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US20080318998A1 - Alkyloxy Substituted Thiazoloquinolines and Thiazolonaphthyridines - Google Patents

Alkyloxy Substituted Thiazoloquinolines and Thiazolonaphthyridines Download PDF

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Publication number
US20080318998A1
US20080318998A1 US11/884,052 US88405206A US2008318998A1 US 20080318998 A1 US20080318998 A1 US 20080318998A1 US 88405206 A US88405206 A US 88405206A US 2008318998 A1 US2008318998 A1 US 2008318998A1
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group
alkyl
het
alkylene
substituted
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Inventor
Ryan B. Prince
Bryon A. Merrill
Philip D. Heppner
Tushar M. Kshirsagar
Joshua R. Wurst
Karl J. Manske
Michael J. Rice
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3M Innovative Properties Co
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Coley Pharmaceutical Group Inc
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Priority to US11/884,052 priority Critical patent/US20080318998A1/en
Assigned to 3M INNOVATIVE PROPERTIES COMPANY & 3M COMPANY reassignment 3M INNOVATIVE PROPERTIES COMPANY & 3M COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HEPPNER, PHILIP D., KSHIRSAGAR, TUSHAR A., MERRILL, BYRON A., PRINCE, RYAN B.
Assigned to 3M INNOVATIVE PROPERTIES COMPANY & 3M COMPANY reassignment 3M INNOVATIVE PROPERTIES COMPANY & 3M COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MERRILL, BYRON A., WURST, JOSHUA R., HEPPNER, PHILIP D., KSHIRSAGAR, TUSHAR A., MANSKE, KARL J., PRINCE, RYAN B.
Assigned to COLEY PHARMACEUTICAL GROUP, INC. reassignment COLEY PHARMACEUTICAL GROUP, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: 3M COMPANY & 3M INNOVATIVE PROPERTIES COMPANY
Assigned to 3M INNOVATIVE PROPERTIES COMPANY & 3M COMPANY reassignment 3M INNOVATIVE PROPERTIES COMPANY & 3M COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RICE, MICHAEL J.
Publication of US20080318998A1 publication Critical patent/US20080318998A1/en
Assigned to 3M INNOVATIVE PROPERTIES COMPANY reassignment 3M INNOVATIVE PROPERTIES COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COLEY PHARMACEUTICAL GROUP, INC.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • IRMs immune response modifiers
  • the present invention provides a new class of compounds that are useful in inducing cytokine biosynthesis in animals.
  • Such compounds are of the following Formula I:
  • R A , R B , and R′′ are as defined below.
  • the compounds of Formula I are useful as immune response modifiers due to their ability to induce cytokine biosynthesis (e.g., induces the synthesis of at least one cytokine) and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
  • the invention further provides pharmaceutical compositions containing an effective amount of a compound of Formula I and methods of inducing cytokine biosynthesis in an animal, treating a viral infection or disease and/or treating a neoplastic disease in an animal by administering an effective amount of a compound of Formula I to the animal.
  • the present invention provides compounds of the following Formulas I through VII:
  • R A , R B , R′′, R, R 2 , R 3 , n, G, and Z are as defined below.
  • the present invention provides a compound of Formula I:
  • R 3 is selected from the group consisting of:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • R′′ is hydrogen or a non-interfering substituent
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • Y is selected from the group consisting of:
  • Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
  • Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • A′ is selected from the group consisting of —O—, —S(O)O 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • V is —C(R 6 )— or —S(O) 2 —, or
  • V is —C(R 6 )— or —S(O) 2 —, or
  • the present invention provides a compound of Formula II:
  • R 3 is selected from the group consisting of:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • n 0 or 1
  • R 2 is selected from the group consisting of:
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • Y is selected from the group consisting of:
  • Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
  • Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • Y′ is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of-C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • V is —C(R 6 )— or —S(O) 2 —, or
  • V is —C(R 6 )— or —S(O) 2 —, or
  • the present invention provides a compound selected from the group consisting Formulas III, IV, V, and VI:
  • R 3 is selected from the group consisting of:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • n 0 or 1
  • R 2 is selected from the group consisting of:
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • Y is selected from the group consisting of:
  • Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
  • Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • Y′ is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • V is —C(R 6 )— or —S(O) 2 —, or
  • V is —C(R 6 )— or —S(O) 2 —, or
  • the present invention provides a compound (which is a prodrug) of Formula VII:
  • R 3 is selected from the group consisting of:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • G is selected from the group consisting of:
  • R′ and R′′′ are independently selected from the group consisting of C 1-10 alkyl, C 3-7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C 1-6 alkyl, C 1-4 alkoxy, aryl, heteroaryl, aryl-C 1-4 alkylenyl, heteroaryl-C 1-4 alkylenyl, halo-C 1-4 alkylenyl, halo-C 1-4 alkoxy, —O—C(O)—CH 3 , —C(O)—O—CH 3 , —C(O)—NH 2 , —O—CH 2 —C(O)—NH 2 , —NH 2 , and —S(O) 2 —NH 2 , with the proviso that R′′′ can also be hydrogen;
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids;
  • Y 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, and benzyl;
  • Y 0 is selected from the group consisting of C 1-6 alkyl, carboxy-C 1-6 alkylenyl, amino-C 1-4 alkylenyl, mono-N—C 1-6 alkylamino-C 1-4 alkylenyl, and di-N,N—C 1-6 alkylamino-C 1-4 alkylenyl;
  • Y 2 is selected from the group consisting of mono-N—C 1-6 alkylamino, di-N,N—C 1-6 alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, and 4-C 1-4 alkylpiperazin-1-yl;
  • R 2 is selected from the group consisting of:
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • Y is selected from the group consisting of:
  • Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
  • Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • Y′ is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • A′ is selected from the group consisting of —O—, —S(O)O 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of-C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • V is —C(R 6 )— or —S(O) 2 —, or
  • V is —C(R 6 )— or —S(O) 2 —, or
  • the present invention provides an intermediate compound of Formula X, which is also an IRM:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • n 0 or 1
  • R 2 is selected from the group consisting of:
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • Y′ is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of-C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • the present invention provides an intermediate compound of Formula XI, which is also an IRM:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • n 0 or 1
  • R 2 is selected from the group consisting of:
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • Y′ is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of-C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • the present invention provides an intermediate compound of Formula XII:
  • R 3 is selected from the group consisting of:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • n 0 or 1
  • R 2 is selected from the group consisting of:
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • Y is selected from the group consisting of:
  • Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
  • Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • Y′ is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of-C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • V is —C(R 6 )— or —S(O) 2 —, or
  • V is —C(R 6 )— or —S(O) 2 —, or
  • the present invention provides an intermediate compound of Formula XIII:
  • R 3 is selected from the group consisting of:
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • n 0or 1
  • R 2 is selected from the group consisting of:
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • Y is selected from the group consisting of:
  • Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
  • Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
  • Y′ is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alklylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen
  • R 5 is selected from the group consisting of:
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S;
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
  • A′ is selected from the group consisting of —O—, —S(O) 0-2 —-, —N(-Q-R 4 )—, and —CH 2 —;
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
  • V is selected from the group consisting of-C(R 6 )—, —O—C(R 6 )—, —N(R 9 )—C(R 6 )—, and —S(O) 2 —;
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —;
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7;
  • V is —C(R 6 )— or —S(O) 2 —, or
  • V is —C(R 6 )— or —S(O) 2 —, or
  • non-interfering means that the ability of the compound or salt, which includes a non-interfering substituent, to modulate the biosynthesis of one or more cytokines is not destroyed by the non-interfering substituent.
  • Illustrative non-interfering R′′ groups include those described above for R 2 .
  • alkyl As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, e.g., cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms.
  • Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.
  • alkylene “-alkylene-”, “alkenylene”, “-alkenylene-”, “alkynylene”, and “-alkynylene-” are the divalent forms of the “alkyl”, “alkenyl”, and “alkynyl” groups defined above.
  • the terms “alkylenyl”, “alkenylenyl”, and “alkynylenyl” are used when “alkylene”, “alkenylene”, and “alkynylene”, respectively, are substituted.
  • an arylalkylenyl group comprises an “alkylene” moiety to which an aryl group is attached.
  • haloalkyl is inclusive of alkyl groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix “halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • aryl as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
  • heteroatom refers to the atoms O, S, or N.
  • heteroaryl includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N).
  • heteroaryl includes a ring or ring system that contains 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and/or N as the heteroatoms.
  • Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
  • heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
  • heterocyclyl includes a ring or ring system that contains 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and N as the heteroatoms.
  • heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1,4-oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imi
  • heterocyclyl includes bicylic and tricyclic heterocyclic ring systems. Such ring systems include fused and/or bridged rings and spiro rings. Fused rings can include, in addition to a saturated or partially saturated ring, an aromatic ring, for example, a benzene ring. Spiro rings include two rings joined by one spiro atom and three rings joined by two spiro atoms.
  • heterocyclyl contains a nitrogen atom
  • the point of attachment of the heterocyclyl group may be the nitrogen atom
  • arylene is the divalent forms of the “aryl”, “heteroaryl”, and “heterocyclyl” groups defined above.
  • arylenyl is used when “arylene”, “heteroarylene,” and “heterocyclylene”, respectively, are substituted.
  • an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
  • each group is independently selected, whether explicitly stated or not.
  • each R 8 group is independently selected for the formula —N(R 8 )—C(R 6 )—N(R 8 )— each R 8 group is independently selected.
  • each R 4 group is independently selected when an R 2 and an R 3 group both contain an R 4 group.
  • each Y group is independently selected, and each R 8 group is independently selected.
  • the invention is inclusive of the compounds described herein (including intermediates) in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, prodrugs, and the like.
  • isomers e.g., diastereomers and enantiomers
  • salts e.g., sodium bicarbonate
  • solvates e.g., sodium bicarbonate
  • polymorphs e.g., sodium bicarbonate
  • prodrugs e.g., sodium bicarbonate
  • the term “compound” includes any or all of such forms, whether explicitly stated or not (although at times, “salts” are explicitly stated).
  • prodrug means a compound that can be transformed in vivo to yield an immune response modifying compound, including any of the salt, solvated, polymorphic, or isomeric forms described above.
  • the prodrug itself, may be an immune response modifying compound, including any of the salt, solvated, polymorphic, or isomeric forms described above.
  • the transformation may occur by various mechanisms, such as through a chemical (e.g., solvolysis or hydrolysis, for example, in the blood) or enzymatic biotransformation.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • each one of the following variables e.g., Z, X, Y, Y′, R A , R B , R, R 2 , R 3 , Q, n, and so on
  • each one of the following variables e.g., Z, X, Y, Y′, R A , R B , R, R 2 , R 3 , Q, n, and so on
  • each one of the following variables in any of its embodiments can be combined with any one or more of the other variables in any of their embodiments and associated with any one of the formulas described herein, as would be understood by one of skill in the art.
  • Each of the resulting combinations of variables is an embodiment of the present invention.
  • R A and R B are taken together to form a fused benzene ring wherein the benzene ring is substituted by one —O—R 3 group, or substituted by one —O—R 3 group and one R group. In certain of these embodiments, the fused benzene ring is substituted by one —O—R 3 group.
  • R A and R B are taken together to form a fused pyridine ring wherein the pyridine ring is substituted by one —O—R 3 group, or substituted by one —O—R 3 group and one R group. In certain of these embodiments, the fused pyridine ring is substituted by one —O—R 3 group.
  • the compound selected from the group consisting of Formulas III, IV, V, and VI, or a pharmaceutically acceptable salt thereof is the compound of Formula III:
  • n is 0 in the above embodiments of Formulas II, III, IV, V, and VI.
  • R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl.
  • R′′ is hydrogen or a non-interfering substituent.
  • R′′ is a non-interfering substituent
  • R′′ is R 2 ; wherein R 2 is selected from the group consisting of —R 4 , —X—R 4 , —X—Y′—R 4 , and —X—R 5 ′.
  • R 2 is selected from the group consisting of —R 4 , —X—R 4 , —X—Y′—R 4 , and —X—R 5 ′.
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
  • R 2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.
  • R 2 is selected from the group consisting of alkyl and alkoxyalkylenyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, ethoxymethyl, methoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, ethoxymethyl, methoxymethyl, and 2-methoxyethyl.
  • n is 0 and R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
  • R 3 is selected from the group consisting of -Z-Y—R 4 , -Z-Y—X—Y—R 4 , -Z-Y—X—Y—X—Y—R 4 , -Z-R 5 , -Z-Het, -Z-Het′-R 4 , and -Z-Het′-Y—R 4 .
  • R 3 is Z-Y—R 4 or -Z-Y—X—Y—R 4 .
  • Y is —N(R 8 )-Q-,
  • R 6 is selected from the group consisting of ⁇ O or ⁇ S
  • R 7 is C 2-3 alkylene
  • R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkylenyl
  • R 10 is C 3-6 alkylene
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl; wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alk
  • Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, and —C(R 6 )—N(R 8 )—;
  • R 6 is selected from the group consisting of ⁇ O or ⁇ S;
  • R 7 is C 2-3 alkylene;
  • R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkylenyl;
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl; wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and aryl; wherein aryl and arylalkylenyl are unsubstituted or
  • Y is —N(R 8 )-Q-.
  • Q is —C(O)—.
  • Q is —S(O) 2 —.
  • Q is —C(R 6 )—N(R 8 )—.
  • 4 is C 1-4 alkyl and R 9 is hydrogen.
  • R 4 is phenyl that is unsubstituted or substituted by methoxy and R 8 is hydrogen.
  • Q is a bond.
  • R 4 is heterocyclyl that is unsubstituted or substituted by one or more alkyl groups, and R 8 is C 1-4 alkyl.
  • R 4 is 1-methylpiperidin-4-yl and R 8 is methyl.
  • R 3 is -Z-Y—R 4 , wherein Y is —O— and R 4 is phenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, cyano, alkoxy, nitro, and haloalkyl.
  • R 3 is -Z-Y—X—Y, —R 4 , wherein Y is —O—, X is phenylene, and Y c —R 4 is selected from the group consisting of —C(O)-alkyl, —C(O)—O-alkyl, —S-alkyl, —NH—C(O)-alkyl, —C(O)—NH 2 , and —S(O) 2 —NH 2 .
  • R 3 is -Z-R 5 .
  • R 5 is selected from the group consisting of:
  • A is —O—, —CH 2 —, or —S(O) 2 —;
  • R 7 is C 2-4 alkylene;
  • R 8 is hydrogen or C 1-4 alkyl; and
  • a and b are each independently 1, 2, or 3.
  • R 5 is
  • R 7 is C 2-4 alkylene.
  • R 3 is -Z-Het or -Z-Het′-R 4 .
  • Het and Het′ are, respectively, selected from the group consisting of the monovalent and divalent forms of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(
  • Het and Het′ are, respectively, selected from the group consisting of the monovalent and divalent forms of pyrrolidinyl, piperidinyl, and morpholinyl, each of which is unsubstituted or substituted by one or more substituents.
  • Het is unsubstituted.
  • Het′ is unsubstituted.
  • Het is substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, hydroxyalkyleneoxyalkylenyl, and dialkylamino.
  • R 4 is heterocyclyl.
  • R 4 is selected from the group consisting of pyrrolidinyl and piperidinyl.
  • R 3 is -Z-Het′-Y—R 4 .
  • Het′ is selected from the group consisting of the divalent form of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2B)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl.
  • —Y—R 4 is selected from the group consisting of —C(O)-alkyl, —C(O)—O—H, —C(O)—O-alkyl, —C(O)—NH 2 —, —C(O)—NH-alkyl, and —NH—C(O)-alkyl.
  • R 3 includes a substituted or unsubstituted thiazolo[4,5-c]quinolinyl group or a substituted or unsubstituted thiazolo[4,5-c]naphthyridinyl group and a connecting group such that the compound is a dimer.
  • R 3 is -Z—Y a —X—Y b —R 4 wherein Y a is —N(R 8 )-Q-, Y b is —O—, and R 4 is thiazolo[4,5-c]quinolinyl or thiazolo[4,5-c]naphthyridinyl.
  • Q is —C(R 6 )—N(R 8 )—.
  • the thiazolo[4,5-c]quinolinyl or thiazolo[4,5-c]naphthyridinyl group is substituted by alkyl and amino.
  • Z is alkylene optionally interrupted with one or more —O— groups.
  • Z is selected from the group consisting of C 1-6 alkylene and —CH 2 CH 2 —O—CH 2 CH 2 —.
  • Z is a bond.
  • —O—R 3 is at the 7-position.
  • —O—R 3 is at the 8-position.
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl.
  • alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and aryl.
  • alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, halogen, and aryl.
  • aryl and arylalkylenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, cyano, dialkylamino, and alkoxy.
  • aryl, heteroaryl, and arylalkylenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, cyano, dialkylamino, and alkoxy.
  • heterocyclyl is unsubstituted or substituted by one or more alkyl substituents.
  • R 4 is hydrogen or alkyl.
  • R 4 is alkyl
  • R 4 is C 1-4 alkyl.
  • R 4 is heterocyclyl.
  • R 4 is selected from the group consisting of pyrrolidinyl and piperidinyl.
  • R 4 is heterocyclyl that is unsubstituted or substituted by one or more alkyl groups.
  • R 4 is 1-methylpiperidin-4-yl.
  • R 4 is phenyl that is unsubstituted or substituted by methoxy.
  • R 4 is heteroaryl
  • R 4 is phenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, cyano, alkoxy, nitro, and haloalkyl.
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • A is —O—, —CH 2 —, or —S(O) 2 —;
  • R 7 is C 2-4 alkylene;
  • R 8 is hydrogen or C 1-4 alkyl; and
  • a and b are each independently 1, 2, or 3. In certain of these embodiments a and b are each 2.
  • R 5 is
  • R 7 is C 2-4 alkylene.
  • R 5 is
  • R 7 is C 2-4 alkylene.
  • R 5 ′ is selected from the group consisting of:
  • R 6 is selected from the group consisting of ⁇ O and ⁇ S.
  • R 6 is ⁇ O.
  • R 6 is ⁇ S.
  • R 7 is C 2-7 alkylene.
  • R 7 is C 2-4 alkylene.
  • R 7 is C 2-3 alkylene.
  • R 7 is C 2-3 alkylene.
  • R 7 is C 2-3 alkylene.
  • R 8 is selected from the group consisting of hydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl.
  • R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkylenyl.
  • R 8 is hydrogen or C 1-4 alkyl.
  • R 8 is hydrogen
  • R 8 is C 1-4 alkyl.
  • R 8 is methyl.
  • R 9 is selected from the group consisting of hydrogen and alkyl.
  • R 10 is C 3-8 alkylene.
  • R 10 is C 4-6 alkylene.
  • R 10 is C 3-6 alkylene.
  • A is selected from the group consisting of —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—.
  • A is —O—, —CH 2 —, or —S(O) 2 —.
  • A is —O— or —S(O) 2 —.
  • A is —O—.
  • A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —.
  • A′ is selected from the group consisting of —CH 2 —, —S(O) 2 —, and —O—.
  • A′ is —CH 2 —.
  • A′ is —O—.
  • Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—.
  • Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —C(R 6 )—N(R 8 )—, and —S(O) 2 —N(R 8 )—.
  • Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, and —C(R 6 )—N(R 8 )—.
  • Q is —C(O)—.
  • Q is —S(O) 2 —.
  • Q is —C(R 6 )—N(R 8 )—.
  • Q is a bond
  • V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —.
  • V is selected from the group consisting of —C(O)— and —N(R 8 )—C(O)—.
  • W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —.
  • W is a bond or —C(O)—.
  • W is a bond
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups.
  • X is phenylene.
  • X is alkylene.
  • Y is selected from the group consisting of —O—, —S(O) 0-2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —O—C(R 6 )—, —O—C(O)—O—, —N(R 8 )-Q-, —C(R 6 )—N(R 8 )—, —O—C(R 6 )—N(R 8 )—, —C(R 6 )—N(OR 8 )—, —O—N(R 8 )-Q-, —O—N ⁇ C(R 4 )—, —C( ⁇ N—O—R 8 )—,
  • Y is selected from the group consisting of —S(O) 0-2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —O—C(R 6 )—, —O—C(O)—O—, —N(R 8 )-Q-, —C(R 6 )—N(R 8 )—, —O—C(R 6 )—N(R 8 )—, —C(R 6 )—N(OR 9 )—, —O—N(R 8 )-Q-, —O—N ⁇ C(R 4 )—, —C( ⁇ N—O—R 8 )—, —CH(—N(—O—R 8 )-Q-R 4 )—,
  • Y can also be —O—.
  • Y can also be —O— when Y is bonded to R 4 , and R 4 is selected from the group consisting of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl can be unsubstituted or substituted by one or more substituents.
  • the one or more substituents are independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, and (dialkylamino)alkyleneoxy.
  • Y can also be —O— when Y is bonded to Z and X, and X is arylene or heteroarylene.
  • Y is —N(R 8 )-Q-
  • Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —C(R 6 )—N(R 8 )—, and —S(O) 2 —N(R 8 )—;
  • R 6 is selected from the group consisting of ⁇ O or ⁇ S;
  • R 7 is C 2-3 alkylene;
  • R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkylenyl;
  • R 10 is C 3-6 alkylene; and
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl; wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of
  • Y is —N(R 8 )-Q- or
  • Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, and —C(R 6 )—N(R 8 )—;
  • R 6 is selected from the group consisting of ⁇ O or ⁇ S;
  • R 7 is C 2-3 alkylene;
  • R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkylenyl;
  • R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl; wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and aryl; wherein aryl and arylalkylenyl are unsubstituted or
  • Y is —N(R 8 )-Q-.
  • Y is selected from the group consisting of —C(O)—, —C(O)—O—, —C(O)—NH—, and —NH—C(O)—.
  • Y is —O—.
  • Y is selected from the group consisting of —C(O)—, —C(O)—O—, —S—, —NH—C(O)—, —C(O)—NH—, and —S(O) 2 —NH—.
  • Y′ is selected from the group consisting of —O—, —S(O) 0-2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —O—C(R 6 )—, —O—C(O)—O—, —N(R 9 )-Q-, —C(R 6 )—N(R 8 )—,
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups.
  • Z is alkylene optionally interrupted with one or more —O— groups.
  • Z is selected from the group consisting of C 1-6 alkylene and —CH 2 CH 2 —O—CH 2 CH 2 —. In certain of these embodiments, Z is selected from the group consisting of C 2-6 alkylene and —CH 2 CH 2 —O—CH 2 CH 2 —.
  • Z is a bond.
  • Z can be a bond when: R 3 is -Z-Het, -Z-Het′-R 4 , or -Z-Het′-Y—R 4 , and Z is attached to an atom other than N in Het or Het′; or R 3 is -Z-Y—R 4 , -Z-Y—X—Y—R 4 , or -Z-Y—X—Y—X—Y—R 4 , and the Y group bonded to Z is —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —C(R 6 )—N(R 8 )—,
  • V is —C(R 6 )— or —S(O) 2 —, or
  • R 3 is -Z-R 5
  • R 5 is
  • V is —C(R 6 )— or —S(O) 2 —, or
  • Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.
  • Het is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and piperazinyl, each of which is unsubstituted or substituted by one or
  • the one or more substituents are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.
  • Het is selected from the group consisting of pyrrolidinyl, piperidinyl, and morpholinyl, each of which is unsubstituted or substituted by one or more substituents.
  • the one or more substituents are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.
  • Het is substituted by one or more substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, hydroxyalkyleneoxyalkylenyl, and dialkylamino.
  • Het is unsubstituted.
  • Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo.
  • Het′ is selected from the group consisting of the divalent forms of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and piperazinyl, each of which is unsubstituted
  • the one or more substituents are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.
  • Het′ is selected from the group consisting of the divalent forms of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl, each of which is unsubstituted or substituted by one or more substituents.
  • the one or more substituents are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.
  • Het′ is selected from the group consisting of the divalent forms of pyrrolidinyl, piperidinyl, and morpholinyl, each of which is unsubstituted or substituted by one or more substituents.
  • the one or more substituents are independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.
  • Het′ is unsubstituted (except by —R 4 or —Y—R 4 ).
  • a and b are independently integers from 1 to 6 with the proviso that a+b is ⁇ 7.
  • a and b are each independently 1, 2, or 3.
  • a and b are each 2.
  • n is 0 or 1.
  • n 0.
  • the —NH 2 group can be replaced by an —NH-G group, as shown in the compound of Formula VII, to form prodrugs.
  • G is selected from the group consisting of —C(O)—R′, ⁇ -aminoacyl, ⁇ -aminoacyl- ⁇ -aminoacyl, —C(O)—O—R′, —C(O)—N(R′′′)R′, —C( ⁇ NY 1 )—R′, —CH(OH)—C(O)—OY 1 , —CH(OC 1-4 alkyl)Y 0 , —CH 2 Y 2 , and —CH(CH 3 )Y 2 .
  • R′ and R′′′ are independently selected from the group consisting of C 1-10 alkyl, C 3-7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C 1-6 alkyl, C 1-4 alkoxy, aryl, heteroaryl, aryl-C 1-4 alkylenyl, heteroaryl-C 1-4 alkylenyl, halo-C 1-4 alkylenyl, halo-C 1-4 alkoxy, —O—C(O)—CH 3 , —C(O)—O—CH 3 , —C(O)—NH 2 , —O—CH 2 —C(O)—NH 2 , —NH 2 , and —S(O) 2 —NH 2 with the proviso that R′′′ can also be hydrogen;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI and a pharmaceutically acceptable carrier.
  • the present invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI, or a pharmaceutical composition comprising an effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI to the animal.
  • the present invention provides a method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI, or a pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI to the animal.
  • the present invention provides a method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI, or a pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI to the animal.
  • Compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis., USA) or are readily prepared using methods well known to those skilled in the art (e.g. prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis , v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R. Katritsky, Otto Meth-Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations , v 1-6, Pergamon Press, Oxford, England, (1995); Barry M.
  • reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • EXAMPLES section below For more detailed description of the individual reaction steps, see the EXAMPLES section below.
  • Other synthetic routes may be used to synthesize the compounds of the invention.
  • specific starting materials and reagents are depicted in the reaction schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional methods well known to those skilled in the art.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc).
  • Suitable hydroxy protecting groups include acetyl and silyl groups such as the tert-butyl dimethylsilyl group.
  • Step (1) of Reaction Scheme I a benzyloxyaniline of Formula XV is treated with the condensation product generated from 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) and triethyl orthoformate to provide an imine of Formula XVI.
  • the reaction can be conveniently carried out by adding a solution of a benzyloxyaniline of Formula XV to a heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an elevated temperature such as 45° C.
  • step (2) of Reaction Scheme I an imine of Formula XVI undergoes thermolysis and cyclization to provide a benzyloxyquinolin-4-ol of Formula XVII.
  • the reaction can be conveniently carried out in a medium such as DOWTHERM A heat transfer fluid at a temperature in the range of 200° C. to 250° C.
  • step (3) of Reaction Scheme I the benzyloxyquinolin-4-ol of Formula XVII is nitrated under conventional nitration conditions to provide a benzyloxy-3-nitroquinolin-4-ol of Formula XVIII.
  • the reaction can be conveniently carried out by adding nitric acid to the benzyloxyquinolin-4-ol of Formula XVII in a suitable solvent such as propionic acid and heating the mixture at an elevated temperature such as 125° C.
  • a benzyloxy-3-nitroquinolin-4-ol of Formula XVIII is reduced to provide a 3-amino-benzyloxyquinolin-4-ol of Formula XIX or a salt thereof, such as the hydrochloride salt thereof.
  • the reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as platinum on carbon.
  • the hydrogenation is conveniently carried out in a Parr apparatus in a suitable solvent such as N,N-dimethylformamide (DMF).
  • the reaction can be carried out at room temperature.
  • a 3-amino benzyloxyquinolin-4-ol of Formula XIX is reacted with a carboxylic acid or an equivalent thereof to provide a compound of Formula XX.
  • Suitable equivalents to carboxylic acid include acid anhydrides and acid chlorides.
  • the selection of the carboxylic acid equivalent is determined by the desired substituent at R 2 .
  • the use of butyryl chloride provides a compound in which R 2 is a propyl group; the use of ethoxyacetyl chloride provides a compound in which R 2 is an ethoxymethyl group.
  • the reaction can be conveniently carried out by adding the acid chloride to a solution of a 3-aminobenzyloxyquinolin-4-ol of Formula XIX in a suitable solvent such as dichloromethane or acetonitrile in the presence of a tertiary amine such as triethylamine, pyridine, or 4-dimethylaminopyridine (DMAP) to afford an amide.
  • a suitable solvent such as dichloromethane or acetonitrile
  • a tertiary amine such as triethylamine, pyridine, or 4-dimethylaminopyridine (DMAP)
  • DMAP 4-dimethylaminopyridine
  • the reaction can be carried out at or below room temperature.
  • the amide of Formula XX can optionally be isolated and purified.
  • step (6) of Reaction Scheme I an amide of Formula XX is reacted with phosphorus pentasulfide to provide a benzyloxy[1,3]thiazolo[4,5-c]quinoline of Formula XXI.
  • the reaction can be carried out by adding phosphorus pentasulfide to a solution or suspension of a compound of Formula XX in a suitable solvent such as pyridine and heating the resulting mixture at an elevated temperature, for example, the reflux temperature of the solvent.
  • a benzyloxy[1,3]thiazolo[4,5-c]quinoline of Formula XXI is oxidized to provide a benzyloxy[1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XXII using a conventional oxidizing agent capable of forming N-oxides.
  • the reaction can be conveniently carried out by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula XXI in a solvent such dichloromethane or chloroform. The reaction can be carried out at room temperature.
  • step (8) of Reaction Scheme I a benzyloxy[1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XXII is aminated to provide a benzyloxy[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XXIII.
  • Step (8) can be carried out by the activation of an N-oxide of Formula XXII by conversion to an ester and then reacting the ester with an aminating agent.
  • Suitable activating agents include alkyl- or arylsulfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, or p-toluenesulfonyl chloride.
  • Suitable aminating agents include ammonia, in the form of ammonium hydroxide, for example, and ammonium salts such as ammonium carbonate, ammonium bicarbonate, and ammonium phosphate.
  • the reaction can be conveniently carried out by adding ammonium hydroxide followed by p-toluenesulfonyl chloride to a solution of the N-oxide of Formula XXII in a suitable solvent such as 1,2-dichloroethane at elevated temperature, for example 65° C.
  • the reaction may also be carried out by adding ammonium hydroxide and p-toluenesulfonyl chloride to the reaction mixture from step (7) without isolating the N-oxide of Formula XXII.
  • step (8) can be carried out by the reaction of a benzyloxy[1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XXII with trichloroacetyl isocyanate followed by hydrolysis of the resulting intermediate to provide a benzyloxy[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XXIII.
  • the reaction can be conveniently carried out in two steps by (i) adding trichloroacetyl isocyanate to a solution of the N-oxide of Formula XXII in a solvent such as dichloromethane and stirring at room temperature to provide an isolable amide intermediate.
  • step (ii) a solution of the intermediate in methanol is treated with a base such as sodium methoxide or ammonium hydroxide at room temperature.
  • step (9) of Reaction Scheme I the benzyl group of a benzyloxy[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XXIII is cleaved to provide a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV.
  • the cleavage is conveniently carried out with an acid such as hydrogen bromide in a suitable solvent such as acetic acid at an elevated temperature, such as 65° C.
  • the cleavage may be carried out on a Parr apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as palladium on carbon in a solvent such as ethanol.
  • step (10) of Reaction Scheme I a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV is converted to an ether-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula II using a Williamson-type ether synthesis.
  • the reaction is effected by treating a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV with an alkyl halide of Formula Halide-R 3 in the presence of a base.
  • the reaction can be conveniently carried out by combining the alkyl halide with a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV in a solvent such as DMF in the presence of a suitable base such as cesium carbonate.
  • the reaction can be carried out at ambient temperature or at an elevated temperature, for example 60° C. to 85° C.
  • the reaction can be carried out by treating a solution of a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV in a solvent such as DMF with sodium hydride and then adding a reagent of Formula Halide-R 3 .
  • reagents of Formulas Halide-Z-Y—R 4 and Halide-Z-Het wherein Z, Y, R 4 , and Het are as defined above, are commercially available. These include, for example, bromo-substituted ketones such as 2-bromoacetophenone and 2-bromo-1-(3-thienyl)-1-ethanone, bromo-substituted esters such as ethyl bromoacetate, and bromoalkyl-substituted heterocycles such as 2-(bromomethyl)tetrahydro-2H-pyran.
  • ketones such as 2-bromoacetophenone and 2-bromo-1-(3-thienyl)-1-ethanone
  • bromo-substituted esters such as ethyl bromoacetate
  • bromoalkyl-substituted heterocycles such as 2-(bromomethyl)tetrahydro-2H-pyran.
  • reagents of Formulas Halide-Z-Y—R 4 , Halide-Z-R 5 , Halide-Z-Y—X—Y—R 4 , and Halide-Z-Het wherein Z, Y, X, R 4 , R 5 , and Het are as defined above, can be prepared using conventional synthetic methods; for example, a bromo-substituted acid halide of Formula ClC(O)-Z-Br or BrC(O)-Z-Br can be treated with a secondary amine in a suitable solvent such as dichloromethane to provide a variety of bromo-substituted amides of Formula Br-Z-C(O)—N(R 8 )—R 4 ,
  • reaction can be run at a sub-ambient temperature such as ⁇ 25° C.
  • Dimers of Formula II wherein R 3 is -Z-O—R 4 , wherein Z is selected from the group consisting of alkylene, alkenylene, and alkynylene wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups, and R 4 is a [1,3]thiazolo[4,5-c]quinoline optionally substituted as defined in R 4 above, can be prepared in step (10) of Reaction Scheme I if half an equivalent of a dialkyl halide of Formula Halide-Z-Halide is used, and the reaction can be carried out according to the conditions described above.
  • Step (10) of Reaction Scheme I can alternatively be carried out by treating a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV with an alcohol of Formula HO—R 3 under Mitsunobu reaction conditions.
  • Numerous alcohols of Formulas HO-Z-Y—R 4 , HO-Z-R 5 , and HO-Z-Het are commercially available, such as, for example, 1-(2-hydroxyethyl)pyrrolidin-2-one, 1-(3-hydroxypropyl)pyrrolidin-2-one, 3-(methylthio)propan-1-ol, and 3-hydroxytetrahydrofuran; other alcohols of Formula HO—R 3 can be prepared using conventional synthetic methods.
  • the reaction can be conveniently carried out by out by adding triphenylphosphine and an alcohol of Formula HO—R 3 to a solution of a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV in a suitable solvent such as tetrahydrofuran and then slowly adding diisopropyl azodicarboxylate or diethyl azodicarboxylate.
  • a suitable solvent such as tetrahydrofuran
  • Step (1) of Reaction Scheme II the benzyl group of a benzyloxy[1,3]thiazolo[4,5-c]quinoline of Formula XXI is cleaved to provide a [1,3]thiazolo[4,5-c]quinolinol of Formula XXV.
  • the reaction can be carried out as described in step (9) of Reaction Scheme I.
  • step (2) of Reaction Scheme II a [1,3]thiazolo[4,5-c]quinolinol of Formula XXV is converted to an ether-substituted [1,3]thiazolo[4,5-c]quinoline of Formula XII.
  • the reaction can be carried out using one of the methods described in step (10) of Reaction Scheme I.
  • steps (3) and (4) of Reaction Scheme II an ether-substituted [1,3]thiazolo[4,5-c]quinoline of Formula XII is oxidized to afford a [1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XXVI, which is aminated to provide a [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula II.
  • Steps (3) and (4) can be carried out as described in steps (7) and (8), respectively, of Reaction Scheme I.
  • Synthetic transformations can be made at R 2 in compounds of Formulas XXI, XXIII, XXIV, XXV, XII, or II, shown in Reaction Scheme I or II, if, for example, the carboxylic acid or equivalent thereof used in step (5) of Reaction Scheme I contains a protected hydroxy or amino group.
  • Some acid chlorides of this type for example acetoxyacetyl chloride, are commercially available. Others can be prepared by known synthetic methods. A protected hydroxy or amino group thus installed at R 2 can then be deprotected by a variety of methods well-known to one of skill in the art.
  • an acetate group installed by using acetoxyacetyl chloride as the carboxylic acid equivalent in step (5) of Reaction Scheme I, is readily hydrolyzed under basic conditions to provide a hydroxy group.
  • the resulting hydroxy group can then be oxidized to an aldehyde or carboxylic acid or converted to a leaving group such as, for example, a chloro group using thionyl chloride or a trifluoromethanesulfonate group using trifluoromethanesulfonic anhydride.
  • the resulting leaving group can then be displaced by a variety of nucleophiles.
  • Sodium azide can be used as the nucleophile to install an azide group, which can then be reduced to an amino group using heterogeneous hydrogenation conditions.
  • the amino group can then be converted to an amide, sulfonamide, sulfamide, or urea using one of the many methods described below in step (7) of Reaction Scheme IV.
  • a leaving group at R 2 such as a chloro or trifluoromethanesulfonate group, can also be displaced with a secondary amine, a substituted phenol, or a mercaptan under the conditions described below in step (2) of Reaction Scheme VI to provide a variety of compounds.
  • R 2 groups see U.S. Pat. No. 6,110,929 (Gerster et al.).
  • a hydroxyalkylenyl group can also be introduced at R 2 by the demethylation of a methoxyalkylenyl group, which can be installed by using a methoxy-substituted carboxylic acid equivalent, for example, methoxyacetyl chloride and 2-methoxypropionyl chloride, in step (5) of Reaction Scheme I.
  • the demethylation can be carried out by treating a compound of Formula II wherein R 2 is a methoxyalkylenyl group with boron tribromide in a suitable solvent such as dichloromethane at a sub-ambient temperature such as 0° C.
  • an R 3 group in a compound of Formula XII may contain a —S— functional group, which can be oxidized to —S(O) 2 — in step (3) of Reaction Scheme II using an excess of the oxidizing agent.
  • Step (4) of Reaction Scheme II may then be carried out to provide a compound of Formula II, wherein R 3 contains a —S(O) 2 — functional group.
  • an R 3 group in a compound of Formula II may be -Z-Y—R 4 , wherein Y is —C(O)—.
  • a ketone of this formula can then be converted to an oxime by adding an aqueous solution of a hydroxylamine salt of formula NH 2 OR 8 .HCl to a solution of the ketone in a suitable solvent such as methanol or ethanol and then adding a base such as sodium hydroxide and heating at an elevated temperature to provide a compound of the invention, wherein R 3 is -Z-Y—R 4 where Y is —C( ⁇ N—OR 8 )—, and R 4 and R 8 are as defined above.
  • the oxime so prepared may be reduced with sodium cyanoborohydride in a mixture of ethanol or methanol in acetic acid to provide a hydroxylamine, which may be treated with one of numerous acid chlorides, sulfonyl chloride, isocyanates, carbamoyl chloride, or sulfamoyl chlorides using one of the methods described in step (7) of Reaction Scheme IV below to provide a compound of the invention wherein R 3 is -Z-Y—R 4 where Y is —CH(—N—(OR 8 )-Q-R 4 )—, and Q, R 4 , and R 8 are as defined above.
  • Reaction Scheme III where R, R 2 , R 3 , and n are as defined above.
  • Reaction Scheme III is analogous to Reaction Scheme I, with a benzyloxypyridine of Formula XXVII used as the starting material in Reaction Scheme III instead of a benzyloxyaniline of Formula XV.
  • Benzyloxypyridines of Formula XXVII can be prepared using conventional synthetic methods; see for example, Holladay et al., Biorg. Med. Chem. Lett., 8, pp. 2797-2802, (1998).
  • compounds of the invention can be prepared according to Reaction Scheme IV, where R, R 2 , R 8 , and n are defined as above; Z is selected from the group consisting of alkylene, alkenylene, and alkynylene wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups; and R 3a is -Z-N(R 8 )-Q-R 4 or
  • R 8 , R 10 , Q, and R 4 as defined above; -Z-R 5 , wherein R 5 is
  • step (1) of Reaction Scheme IV the amine of an amino alcohol of Formula XXXVII is protected with a tert-butoxy carbonyl (Boc) group to provide a hydroxyalkylcarbamate of Formula XXXVIII.
  • a tert-butoxy carbonyl (Boc) group Numerous amino alcohols of Formula XXXVII are commercially available; others can be prepared using known synthetic methods.
  • the reaction can be conveniently carried out by treating the amino alcohol of Formula XXXVII with di-tert-butyl dicarbonate optionally in the presence of a base such as aqueous sodium hydroxide.
  • the reaction can be run at room temperature in a suitable solvent such as tetrahydrofuran or dichloromethane.
  • a hydroxyalkylcarbamate of Formula XXXVIII is converted to an iodoalkylcarbamate of Formula XXXIX using conventional methods.
  • the reaction can be conveniently carried out by treating the hydroxyalkylcarbamate of Formula XXXVIII with a solution of iodine, triphenylphosphine, and imidazole.
  • the reaction can be run at room temperature in a suitable solvent such as dichloromethane or solvent mixture such as diethyl ether/acetonitrile.
  • step (3) of Reaction Scheme IV a [1,3]thiazolo[4,5-c]quinolinol of Formula XXV is treated with an iodoalkylcarbamate of Formula XXXIX to provide an ether-substituted [1,3]thiazolo[4,5-c]quinoline of Formula XL.
  • the reaction can be carried out according to the Williamson conditions described in step (10) of Reaction Scheme I.
  • steps (4) and (5) of Reaction Scheme IV a [1,3]thiazolo[4,5-c]quinoline of Formula XL is oxidized to a [1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XLI, which is aminated to provide a [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLII, which is a subgenus Formulas I and II.
  • Steps (4) and (5) of Reaction Scheme IV can be carried out as described for steps (7) and (8), respectively, of Reaction Scheme I.
  • step (5) the preferred conditions for amination are the activation of an N-oxide of Formula XLI by conversion to an ester and then reacting the ester with an aminating agent.
  • Step (5) is conveniently carried out by adding ammonium hydroxide to a solution of the N-oxide of Formula XLI in a suitable solvent such as 1,2-dichloroethane and then adding p-toluenesulfonyl chloride and stirring at an elevated temperature such as 65° C.
  • step (6) of Reaction Scheme IV the Boc protecting group of a [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLII is removed to provide an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII, which is a subgenus of Formulas I and II.
  • the reaction can be conveniently carried out by adding a solution of hydrochloric acid in ethanol to a [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLII.
  • the reaction can be carried out at an elevated temperature, for example, the reflux temperature of the solvent.
  • an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII is converted to a [1,3]thiazolo[4,5-c]quinolinyl compound of Formula IIa, a subgenus of Formulas I and II, using conventional methods.
  • an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII can react with an acid chloride of Formula R 4 C(O)Cl to provide a compound of Formula IIa in which R 3a is -Z-N(R 8 )—C(O)—R 4 .
  • a [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII can react with sulfonyl chloride of Formula R 4 S(O) 2 Cl or a sulfonic anhydride of Formula (R 4 S(O) 2 ) 2 O to provide a compound of Formula IIa in which R 3a is -Z-N(R 8 )—S(O) 2 —R 4 .
  • Numerous acid chlorides of Formula R 4 C(O)Cl, sulfonyl chlorides of Formula R 4 S(O) 2 Cl, and sulfonic anhydrides of Formula (R 4 S(O) 2 ) 2 O are commercially available; others can be readily prepared using known synthetic methods.
  • the reaction can be conveniently carried out by adding the acid chloride of Formula R 4 C(O)Cl, sulfonyl chloride of Formula R 4 S(O) 2 Cl, or sulfonic anhydride of Formula (R 4 S(O) 2 ) 2 O to a solution of the amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII in a suitable solvent such as chloroform, dichloromethane, N,N-dimethylacetamide (DMA), or 1-methyl-2-pyrrolidinone.
  • a suitable solvent such as chloroform, dichloromethane, N,N-dimethylacetamide (DMA), or 1-methyl-2-pyrrolidinone.
  • a base such as triethylamine, pyridine, or N,N-diisopropylethylamine, or catalytic DMAP, or a combination thereof can be added.
  • the reaction can be carried out at room temperature or initially at a sub-ambient temperature such as 0° C. and then warming to room temperature.
  • reaction can be prepared by treating an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII, wherein R 8 is hydrogen, with a chloroalkanesulfonyl chloride of Formula Cl—R 7 S(O) 2 Cl or a chloroalkanoyl chloride of Formula C 1 —R 7 C(O)Cl.
  • the reaction can be conveniently carried out by adding the chloroalkanesulfonyl chloride or chloroalkanoyl chloride to a solution of the amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII in a suitable solvent such as chloroform at ambient temperature.
  • the isolable intermediate chloroalkanesulfonamide or chloroalkanamide can then be treated with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene or sodium hydride in a suitable solvent such as DMF to effect the cyclization.
  • a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene or sodium hydride in a suitable solvent such as DMF to effect the cyclization.
  • Ureas of Formula IIa where R 3a is -Z-N(R 8 )-Q-R 4 , Q is —C(R 6 )—NH—W—, R 6 is ⁇ O, and W is a bond, can be prepared by reacting an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII with isocyanates of Formula R 4 N ⁇ C ⁇ O, Numerous isocyanates of Formula R 4 N ⁇ C ⁇ O are commercially available; others can be readily prepared using known synthetic methods.
  • the reaction can be conveniently carried out by adding the isocyanate of Formula R 4 N ⁇ C ⁇ O to a solution of the amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII in a suitable solvent such as dichloromethane, chloroform, or DMA.
  • a base such as triethylamine can be added.
  • the reaction can be carried out at room temperature or initially at a sub-ambient temperature such as 0° C. and warming to room temperature.
  • a compound of Formula XLIII can be treated with an isocyanate of Formula R 4 (CO)N ⁇ C ⁇ O, a thioisocyanate of Formula R 4 N ⁇ C ⁇ S, a sulfonyl isocyanate of Formula R 4 S(O) 2 N ⁇ C ⁇ O, or a carbamoyl chloride of Formula R 4 N—(R 8 )—C(O)Cl,
  • Q is —C(R 6 )—N(R 8 )—W—, where R 6 , R 8 , and W are defined as above.
  • Sulfamides of Formula IIa where R 3a is -Z-N(R 8 )—S(O) 2 —N(R 8 )—R 4 can be prepared by reacting a compound of Formula XLIII with sulfuryl chloride to generate a sulfamoyl chloride in situ, and then reacting the sulfamoyl chloride with an amine of Formula HN(R 8 )R 4 .
  • sulfamides of Formula IIa can be prepared by reacting a compound of Formula XLIII with a sulfamoyl chloride of Formula R 4 (R 8 )N—S(O) 2 Cl.
  • Many amines of Formula HN(R 8 )R 4 and some sulfamoyl chlorides of Formula R 4 (R 8 )N—S(O) 2 Cl are commercially available; others can be prepared using known synthetic methods.
  • Compounds of Formula IIa, wherein R 3a is -Z-N(R 8 )—R 4 can be prepared by reductive alkylation of the amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII, wherein R 8 is hydrogen.
  • the alkylation is conveniently carried out in two parts by (i) adding an aldehyde or ketone to a solution of an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII or a salt thereof in a suitable solvent such as DMF in the presence of a base such as N,N-diisopropylethylamine.
  • part (ii) the reduction is carried out by adding a suitable reducing agent such as the borane-pyridine complex. Both part (i) and part (ii) can be carried out at room temperature.
  • a suitable reducing agent such as the borane-pyridine complex.
  • Both part (i) and part (ii) can be carried out at room temperature.
  • R 8 is hydrogen
  • Dimers of Formula IIa wherein R 3a is -Z-[N(R 8 )-Q]-X—[V—N(R 8 )]-X—O—R 4 , wherein X and R 8 are as defined above, Q is selected from the group consisting of —C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—, V is selected from the group consisting of-C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —, and R 4 is a [1,3]thiazolo[4,5-c]quinoline optionally substituted as defined in R 4 above, can be prepared by treating an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII or a salt thereof with a diacid chloride, a disulfonyl chloride, or a diisocyan
  • diacid chlorides disulfonyl chlorides, and diisocyanates are commercially available. These include but are not limited to aliphatic compounds such as fumaryl chloride, succinyl chloride, glutaryl chloride, sebacoyl chloride, 2,2′-oxydiacetyl chloride, 1,4-butanedisulfonyl chloride, 1,4-diisocyanatobutane, hexamethylene diisocyanate, and 1,12-diisocyanatododecane; aromatic compounds such as 1,2-benzenedisulfonyl chloride, 1,3-benzenedisulfonyl chloride, 1,4-phenylene diisocyanate, 1,5-naphthalenediisocyanate, phthaloyl chloride, and isophthaloyl chloride; cycloaliphatic compounds such as dicylcohexylmethane-4,4′-diisocyanate, trans-1,4-cyclohe
  • Dimers of Formula IIa wherein R 3a is -Z-[N(R 8 )—C(O)—N(R 8 )]-X—O—R 4 , wherein X is as defined above, and R 4 is a [1,3]thiazolo[4,5-c]quinoline optionally substituted as defined in R 4 above, can be prepared by treating an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII or a salt thereof with carbonyldiimidazole in a suitable solvent such as DMF at an elevated temperature such as 75° C.
  • a suitable solvent such as DMF
  • R, R 2 , R 10 , and n are as defined above;
  • Z a is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
  • R 3b is
  • Steps (1) through (7) of Reaction Scheme V can be run as described in steps (1) through (7) of Reaction Scheme IV to provide compounds of Formula IIb, a subgenus of Formulas I and II.
  • a compound of Formula XLV can react with a [1,3]thiazolo[4,5-c]quinolinol of Formula XXV under the Mitsunobu reaction conditions described in step (10) of Reaction Scheme I.
  • a [1,3]thiazolo[4,5-c]quinolinol of Formula XXV, triphenylphosphine, and tert-butyl 4-hydroxy-1-piperidinecarboxylate in THF at 5° C. or room temperature and slowly adding diisopropyl azodicarboxylate provides a compound of Formula XLVII wherein Z a is a bond and R 10 is pentylene.
  • step (4) of Reaction Scheme V can be carried out according to the reaction conditions described in step (7) of Reaction Scheme I or by heating a solution of a compound of Formula XLVII in a suitable solvent such as ethyl acetate with peracetic acid at a temperature such as 50° C. and then adding sodium metabisulfate.
  • R, R 2 , and n are as defined above;
  • Z is selected from the group consisting of alkylene, alkenylene, and alkynylene wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups; and
  • R 3c is -Z-Het, -Z-Het′-R 4 , or -Z-Het′-Y—R 4 , wherein Het or Het′ is attached to Z at a nitrogen atom.
  • step (1) of Reaction Scheme VI a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV is treated with a dihalide of Formula I-Z-Cl or Br-Z-Cl using the Williamson conditions described in step (10) of Reaction Scheme I to provide a chloro-substituted compound of Formula X.
  • a chloro-substituted compound of Formula X is treated with a cyclic secondary amine to provide a compound of Formula IIc, a subgenus of Formulas I and II.
  • cyclic secondary amines are commercially available, such as unsubstituted or substituted pyrrolidines, piperidines, morpholines, and piperazines; others can be prepared using conventional methods.
  • the reaction can be conveniently carried out by adding a cyclic secondary amine to a compound of Formula X in a suitable solvent such as DMF.
  • the reaction can be conveniently carried out in the presence of a base such as potassium carbonate at an elevated temperature such as 65° C.
  • Compounds of Formula IIc are also prepared from [1,3]thiazolo[4,5-c]quinolinols of Formula XXV, shown in Reaction Scheme II.
  • a [1,3]thiazolo[4,5-c]quinolinol of Formula XXV is first treated with a dihalide of Formula I-Z-Cl or Br-Z-Cl according to step (1) of Reaction Scheme V.
  • the product is then oxidized and aminated according to the methods described in steps (7) and (8) of Reaction Scheme I to provide a compound of Formula X, which is then treated with a cyclic secondary amine as described in step (2) of Reaction Scheme VI to provide a compound of Formula IIc.
  • a compound of Formula X is also a useful starting material to provide a number of other compounds of the invention.
  • a compound of Formula X can be treated with a non-cyclic secondary amine or a mercaptan under the conditions described in step (2) above to provide a compound in which R 3c is -Z-Y—R 4 , wherein R 4 is as defined above and Y is —N(R 8 )-Q- or —S—, wherein Q is a bond and R 8 is as defined above.
  • a compound of Formula X can be treated under the same conditions with a substituted phenol to provide a compound wherein R 3c is -Z-Y—X—Y—R 4 , in which the Y bonded to Z is —O—, X is phenylene, and R 4 and the Y bonded to R 4 are as defined above or a compound wherein R 3c is -Z-Y—R 4 , in which Y is —O—, and R 4 is phenyl that is optionally substituted.
  • a compound of Formula X can be treated with N-hydroxyphthalimide in the presence of a base, such as triethylamine, in a suitable solvent such as DMF at ambient temperature.
  • the phthalimide group can then be removed from the resulting N-phthalimide-protected hydroxylamine by treatment with hydrazine at ambient temperature in a suitable solvent such as ethanol.
  • the resulting hydroxylamine can then be treated with one of numerous commercially available aldehydes or ketones in a suitable solvent such as methanol to provide a compound of Formula IIc wherein R 3c is -Z-Y—R 4 or -Z-R 5 , where Y is —O—N ⁇ C(R 4 )—, R 5 is
  • R 4 , a, b, and A′ are as defined above.
  • the hydroxylamine prepared after the hydrazine deprotection may be treated with one of numerous acid chlorides, sulfonyl chloride, isocyanates, carbamoyl chloride, or sulfamoyl chlorides using one of the methods described in step (7) of Reaction Scheme IV to provide a compound Formula IIc wherein R 3c is -Z-Y—R 4 where Y is —O—NH-Q-, and Q and R 4 are as defined above.
  • Compounds of the invention can also be prepared using variations of the synthetic routes shown in Reaction Schemes I through VI that would be apparent to one of skill in the art.
  • the synthetic route shown in Reaction Scheme IV for the preparation of quinolines having a R 3a substituent can be used to prepare [1,5]naphthyridines having a R 3a substituent by using a [1,3]thiazolo[4,5-c][1,5]naphthyridinol in lieu of the [1,3]thiazolo[4,5-c]quinolinol.
  • Prodrugs can be prepared in a variety of ways.
  • a compound wherein R 3 or R 2 is —X—OH e.g. hydroxyalkyl
  • R 3 or R 2 is, for example, —X—O—C(R 6 )—R 4 , —X—O—C(R 6 )—O—R 4 , or —X—O—C(R 6 )—N(R 8 )—R 4 , wherein X, R 4 , R 6 , and R 8 are as defined above, using methods known to one skilled in the art.
  • a compound wherein R is hydroxy may also be converted to an ester, an ether, a carbonate, or a carbamate.
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as C 1-6 alkanoyloxymethyl, 1-(C 1-6 alkanoyloxy)ethyl, 1-methyl-1-(C 1-6 alkanoyloxy)ethyl, C 1-6 alkoxycarbonyloxymethyl, N—(C 1-6 alkoxycarbonyl)aminomethyl, succinoyl, C 1-6 alkanoyl, ⁇ -aminoC 1-4 alkanoyl, arylacyl, —P(O)(OH) 2 , —P(O)(O—C 1-6 alkyl) 2 , C 1-6 alkoxycarbonyl, C 1-6 alkylcarbamoyl, and ⁇ -aminoacyl or ⁇ -
  • esters made from carboxylic acids containing one to six carbon atoms are particularly useful prodrugs.
  • unsubstituted or substituted benzoic acid esters are esters made from amino acids.
  • the reaction conditions described above in step (7) of Reaction Scheme IV can be used.
  • Prodrugs can also be made from a compound containing an amino group by conversion of the amino group to a functional group such as an amide, carbamate, urea, amidine, or another hydrolyzable group using conventional methods.
  • a prodrug of this type can be made by the replacement of a hydrogen atom in an amino group, particularly the amino group at the 4-position, with a group such as —C(O)—R′, ⁇ -aminoacyl, ⁇ -aminoacyl- ⁇ -aminoacyl, —C(O)—O—R′, —C(O)—N(R′′′)—R′, —C( ⁇ NY 1 )—R′, —CH(OH)—C(O)—OY 1 , —CH(OC 1-4 alkyl)Y 0 , —CH 2 Y 2 , or —CH(CH 3 )Y 2 ; wherein R′ and R′′′ are each independently C 1-10 alkyl, C 3-7 cycloal
  • amides derived from carboxylic acids containing one to ten carbon atoms particularly useful prodrugs are amides derived from carboxylic acids containing one to ten carbon atoms, amides derived from racemic, D-, or L-amino acids, and carbamates containing one to ten carbon atoms.
  • the reaction can be carried out, for example, by combining a compound of Formula I, II, III, IV, V, or VI with a chloroformate or acid chloride, such as ethyl chloroformate or acetyl chloride, in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane at room temperature.
  • compositions of the invention contain a therapeutically effective amount of a compound or salt described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount and “effective amount” mean an amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral activity.
  • cytokine induction cytokine induction
  • immunomodulation antitumor activity
  • antiviral activity cytokine induction
  • amount of compound or salt used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound or salt, the nature of the carrier, and the intended dosing regimen.
  • compositions of the invention will contain sufficient active ingredient or prodrug to provide a dose of about 100 nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably about 10 micrograms per kilogram ( ⁇ g/kg) to about 5 mg/kg, of the compound or salt to the subject.
  • the method includes administering sufficient compound to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • dosage forms such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
  • These dosage forms can be prepared with conventional pharmaceutically acceptable carriers and additives using conventional methods, which generally include the step of bringing the active ingredient into association with the carrier.
  • the compounds or salts of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts described herein may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.
  • Cytokines whose production may be induced by the administration of compounds or salts of the invention generally include interferon- ⁇ (IFN- ⁇ ) and tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds or salts of the invention include IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds or salts useful in the treatment of viral diseases and neoplastic diseases.
  • IFN- ⁇ interferon- ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-12 interleukins
  • the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of the invention to the animal.
  • the animal to which the compound or salt is administered for induction of cytokine biosynthesis may have a disease as described infra, for example a viral disease or a neoplastic disease, and administration of the compound or salt may provide therapeutic treatment.
  • the compound or salt may be administered to the animal prior to the animal acquiring the disease so that administration of the compound or salt may provide a prophylactic treatment.
  • compounds or salts described herein can affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
  • the compounds or salts may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, the compounds or salts may cause proliferation and differentiation of B-lymphocytes.
  • T H 1 T helper type 1
  • T H 2 T helper type 2
  • the compound or salt or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant.
  • the compound or salt or composition and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.
  • Conditions for which compounds or salts or compositions identified herein may be used as treatments include, but are not limited to:
  • viral diseases such as, for example, diseases resulting from infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g., papillomaviruses, such as those that cause genital warts, common warts, or plantar warts), a hepadnavirus (e.g., hepatitis B virus),
  • bacterial diseases such as, for example, diseases resulting from infection by bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia, Haemophilus , or Bordetella;
  • infectious diseases such as chlamydia, fungal diseases including but not limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic diseases including but not limited to malaria, pneumocystis carnii pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection;
  • neoplastic diseases such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemias including but not limited to acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers;
  • atopic diseases such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
  • diseases associated with wound repair such as, for example, inhibition of keloid formation and other types of scarring (e.g., enhancing wound healing, including chronic wounds).
  • a compound or salt identified herein may be useful as a vaccine adjuvant for use in conjunction with any material that raises either humoral and/or cell mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or bacterial immunogens; toxoids; toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; autologous vaccines; recombinant proteins; and the like, for use in connection with, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningo
  • Compounds or salts identified herein may be particularly helpful in individuals having compromised immune function.
  • compounds or salts may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
  • one or more of the above diseases or types of diseases for example, a viral disease or a neoplastic disease may be treated in an animal in need thereof (having the disease) by administering a therapeutically effective amount of a compound or salt of the invention to the animal.
  • An animal may also be vaccinated by administering an effective amount of a compound or salt described herein, as a vaccine adjuvant.
  • a method of vaccinating an animal comprising administering an effective amount of a compound or salt described herein to the animal as a vaccine adjuvant.
  • An amount of a compound or salt effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12 that is increased (induced) over a background level of such cytokines.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments the induction or inhibition of cytokine biosynthesis may be performed by administering a compound or salt in a dose outside this range.
  • the method includes administering sufficient compound or salt or composition to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • the invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or salt of the invention to the animal.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
  • the precise amount that is effective for such treatment will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • An amount of a compound or salt effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg. In other embodiments, the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments either of these methods may be performed by administering a compound or salt in a dose outside this range.
  • the method includes administering sufficient compound or salt to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • the organic layer was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting dark brown solid was purified by column chromatography using a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) (silica cartridge, eluting with 0 to 30% 80:18:2 chloroform/methanol/concentrated ammonium hydroxide (CMA) in chloroform) to provide 0.48 g of a light yellow solid after drying under high vacuum.
  • HORIZON HPFC system an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA
  • the solid was recrystallized from tert-butyl methyl ether (30 mL, hot filtration), and the crystals were washed with cold tert-butyl methyl ether and dried in a vacuum oven at 60° C. to provide 0.32 g of 7-(2-morpholin-4-ylethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine as light yellow needles, mp 122-125° C.
  • the method described in Part K of Example 1 was used to treat the material from Part J of Example 1 (5.40 mmol) in DMF (25 mL) with cesium carbonate (11.00 g, 33.75 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (1.15 g, 6.75 mmol) with the modification that the reaction was carried out at 70° C. instead of 75° C.
  • the purification methods described in Part K of Example 1 were used to provide 0.33 g of 2-propyl-7-(2-pyrrolidin-1-ylethoxy)[1,3]thiazolo[4,5-c]quinolin-4-amine as light yellow needles, mp 124-127° C.
  • the filtrate was washed sequentially with water (2 ⁇ 500 mL), saturated aqueous sodium thiosulfate (2 ⁇ 250 mL), water (250 mL), and brine (250 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure to provide a mixture of a yellow oil and a white solid.
  • the mixture was diluted with heptane (50 mL) and filtered to remove the solid, which was washed with heptane (50 mL).
  • the filtrate was concentrated under reduced pressure to provide an oil that was diluted with heptane (50 mL) and filtered to remove a solid, which was washed with heptane (50 mL).
  • the filtrate was concentrated under reduced pressure to provide 22.60 g of tert-butyl 3-iodopropylcarbamate as a yellow oil containing about 9 mol % triphenylphosphine oxide as determined by 1 H NMR.
  • the resulting mixture was washed with aqueous sodium carbonate (2 ⁇ 50 mL of 2 M), and the combined washings were extracted with dichloromethane (2 ⁇ 50 mL).
  • the combined organic layers were washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting light brown solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 18% CMA in chloroform) to provide 0.72 g of a light yellow solid after drying under high vacuum.
  • the solid was recrystallized from tert-butyl methyl ether (40 mL, hot filtration), and the crystals were washed with cold tert-butyl methyl ether and dried in a vacuum oven at 40° C. overnight to provide tert-butyl 3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamate as off-white needles, mp 146-149° C.
  • aqueous fraction was made basic with the addition of ammonium hydroxide, and the resulting solution was extracted with dichloromethane (2 ⁇ 50 mL). The organic fractions were combined, washed with brine (75 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 0.58 g of 7-(3-aminopropoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine containing some impurities.
  • Methanesulfonyl chloride (0.14 mL, 1.8 mmol) was added, and the reaction was stirred at room temperature for 5.5 hours. The reaction was monitored by HPLC, and additional methanesulfonyl chloride (0.84 mL, 11 mmol) was added over the course of four days. The reaction mixture was partitioned between chloroform (50 mL) and water (100 mL). The organic fraction was washed with brine (2 ⁇ 50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting light yellow solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 25% CMA in chloroform), and the purified product was dried in a vacuum oven at 60° C. overnight to provide 0.17 g of N- ⁇ 3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propyl ⁇ methanesulfonamide as off-white needles, mp 168-171° C.
  • the reaction was stirred for two hours and then mixed with water (100 mL).
  • the aqueous fraction was extracted with chloroform (2 ⁇ 100 mL), and the combined organic fractions were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting light yellow solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 20% CMA in chloroform), and the purified product was dried under high vacuum to provide 1.17 g of N- ⁇ 3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propyl ⁇ -5-(dimethylamino)naphthalene-1-sulfonamide as a light yellow solid, mp 143-146° C.
  • the resulting light brown solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 5% CMA in chloroform followed by 25% CMA in chloroform) to provide 1.88 g of a light yellow solid after drying under high vacuum.
  • the solid was recrystallized from 2-propanol (175 mL), and the crystals were washed with cold 2-propanol and dried in a vacuum oven at 60° C. overnight to provide 1.54 g of 7-(2-morpholin-4-yl-2-oxoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine as white needles, mp 200-203° C.
  • the resulting light yellow oil (19.36 g) was purified by column chromatography (silica gel, eluting with dichloromethane) to provide 13.53 g of tert-butyl 6-iodohexylcarbamate as a light yellow oil.
  • the organic layer was washed sequentially with saturated aqueous sodium thiosulfate (50 mL), water (50 mL), and brine (50 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure.
  • the resulting solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 6% CMA in chloroform), and the purified product was dried under high vacuum to provide 1.79 g of tert-butyl 6-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamate as a light yellow solid.
  • the resulting light yellow solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 20% CMA in chloroform) to provide 0.47 g of a light yellow solid after drying under high vacuum.
  • the solid was recrystallized from toluene (25 mL), and the crystals were washed with cold toluene and dried in a vacuum oven at 60° C. overnight to provide 0.32 g of N- ⁇ 6-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexyl ⁇ methanesulfonamide as off-white needles, mp 138-134° C.
  • the resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic layer was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate; filtered, and concentrated under reduced pressure.
  • the resulting dark brown solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 8% CMA in chloroform), and the purified product was dried under high vacuum to provide 1.31 g of tert-butyl 2- ⁇ 2-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy ⁇ ethylcarbamate as a light yellow solid.
  • mCPBA (1.20 g, 4.30 mmol, 65% pure) was added in portions to a solution of tert-butyl 2- ⁇ 2-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy ⁇ ethylcarbamate (1.25 g, 2.90 mmol) in dichloromethane (75 mL), and the reaction was stirred at room temperature for 1.75 hours, diluted with chloroform (100 mL), and washed with 10% aqueous sodium carbonate (2 ⁇ 50 mL).
  • the resulting light yellow solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 25% CMA in chloroform) to provide 0.73 g of an off-white solid after drying under high vacuum.
  • the solid was recrystallized from propyl acetate (35 mL, hot filtration), and the crystals were washed with cold propyl acetate and dried in a vacuum oven at 60° C. overnight to provide 0.48 g of N- ⁇ 2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl ⁇ methanesulfonamide as light yellow needles, mp 148-151° C.
  • the method described in Part K of Example 1 was used to treat 4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol acetic acid salt (prepared according to the method described in Part J of Example 1, 1.17 g, 4.51 mmol) in DMF (10 mL) with cesium carbonate (3.27 g, 10.0 mmol) and 2-chloroethylether (288 mg, 2.01 mmol) with the modification that the reaction was carried out at 70° C. instead of 75° C.
  • the purification methods described in Part K of Example 1 were used, with the modification that chromatographic purification was carried out eluting with 0 to 25% CMA in chloroform.
  • the crude solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 20% CMA in chloroform) to provide 0.93 g of a light yellow solid after drying under high vacuum.
  • the solid was recrystallized from tert-butyl methyl ether (35 mL, hot filtration), and the crystals were washed with cold tert-butyl methyl ether and dried in a vacuum oven at 60° C. to provide 0.23 g of 7-[2-(2-chloroethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine as a light yellow solid, mp 101-103° C.
  • a reagent from the table below (1.1 equivalents, 0.11 mmol) was added to a test tube containing a solution of 7-[2-(2-aminoethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine (prepared as described in Part A of Example 11, 35 mg, 0.10 mmol) and N,N-diisopropylethylamine (36 ⁇ L, 0.20 mmol) in N,N-dimethylacetamide (DMA) (1 mL).
  • DMA N,N-dimethylacetamide
  • the compounds were purified by preparative high performance liquid chromatography (prep HPLC) using a Waters FractionLynx automated purification system.
  • the prep HPLC fractions were analyzed using a Waters LC/TOF-MS, and the appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the desired compound.
  • Reversed phase prep HPLC was performed with non-linear gradient elution from 5-95% B where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic acid/acetonitrile. Fractions were collected by mass-selective triggering.
  • the table below shows the acid chloride, sulfonyl chloride, isocyanate, isothiocyanate, or carbamoyl chloride used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
  • the DMF was removed under reduced pressure at 65° C., and the residue was partitioned between chloroform (100 mL) and water (100 mL). The organic layer was separated and washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 25% CMA in chloroform) followed by recrystallization from propyl acetate (25 mL for 0.35 g). The crystals were washed with cold propyl acetate and dried in a vacuum oven at 60° C.
  • Example 102 After the work-up procedure, described in Example 102, the crude product was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 28% CMA in chloroform) followed by recrystallization from acetonitrile (50 mL for 0.67 g). The crystals were washed with cold acetonitrile and dried in a vacuum oven at 60° C. overnight to provide 0.426 g of N- ⁇ 2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl ⁇ acrylamide as a light yellow solid, mp 200-202° C.
  • HORIZON HPFC system sica cartridge, eluting with 0 to 28% CMA in chloroform
  • the crude product was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0 to 25% CMA in chloroform) followed by recrystallization from acetonitrile (25 mL for 0.37 g).
  • the crystals were washed with cold acetonitrile and dried in a vacuum oven at 60° C. to provide 290 mg of N- ⁇ 2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl ⁇ pyrrolidin-2-one as a light yellow solid, mp 163-166° C.
  • a Parr vessel was charged with 7-benzyloxy-3-nitroquinolin-7-ol (50.0 g, 169 mmol), anhydrous DMF (500 mL), and 5% platinum on carbon (5.0 g). The vessel was placed on Parr apparatus, evacuated, and charged with hydrogen gas (approximately 45 psi, 3.1 ⁇ 10 5 Pa). The reaction mixture was shaken overnight and filtered to remove the catalyst. To the resulting dark colored solution was added concentrated aqueous hydrochloric acid (14 mL of 12 N solution). A precipitate formed, and the reaction mixture was stirred over the weekend. The solid was collected by vacuum filtration, washed with diethyl ether (100 mL), and air-dried overnight to provide 44 g of 3-amino-7-benzyloxyquinolin-4-ol hydrochloride.
  • Trichloroacetyl isocyanate (5.6 mL, 46.8 mmol) was slowly added to a vigorously stirred pale orange solution of 7-benzyloxy-2-ethyl-5-oxido[1,3]thiazolo[4,5-c]quinoline (15.0 g, 44.6 mmol) in dichloromethane (200 mL) at room temperature. The solution was maintained at room temperature for 18 hours, and then concentrated ammonium hydroxide solution (60 mL) was added. An off-white precipitate formed and was collected by vacuum filtration.
  • the residue was dissolved in chloroform and purified by column chromatography using a HORIZON HPFC system (eluting with a gradient of 0% to 20% CMA in chloroform over 700 mL and then with 20% CMA in chloroform for 600 mL).
  • the major product isolated from the column fractions was 7-(3-azidopropoxy)-2-ethylthiazolo[4,5-c]quinolin-4-amine (400 mg).
  • a second product isolated from the column was triturated with hot acetonitrile containing a small amount of methanol, and the mixture was allowed to cool to room temperature.
  • mCPBA (1.97 g of 70% pure material, 11 mmol) was added to a solution of tert-butyl 4-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]piperidine-1-carboxylate (3.76 g, 8.79 mmol), and the reaction was stirred at room temperature for 1.5 hours. An analysis by LC/MS indicated the presence of starting material, and additional mCPBA (250 mg) was added.
  • reaction was stirred at room temperature for an additional 1.5 hours; diluted with chloroform (20 mL); washed sequentially with aqueous sodium carbonate (20 mL of 10% w/w), water (20 mL), and brine (20 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide tert-butyl 4-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]piperidine-1-carboxylate as a light yellow solid.
  • a solution of the material from Part C in 1,2-dichloroethane (60 mL) was heated to 65° C. in a pressure vessel.
  • Aqueous ammonium hydroxide (20 mL of 30% w/w) and p-toluenesulfonyl chloride (1.76 g, 9.23 mmol) were quickly added, and the vessel was sealed and heated at 70° C. for 15 hours and allowed to cool to room temperature.
  • the organic layer was separated and washed sequentially with aqueous sodium carbonate (20 mL of 10% w/w) and water (20 mL).
  • the combined aqueous fractions were extracted with chloroform (20 mL).
  • the solid was suspended in a small volume of water, and the suspension was cooled to approximately 0° C. and adjusted to approximately pH 10 with the addition of 50% w/w aqueous sodium hydroxide. A yellow precipitate formed and was collected by filtration, washed with water, and dried overnight under vacuum.
  • the solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0% to 15% CMA in chloroform) followed by recrystallization from acetonitrile. The crystals were dried to provide 7-(piperidin-4-yloxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine as yellow crystals.
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formula (IId) and the following Z, R 3d , and R 2 , substituents, wherein each line of the table is matched with Formula IId to represent a specific embodiment of the invention.
  • R 3d R 2 —CH 2 CH 2 — (methylsulfonyl)amino ethyl —CH 2 CH 2 — (methylsulfonyl)amino propyl —CH 2 CH 2 — (methylsulfonyl)amino butyl —CH 2 CH 2 — (methylsulfonyl)amino 2-methoxyethyl —CH 2 CH 2 — (methylsulfonyl)amino ethoxymethyl —CH 2 CH 2 — pyrrolidin-1-yl ethyl —CH 2 CH 2 — pyrrolidin-1-yl propyl —CH 2 CH 2 — pyrrolidin-1-yl butyl —CH 2 CH 2 — pyrrolidin-1-yl 2-methoxyethyl —CH 2 CH 2 — pyrrolidin-1-yl ethoxymethyl —CH 2 CH 2 — morpholin-4-yl
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formula (IIe) and the following Z, R 3e , and R 2 , substituents, wherein each line of the table is matched with Formula IIe to represent a specific embodiment of the invention.
  • Compounds of the invention have been found to modulate cytokine biosynthesis by inducing the production of interferon ⁇ and/or tumor necrosis factor a in human cells when tested using one of the methods described below.
  • cytokine induction An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon ( ⁇ ) and tumor necrosis factor ( ⁇ ) (IFN- ⁇ and TNF- ⁇ , respectively) secreted into culture media as described by Testerman et. al. in “Cytokine Induction by the Immunomodulators Imiquimod and S-27609”, Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
  • ⁇ interferon
  • ⁇ tumor necrosis factor
  • PBMC Peripheral blood mononuclear cells
  • HISTOPAQUE-1077 Sigma, St. Louis, Mo.
  • Ficoll-Paque Plus Amersham Biosciences Piscataway, N.J.
  • Blood is diluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced Salts Solution (HBSS).
  • DPBS Dulbecco's Phosphate Buffered Saline
  • HBSS Hank's Balanced Salts Solution
  • PBMC whole blood is placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, Fla.) centrifuge frit tubes containing density gradient medium.
  • the PBMC layer is collected and washed twice with DPBS or HBSS and re-suspended at 4 ⁇ 10 6 cells/mL in RPMI complete.
  • the PBMC suspension is added to 96 well flat bottom sterile tissue culture plates containing an equal volume of RPMI complete media containing test compound.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells.
  • the compounds are generally tested at concentrations ranging from 30-0.014 ⁇ M. Controls include cell samples with media only, cell samples with DMSO only (no compound), and cell samples with reference compound.
  • test compound is added at 60 ⁇ M to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells.
  • the PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (usually 30-0.014 ⁇ M).
  • the final concentration of PBMC suspension is 2 ⁇ 10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.
  • IFN- ⁇ concentration is determined with a human multi-subtype colorimetric sandwich ELISA (Catalog Number 41105) from PBL Biomedical Laboratories, Piscataway, N.J. Results are expressed in pg/mL.
  • TNF- ⁇ concentration is determined by ORIGEN M-Series Immunoassay and read on an IGEN M-8 analyzer from BioVeris Corporation, formerly known as IGEN
  • the immunoassay uses a human TNF- ⁇ capture and detection antibody pair (Catalog Numbers AHC3419 and AHC3712) from Biosource International, Camarillo, Calif. Results are expressed in pg/mL.
  • the data output of the assay consists of concentration values of TNF- ⁇ and IFN- ⁇ (y-axis) as a function of compound concentration (x-axis).
  • the reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro- ⁇ , ⁇ -dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanol hydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area is the sum of the median dose values from the past 61 experiments.
  • the minimum effective concentration is calculated based on the background-subtracted, reference-adjusted results for a given experiment and compound.
  • the minimum effective concentration ( ⁇ molar) is the lowest of the tested compound concentrations that induces a response over a fixed cytokine concentration for the tested cytokine (usually 20 pg/mL for IFN- ⁇ and 40 pg/mL for TNF- ⁇ ).
  • the maximal response is the maximal amount of cytokine (pg/ml) produced in the dose-response.
  • the CYTOKINE INDUCTION IN HUMAN CELLS test method described above was modified as follows for high throughput screening.
  • PBMC Peripheral blood mononuclear cells
  • HISTOPAQUE-1077 Sigma, St. Louis, Mo.
  • Ficoll-Paque Plus Amersham Biosciences Piscataway, N.J.
  • Whole blood is placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, Fla.) centrifuge frit tubes containing density gradient medium.
  • the PBMC layer is collected and washed twice with DPBS or HBSS and re-suspended at 4 ⁇ 10 6 cells/mL in RPMI complete (2-fold the final cell density).
  • the PBMC suspension is added to 96-well flat bottom sterile tissue culture plates.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • Controls include cell samples with media only, cell samples with DMSO only (no compound), and cell samples with a reference compound 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro- ⁇ , ⁇ -dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanol hydrate (U.S. Pat. No. 5,352,784; Example 91) on each plate.
  • the solution of test compound is added at 7.5 mM to the first well of a dosing plate and serial 3 fold dilutions are made for the 7 subsequent concentrations in DMSO.
  • RPMI Complete media is then added to the test compound dilutions in order to reach a final compound concentration of 2-fold higher (60-0.028 ⁇ M) than the final tested concentration range.
  • test compound solution is then added to the wells containing the PBMC suspension bringing the test compound concentrations to the desired range (usually 30-0.014 ⁇ M) and the DMSO concentration to 0.4%.
  • the final concentration of PBMC suspension is 2 ⁇ 10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.
  • MSD MULTI-SPOT plates contain within each well capture antibodies for human TNF- ⁇ and human IFN- ⁇ that have been pre-coated on specific spots. Each well contains four spots: one human TNF- ⁇ capture antibody (MSD) spot, one human IFN- ⁇ capture antibody (PBL Biomedical Laboratories, Piscataway, N.J.) spot, and two inactive bovine serum albumin spots.
  • the human TNF- ⁇ capture and detection antibody pair is from MesoScale Discovery.
  • the human IFN- ⁇ multi-subtype antibody (PBL Biomedical Laboratories) captures all IFN- ⁇ subtypes except IFN- ⁇ F (IFN ⁇ 21).
  • Standards consist of recombinant human TNF- ⁇ (R&D Systems, Minneapolis, Minn.) and IFN- ⁇ (PBL Biomedical Laboratories). Samples and separate standards are added at the time of analysis to each MSD plate. Two human IFN- ⁇ detection antibodies (Cat. Nos. 21112 & 21100, PBL) are used in a two to one ratio (weight:weight) to each other to determine the IFN- ⁇ concentrations.
  • the cytokine-specific detection antibodies are labeled with the SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeled detection antibodies to the wells, each well's electrochemoluminescent levels are read using MSD's SECTOR HTS READER. Results are expressed in pg/mL upon calculation with known cytokine standards.
  • the data output of the assay consists of concentration values of TNF- ⁇ or IFN- ⁇ (y-axis) as a function of compound concentration (x-axis).
  • a plate-wise scaling is performed within a given experiment aimed at reducing plate-to-plate variability associated within the same experiment.
  • the greater of the median DMSO (DMSO control wells) or the experimental background (usually 20 pg/mL for IFN- ⁇ and 40 pg/mL for TNF- ⁇ ) is subtracted from each reading. Negative values that may result from background subtraction are set to zero.
  • Each plate within a given experiment has a reference compound that serves as a control. This control is used to calculate a median expected area under the curve across all plates in the assay.
  • a plate-wise scaling factor is calculated for each plate as a ratio of the area of the reference compound on the particular plate to the median expected area for the entire experiment.
  • the data from each plate are then multiplied by the plate-wise scaling factor for all plates. Only data from plates bearing a scaling factor of between 0.5 and 2.0 (for both cytokines IFN- ⁇ , TNF- ⁇ ) are reported. Data from plates with scaling factors outside the above mentioned interval are retested until they bear scaling factors inside the above mentioned interval. The above method produces a scaling of the y-values without altering the shape of the curve.
  • the reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro- ⁇ , ⁇ -dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanol hydrate (U.S. Pat. No. 5,352,784; Example 91).
  • the median expected area is the median area across all plates that are part of a given experiment.
  • a second scaling may also be performed to reduce inter-experiment variability (across multiple experiments). All background-subtracted values are multiplied by a single adjustment ratio to decrease experiment-to-experiment variability.
  • the adjustment ratio is the area of the reference compound in the new experiment divided by the expected area of the reference compound based on an average of previous experiments (unadjusted readings). This results in the scaling of the reading (y-axis) for the new data without changing the shape of the dose-response curve.
  • the reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro- ⁇ , ⁇ -dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanol hydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area is the sum of the median dose values from an average of previous experiments.
  • the minimum effective concentration is calculated based on the background-subtracted, reference-adjusted results for a given experiment and compound.
  • the minimum effective concentration ( ⁇ molar) is the lowest of the tested compound concentrations that induces a response over a fixed cytokine concentration for the tested cytokine (usually 20 pg/mL for IFN- ⁇ and 40 pg/mL for TNF- ⁇ ).
  • the maximal response is the maximal amount of cytokine (pg/ml) produced in the dose-response.

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US20150266901A1 (en) 2015-09-24
CA2597324A1 (fr) 2006-08-17
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US9546184B2 (en) 2017-01-17
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US20170088559A1 (en) 2017-03-30
JP2008530099A (ja) 2008-08-07
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WO2006086449A2 (fr) 2006-08-17
US20180057509A1 (en) 2018-03-01

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