assay. The cells are seeded in 96-well tissue culture plates the day before the assay at a concentration of 1 ⁇ 10 4 cells/well.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS fetal bovine serum
  • growth medium 100 units/m
  • the virus used for this assay is Parainfluenza 3 strain C 243. This virus was obtained from the American Type Culture Collection (ATCC) and was grown in Vero cells for the production of stock virus pools. For each assay, a pre-titered aliquot of virus is removed from the freezer ( ⁇ 80° C.) and allowed to thaw slowly to room temperature in a biological safety cabinet. The virus is resuspended and diluted into tissue culture medium such that the amount of virus added to each well is the amount determined to give between 85 to 95% cell killing at 6-7 days post-infection.
  • ATCC American Type Culture Collection
  • the assay plates are stained with the soluble tetrazolium-based dye MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; CellTiter® 96 Reagent, Promega) to determine cell viability and quantify compound toxicity.
  • MTS is metabolized by the mitochondrial enzymes of metabolically active cells to yield a soluble formazan product, allowing the rapid quantitative analysis of cell viability and compound cytotoxicity.
  • This reagent is a stable, single solution that does not require preparation before use.
  • MTS reagent 20-25 ⁇ L of MTS reagent is added per well and the microtiter plates are then incubated for 4-6 hrs at 37° C., 5% CO 2 to assess cell viability.
  • Adhesive plate sealers are used in place of the lids, the sealed plate is inverted several times to mix the soluble formazan product and the plate is read spectrophotometrically at 490/650 nm with a Molecular Devices Vmax or SpectraMax Plus plate reader.
  • % Cytopathic Effect (CPE) Reduction % Cell Viability
  • IC 25 , IC 50 , IC 95 , TC 25 , TC 50 , and TC 95 and other indices are calculated and the graphical results summary is displayed.
  • Raw data for both antiviral activity and toxicity with a graphical representation of the data are provided in a printout summarizing the individual compound activity.
  • the Table below shows the activity of selected compounds against Parainfluenza 3 virus.

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