Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • 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
• • 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
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• Certain lH-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. Subsequently, certain substituted lH-imidazo[4,5-c]pyridin-4-amine, quinolin-4-amine, tetrahydroquinolin-4-amine, naphthyridin-4-amine, and tetrahydronaphthyridm-4-amine compounds as well as certain analogous thiazolo and oxazolo compounds were synthesized and found to be useful as immune response modifiers (IRMs), rendering them useful in the treatment of a variety of disorders.
• IRMs immune response modifiers
• the present invention provides such compounds, which are of Formula I: I wherein R, n, R', R", and R 3 are as defined below; and pharmaceutically acceptable salts thereof.
• the compounds of the present invention are useful as immune response modifiers
• IRMs due to their ability to induce or inhibit cytokine biosynthesis (e.g., induce or inhibit the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals.
• Compounds can be tested per the test procedures described in the Examples Section.
• Compounds can be tested for induction of cytokine biosynthesis by incubating human peripheral blood mononuclear cells (PBMC) in a culture with the compound(s) at a concentration range of 30 to 0.014 ⁇ M and analyzing for interferon ( ⁇ ) or tumor necrosis factor ( ⁇ ) in the culture supernatant.
• PBMC peripheral blood mononuclear cells
• Compounds can be tested for inhibition of cytokine biosynthesis by incubating mouse macrophage cell line Raw 264.7 in a culture with the compound(s) at a single concentration of, for example, 5 ⁇ M and analyzing for tumor necrosis factor ( ⁇ ) in the culture supernatant.
• the ability to modulate cytokine biosynthesis for example, induce the biosynthesis of one or more cytokines, makes the compounds useful in the treatment of a variety of conditions such as viral diseases and neoplastic diseases, that are responsive to such changes in the immune response.
• the present invention provides pharmaceutical compositions containing the immune response modifier compounds, and methods of inducing or inhibiting cytokine biosynthesis in an animal, treating a viral disease in an animal, and treating a neoplastic disease in an animal, by administering an effective amount of one or more compounds of Formula I and/or pharmaceutically acceptable salts thereof to the animal.
• the invention provides methods of synthesizing compounds of Formula I and intermediates useful in the synthesis of these compounds.
• “a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably.
• the terms “comprising” and variations thereof do not have a limiting meaning where these terms appear in the description and claims.
• R, R ls R 2 , R 3-1 , R 3-2 , R - , R 3-4 , R 3-5 , R 3-6 , and n are as defined below; and pharmaceutically acceptable salts thereof.
• the compounds of Formula VE and salts thereof are also useful as intermediates for the preparation of compounds and salts of Formulas I-V ⁇ .
• the present invention also provides intermediate compounds of Formula LX:
• R 3 is selected from the group consisting of -Z-Y-R 4 , -Z-Y-X-Y-R4, -Z-R 5 , -Z-Het, -Z-Het'-I , and -Z-Het'-Y-R ⁇ 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 -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-C
• 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; 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, heteroarylalky
• R 7 is C 2-7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• 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-, -C(O)-, -S(O) 0-2 -, and -NCR- -;
• 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, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, heterocycly
• 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 consistmg 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;
• R 3 is -Z-R 5 and R 5 is
• the present invention provides compounds of the formula (H):
• R is selected from the group consisting of -Z-Y-R4, -Z-Y-X-Y-R4, -Z-R 5 , ' -Z-Het, -Z-Het'-R ⁇ and 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; R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; n is 0 or 1; Ri is selected from the group consisting of -R4, -X-R4, -X-Y-R4, -X-R 5 ; R 2 is selected from the group consisting of -R4, -X-R ⁇ -X-Y-R 4 , and -X-R 5 ; X is selected from the group consisting of alkylene, alkenylene, alkynylene,
• t 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,
• W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; with the proviso that Z can also be a bond when: R 3 is -Z-Het, -Z-Het'-I , or -Z-Het'-Y-R ⁇ or R 3 is -Z-Y-R 4 or -Z-Y-X-Y-I ⁇ , and Y is selected from -S(O) 0-2 -, -S(O) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-O-, -C(R6)-N(R 8 )-,
• R 3 is -Z-R 5 and R 5 is
• the present invention provides compounds of the formula (IU):
• R 3-1 is selected from the group consisting of -Z-N(R 8 )-C(R 6 )-R 4 , - Z-N- C(R 6 ) R ⁇ 7 ⁇ , and
• Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherem alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more -O- groups;
• R is selected from the group consistmg of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
• n is 0 or 1 ;
• Ri is selected from the group consisting of -R 4 , -X-R 4 , -X-Y-R 4 , -X-Y-X-Y-R 4 , and R 2 is selected from the group consisting of -R4.
• 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 -S(0)o- 2 -, -S(O) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-O-, -O-C(O)-O-, -N(R 8 )-Q-, -C(Rs)-N(R 8 )-, -O-C(R 6 )-N(R 8 )-, -C(R 6 )-N(OR 9 )-,
• 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 7 is C 2-7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• 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-, -C(O)-, -S(O) 0-2 -, and-N(R )-;
• 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-,
• the present invention provides compounds of the formula
• R 3-2 is selected from the group consisting of Z-N(R 8 )-S(O) 2 -R 4 , Z-N(R 8 )-S(O) 2 -N(R 8 )-R 4 ,
• 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;
• R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
• n is O or 1;
• R 1 is selected from the group consisting of -R4, -X-R ⁇ -X-Y-R 4 , -X-Y-X-Y-R ⁇ and -X-R 5 ;
• R 2 is selected from the group consisting of -R4, -X-R 4 , -X-Y-R 4 , and -X-R 5 ;
• X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene 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 7 is C 2-7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• R 9 is selected from the group consisting of hydrogen and alkyl;
• Rio is C 3 .
• A is selected from the group consisting of -O-, -C(O)-, -S(O)o -2 -, and -N(R )-;
• Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R 6 )-, -S(O) 2 -knowingly -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
• the present invention provides compounds of the formula
• R 3-3 is selected from the group consisting of -Z-N(R 8 )-C(R 6 )-N(R 8 )-W-R 4 ,
• 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;
• R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
• n is O or l; is selected from the group consisting of -X-R4, -X-Y-X-Y-R ⁇ and R 2 is selected from the group consisting of -R4, -X-R ⁇ -X-Y-R4, and -X-R 5 ;
• 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
• 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 7 is C 2-7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• 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-, -C(O)- 5 -S(O)o -2 -, and -N ⁇ )-;
• Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Re)-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
• the present invention provides compounds of the formula
• R 3-4 is selected from the group consisting of -Z a -C(R 6 )-R 4 , -Z a -C(R 6 )-O-R 4 , -Z a -C(R 6 )-N(R 8 )-R 4 , and
• 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 is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
• n is O or 1;
• Ri is selected from the group consisting of -R 4 , -X-R 4 , -X-Y-R4, -X-R 5 ;
• R 2 is selected from the group consisting of -R 4 , -X-Y-R4, and 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
• 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, allcoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
• R 7 is C 2 - 7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• R 9 is selected from the group consisting of hydrogen and alkyl;
• Rio is C 3-8 alkylene;
• A is selected from the group consisting of -O-, -C(O)-, -S(O)o -2 -, and -N(R 4 )-;
• A' is selected from the group consisting of -O-, -C(O)-, -S(O)o-2-, -N ⁇ )-, 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
• R 3-5 is selected from the group consisting of -Z-N(R 8 )-C(R 6 )-O-R 4 ;
• 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;
• R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
• n is 0 or 1 ;
• Ri is selected from the group consisting of -R4, -X-Y-R ⁇ -X-Y-X-Y-R t , and -X-R 5 ;
• R 2 is selected from the group consisting of -R4, -X-R4, -X-Y-R4, and -X-R 5 ;
• X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alken
• 1 ⁇ 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 is C 2-7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• R 9 is selected from the group consisting of hydrogen and alkyl;
• Rio is C 3-8 alkylene;
• A is selected from the group consisting of -O-, -C(O)-, -S(O)o -2 -, and -N0 -;
• 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- 5 and -C(R 6 )-N(OR 9
• the present invention provides compounds of the formula (VHT):
• R -6 is selected from the group consisting of -Z-N(R 8 )H, and
• 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;
• R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
• n is 0 or 1;
• Ri is selected from the group consisting of -R4, -X-R , -X-Y-R4, -X-R 5 ;
• R is selected from the group consisting of -R4, -X-R4, -X-Y-R4, and -X-R 5 ;
• 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 hetero
• R 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 7 is C 2-7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• R 9 is selected from the group consisting of hydrogen and alkyl;
• Rio is C 3-8 alkylene;
• A is selected from the group consisting of -O-, -C(O)-, -S(O)o -2 -, and -N(R )-;
• 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 )
• R 7 is C 2-7 alkylene;
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl;
• R 9 is selected from the group consisting of hydrogen and alkyl;
• Rio is C 3-8 alkylene;
• A is selected from the group consisting of -O-, -C(O)-, -S(O)o- 2 -, and -N ⁇ )-;
• 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, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl,
• W is selected from the group consisting of a bond, -C(O)-, and -S(O) -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; with the proviso that Z can also be a bond when: R 3 is -Z-Het, -Z-Het'-R ⁇ or -Z-Hef-Y-R ⁇ or R 3 is -Z-Y-R 4 or -Z-Y-X-Y-R ⁇ and Y is selected from -S(O) 0-2 -, -S(O) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-O-, -C(R 6 )-N(R 8 )-,
• 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).
• heterocyclylene are substituted.
• an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
• each group (or substituent or variable) is independently selected, whether explicitly stated or not.
• each R 8 group is independently selected, hi another example, when an R 2 and an R 3 group both contain an R 4 group, each R 4 group is independently selected.
• each Y group is independently selected, and each R 8 group is independently selected.
• the invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, and the like, hi particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers. It should be understood that the term
• Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, dihydroxyalkyl, alkylsulfonylalkylenyl, -X-Y-R ⁇ -X-R 5 , and heterocyclylalkylenyl, wherein the heterocyclyl of the heterocyclylalkylenyl group is optionally substituted by one or more alkyl groups; wherein X is alkylene; Y is -N(R 8 )-C(O)-, -N(R 8 )-S(O) 2 -, -N(R 8 )-C(O)-
• R is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, ethoxymethyl, methoxyethyl, methoxymethyl, hydrogen, hydroxymethyl, 2-methoxy(ethoxymethyl), 4-(3- phenylureido)butyl, cyclopropylmethyl, trifluoromethyl, phenyl, and benzyl.
• R 3 is selected from the group consisting of -Z-Y-R4, -Z-Y-X-Y-R4, -Z-R 5 , -Z-Het, -Z-Het'-R*, and -Z-Het'-Y-Rj.
• R 3 is -Z-Y ⁇ or -Z-Y-X-Y-R4.
• R 3 is -Z-R 5 .
• R 3 is -Z-Y-R 4 . or -Z-Y-X-Y-R ⁇
• Z is a bond.
• Rio is C 4-6 alkylene
• R 4 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo.
• R 4 is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkylenyl, and alkylheteroarylenyl, wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, trifluoromethoxy.
• R 3 - 2 is In some embodiments of Formula IV, R 3 . 2 is -Z-N(R 8 )-S(O) 2 -N(R 8 )-R or
• R 10 is
• R 3-3 is -Z-N(R 8 )-C(R 6 )-N(R 8 )-W-R 4 .
• R 8 is hydrogen or C ⁇ -4 alkyl
• W is a bond, -C(O)-, or -S(O) -
• R 4 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro, dialkylamino
• R 6 O
• R 8 is hydrogen
• a and b are each independently 1 to 3
• A is -O-.
• Z is ethylene or propylene
• a and b are each 2.
• R 3-3 is
• R 3-3 is
• R 8 is hydrogen or C 1- alkyl
• io is C 4-6 alkylene
• W is a bond, -C(O)-, or - S(O) 2 -, and is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo.
• W is a bond or - C(O)-.
• W is selected from the group consisting of alkyl, aryl, arylalkylenyl, and heteroaryl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.
• Z is a bond.
• R 3-3 is In some embodiments of Formula V, R 3-3 is
• R 8 is hydrogen or C ⁇ -4 alkyl
• Rio is C 4-6 alkylene
• R- t is hydrogen or alkyl.
• R 3-4 is -Z a -C(R 6 )-R , -Z a -C(R 6 )-O-R 4 ,
• R 8 is hydrogen, alkyl, or alkoxyalkylenyl
• R 4 is alkyl, aryl, or arylalkylenyl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.
• R - is
• R 6 O
• Rio is C 4-6 alkylene
• R ⁇ is alkyl
• Z is a bond.
• R -5 is -Z-N(R 8 )-C(R 6 )-C(R 6 )-R .
• R 8 is hydrogen
• R 4 is alkyl, aryl, or heteroaryl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.
• 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
• R 4 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl, wherein the alkyl, alkenyl, aryl, arylalkylenyl, aryloxyalkylenyl, and heteroaryl groups can be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, aryl, halogen, alkoxy, cyano, arylalkyleneoxy, nitro, dialkylamino, aryloxy, heterocyclyl, trifluoromethyl, trifluormethoxy, and in the case of alkyl, oxo.
• 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, aryloxyalkylenyl, heteroaryl, and heterocyclyl, wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and heterocyclyl, and wherein arylalkylenyl and heteroarylalkylenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, and alkoxy.
• R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, aryloxyalkylenyl, heteroaryl, and heterocyclyl.
• R 4 is selected from the group consisting of hydrogen and alkyl.
• R 4 is alkyl.
• R 4 is alkyl or aryl.
• R 4 is C 1- alkyl. i certain embodiments, R 4 is isopropyl.
• 4 is alkyl, aryl, or heterocyclyl.
• R 4 is selected from the group consisting of alkyl, aryl, alkenyl, heteroaryl, arylalkylenyl, and alkylheteroarylenyl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.
• R 4 is alkyl, aryl, or arylalkylenyl; wherein aryl can be optionally substituted with halogen, methoxy, cyano, trifluoromethyl, and trifluoromethoxy.
• R 5 is selected from the group consisting of
• R 5 is selected from the group consisting of
• R is C 3-5 alkylene
• R o is C 4-6 alkylene; and a and b are each independently 1 to 3.
• R 6 O.
• R 7 is a C -7 alkylene.
• R 7 is C 3-5 alkylene.
• R 7 is C 2-4 alkylene.
• R 7 is propylene.
• R 8 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl.
• A' is selected from the group consisting of -O-, -C(O)-, -S(O)o-2- 3 -N(R 4 )-, and -CH 2 -. certain embodiments, A' is selected from the group consisting of -CH -, -S(O) 2 -, and -O-. In certain embodiments, A' is -CH -. In certain embodiments, A' is -O-.
• Q is selected from the group consisting of a bond, -C(O)-, -C(O)-O-, -S(O) 2 -, -C(R 6 )-N(R 8 )-W-, and -S(O) 2 -N(R 8 )-.
• 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) -.
• 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.
• Y is selected from the group consisting of -S(O) 0-2 -, -S(O) 2 -N(R 8 )-, -C(R 6 )- 5 -C(R 6 )-O-, -O-C(Rs)-, -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 )-,
• W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -;
• R 8 is selected from the group consisting of hydrogen, C M alkyl, and alkoxyalkylenyl; and
• Rio is selected from the group consisting of C 4 .
• alkylene is selected from the group consisting of alkylene, arylene, heterocyclylene, heteroarylene, and alkylene terminated with heteroarylene; and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, aryloxyalkylenyl, heteroaryl, and heterocyclyl, wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and heterocyclyl, and wherein arylalkylenyl and heteroarylalkylenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, and alkoxy.
• Y is selected from the group consisting of -S(O)o- 2 -, -C(O)-, -C(O)-O-, -O-C(O)-, -N(R 8 )-Q-, -C(R 6 )-N(R 8 )-,
• Q is selected from the group consisting of a bond, -C(O)-, -C(O)-O-, -S(O) 2 -, -C(R 6 )-N(R 8 )-W-, and -S(O) 2 -N(R 8 )-;
• W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -;
• R 8 is selected from the group consisting of hydrogen, C M alkyl, and alkoxyalkylenyl; and Rio is selected from the group consisting of C 4 . 6 alkylene.
• Y is selected from the group consisting of -S(O)o-2-, -C(O)-, -C(O)-O-, -N(R 8 )-Q-, -C(R 6 )-N(R 8 ),
• Y is selected from the group consisting of -C(O)-,
• 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 can also be a bond, hi some embodiments (e.g., of Formulas I-LX), Z is alkylene. In certain of these embodiments, Z is
• Z is ethylene or propylene.
• Z is a bond.
• Z can be a bond when: R 3 is -Z-Het, -Z-Het'-R ⁇ or -Z-Het'-Y-R ⁇ or R 3 is -Z-Y-Rj or -Z-Y-X-Y-IU, and Y is selected from -S(O)o-2-, -S(O) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-O-, -C(R 6 )-N(R 8 )-, and ; or R 3 is -Z-R 5 and R 5 is
• Z can be a bond when R 3- ⁇ is
• Z can be a bond when R 3-2 is
• Z can be a bond when R 3-5 is
• Z can be a bond when R 3-6 is
• Z can be a bond when R 3 is -Z-S(O) 2 -CH 3 or -Z-C(O)-NH-CH(CH 3 ) 2 .
• 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, h certain embodiments, Z a is a bond or alkylene. hi certain of these embodiments, Z a is C M alkylene. In certain embodiments,
• 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, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino,
• Het is substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, hydroxyalkyleneoxylalkylenyl, diakylamino, and heterocyclyl.
• Het is selected from the group consisting of tetrahydropyranyl and tetrahydrofuranyl.
• 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, mercapto, cyano, aryloxy, arylalkyleneoxy, heteroaryloxy, heteroarylalkyleneoxy, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and oxo.
• Het or Het' is selected from the group consisting of tetrahydropyranyl, tefrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, thiazolidinyl, aziridinyl, azepanyl, diazepanyl, dihydroisoquinolin-(lH)-yl, octahydroisoquinolin-(lH)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-lH-imidazolyl, and piperazinyl.
• Het is substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, hydroxyalkyleneoxylalkylenyl, diakylamino, and heterocyclyl;
• Y is selected from the group consisting of -C(O)-, -C(O)-O-, -C(O)-N(H)-, and -N(H)-C(O)-; and
• R 4 is selected from the group consisting of hydrogen and alkyl.
• Formulas I-IX, R 3 -O ⁇ , R 3- ⁇ -O-, R 3-2 -O-, R 3-3 -O-, R 3-4 -O-, R 3-5 -O-, or R 3-6 -O- is at the 7- or 8-position.
• R 3 -O-, R 3- ⁇ -O-, R 3- -O-, R -3 -O-, R 3-4 -O-, R 3-5 -O-, or R -6 -O- is at the 7-position.
• 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 to 3.
• a is 1 or 2
• b is 2.
• hi certain embodiments, a and b are each 2.
• n is 0 or 1. hi some embodiments (e.g., of Formulas I-IX), n is O.
• the reaction is conveniently carried out in medium such as DOWTHERM A heat transfer fluid at a temperature between 200 and 250 °C.
• the product can be isolated using conventional methods.
• 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 XVIH.
• the reaction is conveniently carried out by adding nitric acid to the benzyloxyquinolin-4-ol of Formula XVH in a suitable solvent such as propionic acid and heating the mixture at an elevated temperature such as 125 °C.
• the product can be isolated using conventional methods.
• a benzyloxy-3-nitroquinolin-4-ol of Formula XVLn is chlorinated using conventional chlorination chemistry to provide a benzyloxy-4- chloro-3-nitroquinoline of Formula XLX.
• the reaction is conveniently carried out by treating the benzyloxy-3-nitroquinolin-4-ol of Formula XVLT with phosphorous oxychloride in a suitable solvent such as N,N-dimethylformamide (DMF).
• DMF N,N-dimethylformamide
• the reaction can be carried out at an elevated temperature such as 100 °C, and the product can be isolated using conventional methods.
• abenzyloxy-4-chloro-3-nitroquinoline of Formula XIX is treated with an amine of Formula R ⁇ - ⁇ H 2 to provide a benzyloxy-3- nitroquinolin-4-amine of Formula XX.
• the reaction is conveniently carried out by adding the amine of Formula R ⁇ -NH 2 to a solution of the benzyloxy-4-chloro-3-nitroquinoline of Formula XLX in a suitable solvent such as dichloromethane or methanol in the presence of a tertiary amine such as triethylamine.
• the reaction can be carried out at ambient temperature or at an elevated temperature such as, for example, the reflux temperature of the solvent.
• the reaction product can be isolated using conventional methods.
• the hydrogenation is conveniently carried out in a Parr apparatus in a suitable solvent such as toluene, methanol, or acetonitrile.
• a suitable solvent such as toluene, methanol, or acetonitrile.
• the reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
• the reduction in step (6) can be carried out using nickel boride, prepared in situ from sodium borohydride and nickel(fl) chloride.
• the reduction is conveniently carried out by adding a solution of the benzyloxy-3-nitroquinolin-4-amine of
• XXI is treated with a carboxylic acid equivalent to provide a benzyloxy-lH-imidazo[4,5- c]quinoline of Formula XXH.
• Suitable carboxylic acid equivalents include orthoesters of Formula R 2 C(O-alkyl) 3 , 1,1-dialkoxyalkyl alkanoates of Formula R 2 C(O-alkyl) 2 (O-C(O)- alkyl), and acid chlorides of Formula R 2 C(O)Cl.
• the selection of the carboxylic acid equivalent is determined by the desired substituent at R 2 . For example, triethyl orthoformate will provide a compound where R 2 is hydrogen, and trimethyl orthovalerate will provide a compound where R 2 is a butyl group.
• step (7) can be carried out in two steps when an acid chloride of Formula R 2 C(O)Cl is used as the carboxylic acid equivalent. Part (i) of step (7) is conveniently carried out by adding the acid chloride to a solution of a benzyloxyquinoline-
• step (7) involves heating the amide prepared in part (i) to provide a benzyloxy-lH-imidazo[4,5-c]quinoline of Formula XXLI.
• the reaction is conveniently carried out in a suitable solvent such as toluene at a temperature sufficient to drive off water formed during the reaction.
• the reaction can also be carried out in a solvent such as ethanol or methanol in the presence of a base such as triethylamine.
• a solvent such as ethanol or methanol
• a base such as triethylamine.
• the benzyloxy-lH-imidazo[4,5-c]quinoline of Formula XXH can be isolated using conventional methods.
• step (8) of Reaction Scheme I the benzyl group of a benzyloxy-lH-imidazo[4,5- c]quinoline of Formula XXII is cleaved to provide a lH-imidazo[4,5-c]quinolinol of Formula XXIH.
• the cleavage is conveniently 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.
• the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst.
• the transfer hydrogenation is conveniently carried out by adding ammonium formate to a solution of a benzyloxy-lH-imidazo[4,5-c]quinoline of Formula XXII in a suitable solvent such as ethanol in the presence of a catalyst such as palladium on carbon.
• the reaction is carried out at an elevated temperature, for example, the refluxing temperature of the solvent..
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• the reaction is effected by treating a lH-imidazo[4,5- c]quinolinol of Formula XXHI with an alkyl halide of Formula ⁇ alide-Z-Y-R 4 , Halide-Z- R 5 , Halide-Z-Y-X-Y-IU, or Halide-Z-Het, wherein Z, Y, X, IU, R 5 , and Het are as defined above, in the presence of a base.
• the reaction is conveniently carried out by combining the alkyl halide with a lH-imidazo[4,5-c]quinolinol of Formula XXIH 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 65 °C or 85 °C.
• the reaction can be carried out by treating a solution of a 1H- imidazo[4,5-c]quinolinol of Formula XXIH in a solvent such as DMF with sodium hydride and then adding a reagent of Formula ⁇ alide-Z-Y-R-j, ⁇ alide-Z-R 5 , Halide-Z-Y-X-Y-IU, or Halide-Z-Het.
• a solvent such as DMF
• a reagent of Formula ⁇ alide-Z-Y-R-j, ⁇ alide-Z-R 5 , Halide-Z-Y-X-Y-IU, or Halide-Z-Het can be isolated using conventional methods.
• reagents of Formulas Halide-Z-Y ⁇ and Halide-Z-Het are commercially available, for example, bromo-substituted ketones, esters, and heterocycles.
• Other reagents of Formulas Halide-Z-Y-IU, Halide-Z-R 5 , Halide-Z-Y-X-Y-R ⁇ and Halide-Z-Het 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 or
• Step (9) of Reaction Scheme I can alternatively be carried out by treating a 1H- imidazo[4,5-c]quinolinol of Formula XXJTI with an alcohol of Formula ⁇ O-Z-Y-IU, ⁇ O-Z-R 5 , or HO-Z-Het under Mitsunobu reaction conditions.
• Numerous alcohols of these formulas are commercially available, and others can be prepared using conventional synthetic methods.
• the reaction is conveniently carried out by out by adding triphenylphosphine and an alcohol of Formula HO-Z-Y-IU, HO-Z-Het, or HO-Z-R 5 , for example, l-(2-hydroxyethyl)pyrrolidin-2-one or l-(3-hydroxypropyl)pyrrolidin-2-one, to a solution of a lH-imidazo[4,5-c]quinolinol of Formula XXIH in a suitable solvent such as tetrahydrofuran and then slowly adding diisopropyl azodicarboxylate or diethyl azodicarboxylate.
• triphenylphosphine and an alcohol of Formula HO-Z-Y-IU, HO-Z-Het, or HO-Z-R 5 for example, l-(2-hydroxyethyl)pyrrolidin-2-one or l-(3-hydroxypropyl)pyrrolidin-2-one
• the reaction can be carried out at ambient temperature or at a sub- ambient temperature, such as 0 °C.
• the product can be isolated using conventional methods.
• hi step (10) of Reaction Scheme I an ether-substituted lH-imidazo[4,5-c]quinoline of Formula LX is oxidized to provide a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula X using a conventional oxidizing agent capable of forming N-oxides.
• the reaction is conveniently carried out by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula IX in a solvent such as dichloromethane or chloroform.
• the reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
• Step (11) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula X is animated to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula ⁇ .
• Step (11) can be carried out by the activation of an N-oxide of Formula X 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/?-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.
• ammonium hydroxide in the form of ammonium hydroxide
• ammonium salts such as ammonium carbonate, ammonium bicarbonate, and ammonium phosphate.
• the reaction is conveniently carried out by adding ammonium hydroxide to a solution of the N-oxide of Formula X in a suitable solvent such as dichloromethane or chloroform and then adding p- toluenesulfonyl chloride.
• the reaction can be carried out at ambient temperature.
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• step (11) can be carried out by the reaction of a lH-imidazo[4,5- c]quinoline-5N-oxide of Formula X with trichloroacetyl isocyanate followed by base- promoted hydrolysis of the resulting intermediate to provide a lH-imidazo[4,5-c]quinolin- 4-amine of Formula LT.
• the reaction is conveniently carried out in two steps by (i) adding trichloroacetyl isocyanate to a solution of the N-oxide of Formula X in a solvent such as dichloromethane and stirring at ambient temperature to provide an isolable amide intermediate, hi step (ii), a solution of the intermediate in methanol is treated with a base such as sodium methoxide or ammonium hydroxide at ambient temperature.
• a base such as sodium methoxide or ammonium hydroxide
• Steps (10) and (11) can alternatively be combined and carried out as a one-pot procedure by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula LX in a solvent such as dichloromethane or chloroform and then adding ammonium hydroxide and ?-toluenesulfonyl chloride without isolating the N-oxide of Formula X.
• a solvent such as dichloromethane or chloroform
• step (3) of Reaction Scheme II the benzyl group of the benzyloxy-lH-imidazo[4,5-c]quinolin-4-amine of Formula XXV is cleaved to provide a lH-imidazo[4,5-c]quinolinol of Formula XXVI, which is converted in step (4) to an ether-substituted lH-imidazo[4,5-c]quinolin-4-amine of Formula II.
• Steps (1), (2), (3), and (4) of Reaction Scheme II can be carried out as described for steps (10), (11), (8), and (9), respectively, of Reaction Scheme I.
• R ⁇ -N ⁇ 2 used in step (5) of Reaction Scheme I, may be substituted by a hydroxy or second amino group, which can be further functionalized before step (6) of Reaction Scheme I.
• the reaction can be conveniently carried out by adding the sulfonic anhydride to a solution of a benzyloxy-3-nitroquinolin-4-amine of Formula XX, in which R ⁇ has an amino substituent, and a base such as triethylamine in a suitable solvent such as dichloromethane.
• the reaction can be carried out at ambient temperature.
• Amines of Formula R 1 -N ⁇ 2 used in step (5) of Reaction Scheme I, may contain a protected functional group, such as a tert-butoxycarbonyl-protected amino group or a isopropylidene ketal-protected diol.
• the protecting group installed in step (5) may be removed later in Reaction Scheme I or Reaction Scheme II to reveal, for example, an amino substituent or a diol on the Ri group.
• An amino group introduced in this manner maybe functionalized as described above, if desired.
• Functional groups can also be installed at Ri using a variety of other known methods. See, for example, U.S. Patent Nos.
• A are as defined above, using a coupling reagent.
• the reaction is conveniently carried out by treating a solution of the lH-imidazo[4,5-c]quinoline of Formula IX, in which R 3 is
• reaction can be carried out at ambient temperature in a suitable solvent such as pyridine, and the product can be treated according to steps (10) and (11) of
• Reaction Scheme I to provide a compound of Formula II.
• an R 3 group in a compound of Formula IX may contain a -S- functional group, which can be oxidized to -S(O) 2 - in step (10) of Reaction Scheme I using an excess of the oxidizing agent.
• Step (11) of Reaction Scheme I may then be carried out to provide a compound of Formula LT, wherein R 3 contains a -S(O) 2 - functional group.
• compounds of the invention can be prepared according to
• Reaction Scheme HI where R, R ls 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
• reaction can be run at ambient temperature in a suitable solvent such as tetrahydrofuran, and the product can be isolated using conventional methods.
• a hydroxyalkylcarbamate of Formula XXVILT is converted to an iodoalkylcarbamate of Formula XXIX using conventional methods.
• the reaction is conveniently carried out by treating the hydroxyalkylcarbamate of Formula XXVi ⁇ with a solution of iodine, triphenylphosphine, and imidazole.
• the reaction can be run at ambient temperature in a suitable solvent such as dichloromethane, and the product can be isolated using conventional methods.
• a lH-imidazo[4,5-c]quinolinol of Formula XXm is treated with an iodoalkylcarbamate of Formula XXLX to provide an ether- substituted lH-imidazo[4,5-c] quinoline of Formula XXX.
• the reaction can be carried out according to the Williamson conditions described in step (9) of Reaction Scheme I, and the product can be isolated using conventional methods.
• a lH-imidazo[4,5-c]quinoline of Formula XXX is oxidized to a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XXXI, which is aminated to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXXII, which is a subgenus Formula VU.
• Steps (4) and (5) of Reaction Scheme HI can be carried out as described for steps (10) and (11), respectively, of Reaction Scheme I.
• step (5) the preferred conditions for amination are the activation of an N-oxide of Formula XXXI 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 XXXI in a suitable solvent such as dichloromethane and then adding p- toluenesulfonyl chloride and stirring at ambient temperature.
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• step (6) of Reaction Scheme ILT the Boc protecting group of a lH-imidazo[4,5- c]quinolin-4-amine of Formula XXXH is removed to provide an amino-substituted 1H- imidazo[4,5-c]quinolin-4-amine of Formula XXXILT, which is a subgenus of Formula VLTI.
• the reaction is conveniently carried out by adding a solution of hydrochloric acid in ethanol to the lH-imidazo[4,5-c]quinolin-4-amine of Formula XXXII.
• the reaction can be carried out at an elevated temperature, for example, the reflux temperature of the solvent.
• the product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
• step (7) of Reaction Scheme HI an amino-substituted lH-imidazo[4,5- c]quinolin-4-amine of Formula XXXI ⁇ is converted to a lH-imidazo[4,5-c]quinolin-l-yl compound of Formula ⁇ d, a subgenus of Formulas I and ⁇ , using conventional methods.
• an amino-substituted lH-imidazo[4,5-c]quinolin-4-amine of Formula XXXT ⁇ can react with an acid chloride of Formula R 4 C(O)Cl to provide a compound of Formula Hd in which R 3a is -Z-N(R 8 )-C(O)-R .
• a lH-imidazo[4,5-c]quinolin- 4-amine of Formula XXXLfl 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 ⁇ d in which R 3a is -Z-N(R 8 )-S(O) 2 -R .
• Numerous acid chlorides of Formula C(O)Cl, sulfonyl chlorides of Formula R 4 S(O) Cl, and sulfonic anhydrides of Formula (R S(O) 2 ) 2 O are commercially available; others can be readily prepared using known synthetic methods.
• reaction is conveniently carried out by adding the acid chloride of Formula R 4 C(O)Cl, sulfonyl chloride of Formula R S(O) 2 Cl, or sulfonic anhydride of Formula (R 4 S(O) 2 ) 2 O to a solution of the amino-substituted lH-imidazo[4,5-c]quinolin-4-amine of Formula
• XXXm in a suitable solvent such as chloroform, dichloromethane, or l-methyl-2- pyrrolidinone.
• a base such as triethylamine can be added.
• the reaction can be carried out at ambient temperature or a sub-ambient temperature such as 0 °C.
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• Amides of Formula ⁇ d can alternatively be prepared by treating an amino- substituted lH-imidazo[4,5-c]quinolin-4-amine of Formula XXX ⁇ I with a carboxylic acid of Formula R 4 C(O)O ⁇ in the presence of a coupling reagent.
• the reaction is conveniently carried out by adding a solution of a carboxylic acid of Formula R C(O)OH and a base such as triethylamine to a cooled solution of the amino-substituted lH-imidazo[4,5- c]quinolin-4-amine of Formula XXX ⁇ I and benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate.
• the reaction can be carried out in a suitable solvent such as dichloromethane at a sub-ambient temperature such as 0 °C.
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• Compounds of Formula ⁇ d where R 3a is -Z-R 5 and R 5 is — N — S(0) 2 N — C(O) R 7 or R 7 can be prepared by treating an amino-substituted lH-imidazo[4,5-c]quinolin-4-amine of Formula XXX ⁇ I, wherein R 8 is hydrogen, with a chloroalkanesulfonyl chloride of Formula Cl-R 7 S(O) 2 Cl or a chloroalkanoyl chloride of Formula Cl-R 7 C(O)Cl.
• the reaction is conveniently carried out by adding the chloroalkanesulfonyl chloride or chloroalkanoyl chloride to a solution of the amino-substituted lH-imidazo[4,5-c]quinolin- 4-amine of Formula XXXT ⁇ in a suitable solvent such as chloroform at ambient temperature.
• a suitable solvent such as chloroform at ambient temperature.
• the isolable intermediate chloroalkanesulfonamide or chloroalkanamide can then be treated with a base such as l,8-diazabicyclo[5.4.0]undec-7-ene in a suitable solvent such as DMF to effect the cyclization.
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• a base such as triethylamine can be added.
• the reaction can be carried out at ambient temperature or a sub-ambient temperature such as 0 °C.
• Sulfamides of Formula Hd where R 3a is -Z- ⁇ R ⁇ -Q ⁇ , Q is -S(O) 2 -N(R 8 )-, and Z, , and R 8 are as defined above, can be prepared by reacting a compound of Formula XXXi ⁇ 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 .
• sulfamides of Formula Hd can be prepared by reacting a compound of Formula XXXHI with a sulfamoyl chloride of formula R 4 (R 8 )N-S(O) 2 Cl.
• the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• Many amines of Formula HN(R 8 )R 4 and some sulfamoyl chlorides of formula R (R 8 )N-S(O) 2 Cl are commercially available; others can be prepared using known synthetic methods.
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• the alkylation is conveniently carried out in two parts by (i) adding an aldehyde or ketone to a solution of a amino-substituted lH-imidazo[4,5-c]quinolin-4-amine of Formula XXX ⁇ I or a salt thereof in a suitable solvent such as DMF in the presence of a base such as NN- diisopropylethylamine.
• a suitable solvent such as DMF
• a base such as NN- diisopropylethylamine
• 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 ambient temperature, and the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• R, Ri, R 2 , Rio, 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 3 is
• Steps (1) through (7) of Reaction Scheme LV can be run as described in steps (1) through (7) of Reaction Scheme HI to provide compounds of Formula He, a subgenus of Formulas I and H.
• a compound of Formula XXXV can react with a lH-imidazo[4,5- cjquinolinol of Formula XXHI under the Mitsunobu reaction conditions described in step (9) of Reaction Scheme I.
• step (4) of Reaction Scheme LV can be carried out according to the reaction conditions described in step (10) of Reaction Scheme I or by heating a solution of a compound of Formula XXXV ⁇ in a suitable solvent such as ethyl acetate with peracetic acid at a temperature such as 50 °C and then adding sodium metabisulfate.
• R, Ri, 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 ⁇ or -Z-Het'- Y-R4, wherein Het or Het' is attached to Z at a nitrogen atom.
• step (1) of Reaction Scheme V a lH-imidazo[4,5-c]quinolinol of Formula XXVI is treated with a dihalide of Formula I-Z-Cl or Br-Z-Cl using the Williamson conditions described in step (9) of Reaction Scheme I to provide a chloro-substituted compound of Formula XLI, a subgenus of Formulas I and H.
• the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
• step (2) of Reaction Scheme V a chloro-substituted compound of Formula XLI is treated with a cyclic secondary amine to provide a compound of Formula Hf, a subgenus of Formulas I and H.
• cyclic secondary amines are commercially available, such as unsubstituted or substituted aziridines, pyrrolidines, piperidines, mo ⁇ holines, thiazolidines, thiomo ⁇ holines, piperazines, azepanes, diazepanes, dihydroisoquinolines, octahydroisoquinolines, dihydroquinolines, octahydroquinolines, and dihydroimidazoles; others can be prepared using conventional methods.
• the reaction is conveniently carried out by adding a cyclic secondary amine to a compound of Fonnula XLI in a suitable solvent such as DMF.
• the reaction is conveniently carried out in the presence of a base such as potassium carbonate at an elevated temperature such as 65 °C.
• a base such as potassium carbonate
• the product of Formula Hf or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
• Compounds of Formula Hf are also prepared from lH-imidazo[4,5-c]quinolinols of
• Reaction Scheme V to provide a compound of Fonnula ⁇ f.
• the product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
• compositions of the invention contain a therapeutically effective amount of a compound or salt of the invention as 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.
• compositions of the invention will contain sufficient active ingredient 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.
• a variety of dosage forms may be used, such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
• the compounds or salts of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts of the invention 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.
• Compounds or salts of the invention have been shown to induce or inhibit the production of certain cytokines in experiments performed according to the tests set forth below.
• Cytokines whose production maybe induced by the administration of compounds or salts of the invention generally include interferon- ⁇ (IFN- ⁇ ) and/or tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (TL).
• 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.
• the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal.
• the animal to which the compound or salt or composition 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 of the invention 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.
• Compounds or salts of the invention can also have an effect on the acquired immune response. For example, the production of the T helper type 1 (Tjjl) cytokine IFN- ⁇ may be induced indirectly and the production of the T helper type 2 (T H 2) cytokines LL-4,
• IL-5, and IL-13 may be inhibited upon administration of the compounds or salts.
• Other cytokines whose production may be inhibited by the administration of compounds or salts of the invention include tumor necrosis factor- ⁇ (TNF- ⁇ ).
• TNF- ⁇ tumor necrosis factor- ⁇
• inhibition of TNF- ⁇ production can provide prophylaxis or therapeutic treatment of TNF- ⁇ mediated diseases in animals, making the compounds or salt useful in the treatment of, for example, autoimmune diseases.
• the invention provides a method of inl ⁇ biting TNF- ⁇ biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal.
• the animal to which the compound or salt or composition is administered for inhibition of TNF- ⁇ biosynthesis may have a disease as described infra, for example an autoimmune 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.
• 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 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 IRMs identified herein may be used as treatments include, but are not limited to: (a) viral diseases such as, for example, diseases resulting from infection by an adenovirus, a he ⁇ esvirus (e.g., HSV-I, HSV-H, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
• 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
• a flavivirus e.g., hepatitis C virus or Dengue virus
• a retrovirus e.g., a lentivirus such as HLV
• bacterial diseases such as, for example, diseases resulting from infection by bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria,
• 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 myelogeous leukemia
• an IRM compound or salt of the present invention 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, men
• Certain IRM compounds or salts of the present invention may be particularly helpful in individuals having compromised immune function.
• certain 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 HLV 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 amount of a compound or salt effective to induce or inhibit 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, LFN- ⁇ , TNF- ⁇ , IL-1, IL-6, L -10 and EL- 12 that is increased (induced) or decreased (inhibited) 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 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 or composition 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.
• Part B A mixture of 5- ⁇ [(3-benzyloxy)phenylimino]methyl ⁇ -2,2-dimethyl-[ 1 ,3]-dioxane- 4,6-dione (170.65 g, 0.483 mol) and DOWTHERM A heat transfer fluid (800 mL) was heated to 100 °C and then slowly added to a flask containing DOWTHERM A heat transfer fluid (1.3 L, heated at 210 °C) over a period of 40 minutes. During the addition, the reaction temperature was not allowed to fall below 207 °C. Following the addition, the reaction was stirred at 210 °C for one hour, and then allowed to cool to ambient temperature.
• a precipitate formed which was isolated by filtration, washed with diethyl ether (1.7 L) and acetone (0.5 L), and dried in an oven to provide 76.5 g of 7- benzyloxyquinolin-4-ol as a tan powder.
• Part C A mixture of 7-benzyloxyquinolin-4-ol (71.47 g, 0.2844 mol) and propionic acid (700 mL) was heated to 125 °C with vigorous stirring. Nitric acid (23.11 mL of 16 M) was slowly added over a period of 30 minutes while maintaining the reaction temperature between 121 °C and 125 °C. After the addition, the reaction was strrred at 125 °C for 1 hour then allowed to cool to ambient temperature. The resulting solid was isolated by filtration, washed with water, and dried in an oven for 1.5 days to provide 69.13 g of 7- benzyloxy-3-nitroquinolin-4-ol as a grayish powder.
• Part i The material from Part ⁇ was dissolved in dichloromethane (800 mL), and concentrated ammonium hydroxide (300 mL) was added. j?-Toluenesulfonyl chloride (16.6 g, 86.8 mmol) was added in small portions to the resulting mixture, and the reaction was stirred for 30 minutes and then diluted with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
• Part A The general procedure described in Part A of Example 1 was used with the following modification.
• the addition of this solution was carried out over a period of one hour while maintaining the temperature between 57-60 °C.
• the reaction product, 5- ⁇ [(4-benzyloxy)phenylimino)]methyl ⁇ -2,2- dimethyl-[l,3]-dioxane-4,6-dione (136.7 g) was isolated as a yellow powder.
• Part D The general method described in Part D of Example 1 was used to convert 6- benzyloxy-3-nitroquinolin-4-ol (46.93 g, 158.4 mmol) to 6-benzyloxy-4-chloro-3- nitroquinoline, which was isolated as a tan solid containing some DMF.
• Part F (6-Benzyloxy-3-nitroquinolin-4-yl)propylamine (18.00 g, 53.35 mmol), 5% platinum on carbon (5.3 g), toluene (200 mL) and 2-propanol (20 mL) were added to a Parr vessel. The vessel was purged with nitrogen and then placed under hydrogen pressure
• reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol (2 L).
• the filtrate was concentrated under reduced pressure, and the resulting orange oil was dissolved in toluene and concentrated under reduced pressure to provide 10.7 g of 2-ethoxymethyl-l -propyl- lH-imidazo[4,5- c]quinolin-8-ol as a granular, orange solid.
• Part M mCPBA 50% pure, 12.76 g, 44.36 mmol
• tert-butyl [2-(2-ethoxymethyl-l-propyl-lH-imidazo[4,5-c]quinolin-8- yloxy)ethyl]carbamate 14.4 g, 33.6 mmol
• chloroform 150 mL
• the reaction mixture was stirred for 30 minutes.
• the reaction mixture was then poured into saturated aqueous sodium carbonate (100 mL) and stirred for 30 minutes.
• Methanesulfonic anhydride (0.265 g, 1.52 mmol) was added in one portion to a solution of 8-(2-aminoethoxy)-2-ethoxymethyl-l-propyl-lH-imidazo[4,5-c]quinolin-4- amine (0.500 g, 1.46 mmol) in dichloromethane (10 mL), and the reaction was stirred for 30 minutes. A precipitate fonned. Aqueous sodium hydroxide (25 mL of 10%) was added, and the mixture was strrred for 20 minutes. The aqueous layer was separated and extracted with dichloromethane.
• the reaction was stirred at 0 °C for 30 minutes, allowed to warm to ambient temperature, stirred for two hours, and poured into water.
• the aqueous layer was extracted with dichloromethane.
• the combined organic fractions were washed sequentially with water (2 x) and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
• the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 96:4) to provide the desired product and a bis amide by-product.
• the bis amide by-product was treated with IN aqueous hydrochloric acid, heated at reflux for 1.5 hours, and cooled to 0 °C.
• Part B The general methods described in Parts j and K of Example 2 were used to prepare 16.2 g of tert-butyl 3-iodopropylcarbamate from 3 -amino- 1 -propanol (6.55 g, 8.72 mmol); the product was isolated as a yellow solid.
• Part C A modification of the general method described in Part L of Example 2 was used to treat l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7-ol with tert-butyl 3- iodopropylcarbamate. The reaction mixture was diluted with water; a precipitate formed.
• the precipiate was isolated by filtration, washed with water and then with diethyl ether until the filtrate was clear, and dried overnight in a vacuum oven at 60 °C to yield tert- butyl 3- ⁇ [l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7- yl]oxy ⁇ propylcarbamate as a tan powder.
• Part D The general methods described in Parts M and N of Example 2 were used to convert tert-butyl 3- ⁇ [l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7- yl]oxy ⁇ propylcarbamate to tert-butyl 3- ⁇ [4-amino-l-(2-methylpropyl)-2-propyl-lH- imidazo[4,5-c]quinolin-7-yl]oxy ⁇ propylcarbamate, which was isolated as off-white crystals, mp 162.5-164 °C.
• Part A The preparation of 7-benzyloxy-N 4 -(2-methylpropyl)quinoline-3,4-diamine is described in Parts A-F of Example 1. Under a nitrogen atmosphere, triethyl orthoacetate (4.59 mL, 25.0 mmol) was added to a solution of 7-benzyloxy-N 4 -(2- methylpropyl)quinoline-3,4-diamine (8.05 g, 25.0 mmol) in xylenes (130 mL), and the resulting solution was heated at reflux (160 °C) overnight. The solvent volume was reduced to 70 mL using a Dean-Stark trap. Over a period of a few days, a precipitate formed.
• Part D The general methods described in Parts M and N of Example 2 were followed using tert-butyl 2- ⁇ [2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-7- yl]oxy ⁇ ethylcarbamate as the starting material.
• the crude product was recrystallized from ethanol to yield 1.29 g of tert-butyl 2- ⁇ [4-amino-2-methyl-l-(2-methylpropyl)-lH- imidazo[4,5-c]quinolin-7-yl]oxy ⁇ ethylcarbamate as a yellow-orange solid, mp 226.9-228.2 °C.
• Methanesulfonic anhydride (0.245 g, 1.41 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5- c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 18 hours. Saturated aqueous sodium bicarbonate was added, and the reaction was stirred for 20 minutes. The aqueous layer was separated and extracted with chloroform. The combined organic fractions were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
• Example 11 The general method described in Example 11 was used to convert 7-(3- aminopropoxy)-2-methyl- 1 -(2-methylpropyl)- IH-imidazo [4,5-c] quinolin-4-amine to 0.014 g of N- ⁇ 2-[4-amino-2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-7- yloxy] ethyl ⁇ methanesulfonamide, which was obtained as a white solid.
• Example 13 7- [3 -( 1 , 1 -Dioxidoisothiazolidin-2-yl)propoxy] - 1 -(2-methylpropyl)-2-propyl- IH- imidazo [4,5-c] quinolin-4-amine
• 2-(l-Naphthyl)ethanesulfonyl chloride (0.358 g, 1.40 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-l-(2-methylpropyl)-2-propyl-lH- imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 30 minutes. Triethylamine (0.250 mL, 1.79 mmol) was then added. The reaction mixture was poured into saturated aqueous sodium carbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
• the resulting pale yellow oil was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 94:6) and subsequent recrystallization from acetonitrile to yield 0.341 g ofN-(3- ⁇ [4-amino-l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7- yl]oxy ⁇ propyl)-2-(l-naphthyl)ethanesulfonamide as white crystals, mp 164-168 °C.
• Example 15 The method described in Example 15 was used to convert 7-(2-aminoethoxy)-2- methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-4-amine to 0.170 g of N- ⁇ 2-[4- amino-2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-7-yloxy]ethyl ⁇ -2- methylpropanamide, which was isolated as flocculent, white crystals, mp 205-206 °C.
• Part B The general methods described in Parts M and N of Example 2 were used to convert the material from Part A to 0.120 g of l- ⁇ 2-[4-amino- 1 -(2-methylpropyl)-2- propyl-lH-imidazo[4,5-c]quinolin-7-yloxy]ethyl ⁇ pyrrolidin-2-one, which was obtained as tan, granular crystals, mp 206-208 °C.
• Example 19 The general method described in Example 19 was used to convert 7-(3- aminopropoxy)-l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-4-amine to N-(3- ⁇ [4-amino-2-propyl- 1 -(2-methylpropyl)- IH-imidazo [4,5-c] quinolin-7- yl]oxy ⁇ propyl)mo ⁇ holine-4-carboxamide, which was isolated as a white solid, mp 145
• Part A The general methods described in Parts J and K of Example 2 were used to prepare tert-butyl 4-(2-iodoethyl)piperidine-l-carboxylate, which was isolated as a yellow oil.
• Part B The general method described in Part L of Example 2 was used to treat l-(2- methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7-ol with tert-butyl 4-(2- iodoethyl)piperidine-l-carboxylate.
• tert-butyl 4-(2- ⁇ [l-(2- methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7-yl]oxy ⁇ ethyl)piperidine-l- carboxylate was isolated as a gray-brown solid and used without purification.
• Part C The general methods described in Parts M and N of Example 2 were used to aminate tert-butyl 4-(2- ⁇ [l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7- yl]oxy ⁇ ethyl)piperidine-l-carboxylate.
• Part A The general method described in Part L of Example 2 was used to treat 2-methyl- 1- (2-methylpropyl)-lH-imidazo[4,5-c]quinolin-7-ol with tert-butyl 4-(2- iodoethyl)piperidine-l -carboxylate. After chromatographic purification, tert-butyl 4-(2- ⁇ [2-methyl- 1 -(2-methylpropyl)- lH-imidazo[4,5-c] quinolin-7-yl]oxy ⁇ ethyl)piperidine- 1 - carboxylate was isolated as a viscous, orange oil.
• Part B The general methods described in Parts M and N of Example 2 were used to aminate tert-butyl 4-(2- ⁇ [2-methyl- 1 -(2-methylpropyl)- IH-imidazo [4,5-c] quinolin-7- yl] oxy ⁇ ethyl)piperidine-l -carboxylate (3.6 g, 9.8 mmol).
• Part C The general method described in Part O of Example 2 was used to convert the material from Part B to 1.93 g of 2-methyl- l-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)- lH-imidazo[4,5-c]quinolin-4-amine, which was isolated as a tan solid.
• 1H NMR 300 MHz, DMSO-rf*
• Example 25 7- ⁇ 2-[ 1 -(Methanesulfonyl)piperidin-4-yl] ethoxy ⁇ -2-methyl- 1 -(2-methylpropyl)- 1H- imidazo[4,5-c]quinolin-4-amine
• Example 11 The general method described in Example 11 was used to convert 2-methyl- 1 -(2- methylpropyl)-7-(2-piperidin-4-ylethoxy)-lH-imidazo[4,5-c]quinolin-4-amine to 0.150 g of7- ⁇ 2-[l-(methanesulfonyl)piperidin-4-yl]ethoxy ⁇ -2-methyl-l-(2-methylpropyl)-lH- imidazo[4,5-c]quinolin-4-amine, which was isolated as an off-white powder.
• Example 15 The general method described in Example 15 was used to convert 2-methyl- 1 -(2- methylpropyl)-7-(2-piperidin-4-ylethoxy)-lH-imidazo[4,5-c]quinolin-4-amine to 0.158 g of l-(4- ⁇ 2-[4-amino-2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-7- yloxy]ethyl ⁇ piperidin-l-yl)-2-methylpropan-l-one, which was isolated as an off-white solid, mp 205.1-207.1 °C.
• Example 15 The general method described in Example 15 was used to treat 2-methyl- 1 -(2- methylpropyl)-7-(2-piperidin-4-ylethoxy)-lH-imidazo[4,5-c]quinolin-4-amine with cyclopentanecarbonyl chloride to provide 0.158 g of 7- ⁇ 2-[l- (cyclopentylcarbonyl)piperidin-4-yl] ethoxy ⁇ -2-methyl- 1 -(2-methylpropyl)- IH- imidazo [4,5-c] quinolin-4-amine, which was isolated as an off-white solid, mp 235.7-238.1 °C.
• Part B The general method described in Part J of Example 1 was followed using 7- benzyloxy-2-ethyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinoline (3.43 g, 9.54 mmol) in lieu of 7-benzyloxy-l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-4-amine.
• the reaction was heated at reflux overnight, and a Dean-Stark trap was used to collect the volatiles.
• the reaction was then heated at 170 °C for 4.5 hours, and about 100 mL of solvent were removed by distillation.
• the reaction mixture was allowed to cool to ambient temperature; a precipitate formed over a period of three days.
• the mixture was diluted with hexanes, and the precipitate was isolated by filtration and washed with hexanes to provide 15.64 g of 8-benzyloxy-2-butyl-l-methyl-lH-imidazo[4,5-c]quinoline.
• Part D A modification of the general method described in Part J of Example 1 was followed using 8-benzyloxy-2-butyl-l-methyl-lH-imidazo[4,5-c]quinoline (14.65 g, 42.4 mmol) in lieu of 7-benzyloxy-l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-4- amine.
• the reaction was placed under hydrogen pressure for 3.5 hours.
• the catalyst was removed by filtration and washed with ethyl acetate.
• the filtrate was concentrated under reduced pressure to a small volume, and hexanes were added. A precipitate formed, and the mixture was stored overnight in a refrigerator.
• Part F A modification of the general method described in Part D of Example 30 was followed using 2-butyl-l-methyl-lH-imidazo[4,5-c]quinolin-8-ol (1.2 g, 4.7 mmol) in lieu of2-ethyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-7-ol and 4-(5- bromopentanoyl)mo ⁇ holine (3.7 mmol) in lieu of 4-(2-bromoacetyl)mo ⁇ holine. After the reaction was heated overnight, an analysis by TLC indicated the presence of starting material.
• Part G The general method described in Part E of Example 30 was used to convert 2- butyl-l-methyl-8-[(5-mo ⁇ holin-4-yl-5-oxopentyl)oxy]-lH-imidazo[4,5-c]quinoline (0.770 g, 1.81 mmol) to 2-butyl-l-methyl-8-[(5-mo ⁇ holin-4-yl-5-oxopentyl)oxy]-5-oxido-lH- imidazo[4,5-c]quinoline, obtained as mixture with starting material.
• Micromass Platform LC/MS and the appropriate fractions were centrifuge evaporated.
• the prep ⁇ PLC separation was done by reversed phase chromatography with a Phenomenex Luna C18(2) column (10 50 mm, 5 micron particle size) at a flow rate of 16 mL/min.
• the mobile phase was a gradient mixture of water and acetonitrile (0.05% trifluoroacetic acid in each) from 5 to 95% acetonitrile in 6.5 minutes.
• Part A The general methods described in Parts C-E of Example 30 were followed. According to the method of Part C the amine listed in the table below was used to prepare the bromo reagent listed in the table below. According to the method of Part D, 2-butyl-l- methyl-lH-imidazo[4,5-c]quinolin-8-ol was treated with the bromo reagent, and the product was oxidized according to the method of Part E. For Example 35, the crude product isolated after Part D was recrystallized from water. Chromatographic purification as described in Part E was carried out only for Example 36; the remaining N-oxides were used without purification.
• Example 33 2-Butyl-l-methyl-8-(2-oxo-2-piperidin-l-ylethoxy)-lH-imidazo[4,5-c]quinolin-4-amine
• the crude product was recrystallized from methyl acetate and dried for four hours in a vacuum oven at 45 °C to provide 2-butyl-l-methyl-8-(2-oxo-2-piperidin-l-ylethoxy)- lH-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 222.5-223.4 °C.
• Example 34 2-[(4-Amino-2-butyl-l-methyl-lH-imidazo[4,5-c]quinolin-8-yl)oxy]-N-benzyl-N- methylacetamide
• the crude product was recrystallized from a mixture of DMF and water to provide 2-[(4-amino-2-butyl-l-methyl-lH-imidazo[4,5-c]quinolin-8-yl)oxy]-N-benzyl-N- methylacetamide as an off-white solid, mp 167.4-168.8 °C.
• Example 35 2-[(4-Amino-2-butyl-l-methyl-lH-imidazo[4,5-c]quinolin-8-yl)oxy]-NN- diethylacetamide
• the crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol). The pure fractions were concentrated under reduced pressure to a small volume, and hexanes were added.
• Example 36 2-[(4-Amino-2-butyl-l-methyl-lH-imidazo[4,5-c]quinolin-8-yl)oxy]-N,N-bis(2- methoxyethyl)acetamide
• the product from the reaction with sodium methoxide did not precipitate from the reaction solution.
• the solvent was removed under reduced pressure, and the residue was recrystallized from 2-propanol, isolated by filtration, washed with hexanes, stined with water for two hours, isolated by filtration, and washed with water.
• the solid was then recrystallized twice from methanol, purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol), and recrystallized from dimethyl sulfoxide to provide 2-[(4-amino-2-butyl-l-methyl-lH-imidazo[4,5-c]quinolin-8-yl)oxy]-N,N-bis(2- methoxyethyl)acetamide as a peach-colored, crystalline solid, mp 125-128 °C.
• Part A The method described in Part L of Example 2 was used to treat 2-butyl-l-methyl- lH-imidazo[4,5-c]quinolin-8-ol with tert-butyl 4-(2-iodoethyl)piperidine-l -carboxylate. Following chromatographic purification, tert-butyl 4-[2-(4-amino-2-butyl-l-methyl-lH- imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidine-l-carboxylate was isolated as a viscous, pale yellow oil containing some DMF.
• Part B The methods described in Parts M and N of Example 2 were used to convert tert- butyl 4-[2-(4-amino-2-butyl-l-methyl-lH-imidazo[4,5-c]quinolin-8- yloxy)ethyl]piperidine-l -carboxylate to tert-butyl 4-[2-(4-amino-2-butyl-l -methyl- 1H- imidazo[4,5-c]quinolin-8-yloxy)ethyl]piperidine-l-carboxylate, which was obtained as an off-white powder, mp 171.1-173.2 °C.
• Example 15 A modification of the method described in Example 15 was followed.
• the reaction solvent was l-methylpyrrolidin-2-one, and 2-butyl-l-methyl-8-(2-piperidin-4-ylethoxy) ⁇ lH-imidazo[4,5-c]quinolin-4-amine was used as the starting material.
• l- ⁇ 4-[2-(4-amino-2-butyl-l-methyl-lH-imidazo[4,5- c]quinolin-8-yloxy)ethyl]piperidin-l-yl ⁇ -2-methylpropan- 1 -one was isolated as yellow needles, mp 189.4-192.6 °C.
• Example 15 A modification of the method described in Example 15 was used to treat 2-butyl-l- methyl-8-(2-piperidin-4-ylethoxy)-lH-imidazo[4,5-c]quinolin-4-amine with cyclopentanecarbonyl chloride.
• the crude product was purified by column chromatography on silica gel to provide 2-butyl-8- ⁇ 2-[l-(cyclopentylcarbonyl)piperidin-4- yl]ethoxy ⁇ -l-methyl-lH-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 147.2-150.1 °C.
• Example 19 A modification of the method described in Example 19 was followed.
• the reaction solvent was l-methylpyrrolidin-2-one, and 2-butyl-l-methyl-8-(2-piperidin-4-ylethoxy)- lH-imidazo[4,5-c]quinolin-4-amine was used as the starting material.
• the reaction mixture was poured into water, and a precipitate formed.
• Part B The general method described in Part E of Example 30 was used to convert N- ⁇ 2-
• Part A 7-Benzyloxy-l,2-dimethyl-lH-imidazo[4,5-c]quinoline was prepared according to the methods described in Parts A-C of Example 31.
• triethyl orthoformate was used in lieu of trimethyl orthovalerate.
• a solution of 7-benzyloxy-l,2- dimethyl- 1H- imidazo[4,5-c]quinoline in ethanol was added to a Parr vessel with 10% palladium on carbon. The reaction was placed under hydrogen pressure (35 psi, 2.4 x 10 5 Pa) for 20 hours. The reaction mixture was then filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid with heating, and the hot solution was filtered and concentrated under reduced pressure.
• the resulting beige solid was dissolved in 1 ⁇ aqueous hydrochloric acid, and deactivated carbon was added. The solution was heated, filtered, and treated with 50% aqueous sodium hydroxide. A precipitate formed and was isolated by filtration to provide 1,2- dimethyl-lH-imidazo[4,5-c]quinolin-8-ol as a solid, mp > 300 °C.
• Part B Sodium hydride (0.61 g, 15 mmol, available as a 60% dispersion in mineral oil) was added to a solution of l,2-dimethyl-lH-imidazo[4,5-c]quinolin-8-ol (2.5 g, 12 mmol) in DMF.
• the reaction mixture was stined for 30 minutes, and ethyl bromoacetate (1.96 g, 11.7 mmol) was added. The stirring was continued for five hours, and a small volume of ethanol was added. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed three times with deionized water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow solid was recrystallized from ethyl acetate to provide 1.65 g of ethyl 2-[(l,2-dimethyl-lH-imidazo[4,5-c]quinolin-8-yl)oxy]acetate as a white solid.
• Example 1 E of Example 1. l,2-Diamino-2-methylpropane (5.29 mL, 50.6 mmol) was used in lieu of isobutylamine. After the work-up, the crude product was passed through a layer of silica gel (eluting sequentially with chloroform and 96:4 chloroform:methanol) to provide 12.4 g of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine as a yellow solid.
• silica gel eluting sequentially with chloroform and 96:4 chloroform:methanol
• the reaction was stirred for an additional 90 minutes, and additional methanesulfonic anhydride (0.7 g, 4 mmol) was added.
• the reaction was stined for an additional three hours, and saturated aqueous sodium bicarbonate (200 mL) was added. A precipitate began to form in the organic layer, which was separated and concentrated under reduced pressure to provide a yellow solid.
• reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with acetonitrile. The filtrate was concenfrated under reduced pressure. Toluene and dichloromethane were added and removed under reduced pressure twice to yield 12.6 g of N-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-l,l- dimethylethyl]methanesulfonamide as a solid.
• Triethylamine 13 mL was added, and the reaction was heated at reflux overnight and allowed to cool to ambient temperature. The volatiles were removed under reduced pressure. The residue was dissolved in dichloromethane (300 mL), and the resulting solution was washed with water (2 x 100 mL) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil.
• the oil was purified by column chromatography on silica gel (eluting with 97.5:2.5 chloroform:methanol) to provide 12.4 g of N-[2-(7-benzyloxy-2- ethoxymethyl- lH-imidazo[4,5-c] quinolin- 1 -yl)- 1 , 1 -dimethylethyl]methanesulfonamide as a beige solid.
• reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol and methanol.
• the filtrate was concentrated under reduced pressure, and the residue was several times dissolved in toluene and concentrated under reduced pressure to yield a yellow powder, which was dried under high vacuum to provide 7.37 g of N-[2-(2- ethoxymethyl-7-hydroxy- IH-imidazo [4, 5 -c] quinolin- 1 -yl)- 1,1- dimethylethyl]methanesulfonamide as a yellow solid.
• Part F The methods described in Parts J and K of Example 2 were followed using 6- amino-1-hexanol (62 g, 0.53 mmol) in lieu of 2-aminoethanol to provide tert-butyl 6- iodohexylcarbamate as a light-yellow oil.
• Part G The general method described in Part L of Example 2 was followed.
• the crude product was purified by column chromatography on silica gel (eluting sequentially with 95:5 and 92.5:7.5 dichloromethane methanol) to provide 8.5 g of tert-butyl ⁇ 6-[2-ethoxymethyl-l-(2- methanesulfonylamino-2-methylpropyl)-lH-imidazo[4,5-c]quinolin-l- yloxy]hexyl ⁇ carbamate as a white solid.
• Part ⁇ A modificaton of the method described in Part M of Example 2 was used to convert tert-butyl ⁇ 6-[2-ethoxymethyl- 1 -(2-methanesulfonylamino-2-methylpropyl)- 1H- imidazo[4,5-c]quinolin-l-yloxy]hexyl ⁇ carbamate (8.5 g, 14.4 mmol) to tert-butyl ⁇ 6-[2- ethoxymethyl-l-(2-methanesulfonylamino-2-methylpropyl)-5-oxido-lH-imidazo[4,5- c]quinolin-l-yloxy]hexyl ⁇ carbamate, which was obtained as a orange solid.
• Part J A modification of the method described in Part O of Example 2 was used to deprotect tert-butyl ⁇ 6-[4-amino-2-ethoxymethyl-l-(2-methanesulfonylamino-2- methylpropyl)-lH-imidazo[4,5-c]quinolin-l-yloxy]hexyl ⁇ carbamate with hydrochloric acid in ethanol (50 mL of 4.25 M).
• reaction solution was washed with saturated aqueous sodium bicarbonate (2 x) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
• the residue was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane :methanol) and recrystallization from dichloroethane. The crystals were partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with dichloromethane.
• Part C A modification of the method described in Part E of Example 1 was used to treat 7- benzyloxy-4-chloro-3-nitroquinoline (14.4 g, 45.8 mmol) withN-(4- aminobutyl)methanesulfonamide hydrochloride (10.2 g, 50.4 mmol) and triethylamine
• Part D The method described in Part C of Example 45 was used to convert N-[4-(3-nitro- 7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide (16.8 g, 37.8 mmol) to 15.1 g of N- [4-(3 -amino-7-benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide, which was obtained as a dark yellow solid.
• Part E The method described in Part D of Example 45 was used to treat N-[4-(3-amino-7- benzyloxyquinolin-4-ylamino)butyl]methanesulfonamide (15.1 g, 36.5 mmol) with butyryl chloride (4.77 mL, 46.2 mmol).
• the crude product was purified by column chromatography on silica gel (eluting with 96:4 chloroform:methanol containing ammonium hydroxide) to provide 11.8 g of N-[4-(7-benzyloxy-2-propyl-lH-imidazo[4,5- c]quinolin-l-yl)butyl]methanesulfonamide as a tan solid.
• Part F The method described in Part E of Example 45 was used to convert N-[4-(7- benzyloxy-2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide (7.60 g, 16.3 mmol) to 5.75 g of N-[4-(7-hydroxy-2-propyl-lH-imidazo[4,5-c]quinolin-l- yl)butyl]methanesulfonamide, which was obtained as a light-yellow solid.
• Part G The general method described in Part L of Example 2 was followed.
• N-[4-(7- hydroxy-2-propyl-lH-imidazo[4,5-c]quinolin-l-yl)butyl]methanesulfonamide (5.75 g, 15.3 mmol) was treated with tert-butyl 6-iodohexylcarbamate (5.50 g, 16.8 mmol).
• the crude product was purified by column chromatography on silica gel (eluting sequentially with 95:5 and 92.5:7.5 dichloromethane :methanol) to provide 6.19 g of tert-butyl (6- ⁇ l-[4- (methanesulfonylamino)butyl] -2-propyl- IH-imidazo [4,5-c] quinolin- 1 - yloxy ⁇ hexy ⁇ )carbamate as a yellow solid.
• PartH A modification of the method described in Part M of Example 2 was used to convert tert-butyl (6- ⁇ l-[4-(methanesulfonylamino)butyl]-2-propyl-lH-imidazo[4,5- c]quinolin-l-yloxy ⁇ hexyl)carbarnate (2.51 g, 4.36 mmol) to 2.54 g of tert-butyl (6- ⁇ l-[4- (methanesulfonylamino)butyl]-5-oxido-2-propyl-lH-imidazo[4,5-c]quinolin-l- yloxy ⁇ hexyl)carbamate, which was obtained as a yellow solid. The reaction was allowed to run overnight, and the product was used without purification.
• Part i The method described in Part I of Example 45 was used to convert tert-butyl (6- ⁇ l- [4-(methanesulfonylamino)butyl]-5-oxido-2-propyl-lH-imidazo[4,5-c]quinolin-l- yloxy ⁇ hexyl)carbamate (2.54 g, 4.29 mmol) to 2.51 g of tert-butyl (6- ⁇ 4-amino- 1 -[4- (methanesulfonylamino)butyl]-2 -propyl- lH-imidazo[4,5-c]quinolin-l- yloxy ⁇ hexyl)carbamate, obtained as a tan solid. Part I The method described in Part J of Example 45 was used to deprotect tert-butyl (6-
• Part K A modification of the method described in Part K of Example 45 was followed using N- ⁇ 4-[4-amino-7-(6-aminohexyloxy)-2-propyl-lH-imidazo[4,5-c]quinolin-l- yl]butyl ⁇ methanesulfonamide (0.86 g, 1.8 mmol) as the starting material. Methanesulfonic anhydride (470 mg, 2.7 mmol) was added over a period of 24 hours.
• the crude product was purified by column chromatography on silica gel (eluting sequentially with 90:10 and 85:15 dichloromethane-.methanol), recrystallization from ethyl acetate, and a second recrystallization from 2-propanol to provide 0.38 g of N-(4- ⁇ 4-amino-7-[6- (methanesulfonylamino)hexyloxy] -2-propyl- IH-imidazo [4,5-c] quinolin- 1 - yl ⁇ butyl)methanesulfonamide as a white powder, mp 138-140 °C.
• Part B The method described in Part C of Example 45 was used to convert the material from Part B to 6.16 g of N-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-l,l- dimethylethyl] acetamide, obtained as an orange solid.
• Part C A modification of the method described in Part D of Example 45 was followed using N- [2-(3 -amino-7-benzyloxyquinolin-4-ylamino)- 1 , 1 -dimethylethyl] acetamide (6.16 g, 21.0 mmol) as the starting material. A solution of the intermediate in ethanol was heated at reflux for 24 hours.
• the resulting orange solid was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane :methanol) to provide 4.79 g ofN-[2-(7-benzyloxy-2-ethoxymethyl-lH-imidazo[4,5-c]quinolin-l-yl)-l,l- dimethylethyl] acetamide as a yellow solid.
• Part D The method described in Part E of Example 45 was used to convert N-[2-(7- benzyloxy-2-ethoxymethyl-lH-imidazo[4,5-c] quinolin- 1 -yl)- 1 , 1 -dimethylethyl] acetamide (4.79 g, 10.7 mmol) to N-[2-(2-ethoxymethyl-7-hydroxy- IH-imidazo [4,5-c] quinolin- 1 -yl)- 1,1 -dimethylethyl] acetamide, obtained as a yellow solid.
• Part E The method described in Part L of Example 2 was followed. The material from
• Part D was treated with tert-butyl 6-iodohexylcarbamate (3.86 g, 11.8 mmol), and the reaction was complete in four hours.
• the crude product was purified by column chromatography on silica gel (eluting sequentially with 95:5 and 92.5:7.5 dichloromethane:methanol), and the resulting solid was dried overnight under high vacuum to provide 4.69 g of tert-butyl ⁇ 6-[l-(2-acetylamino-2-methylpropyl)-2- ethoxymethyl-lH-imidazo[4,5-c]quinolin-7-yloxy]hexyl ⁇ carbamate as an off-white solid.
• Part F A modificaton of the method described in Part M of Example 2 was used to convert tert-butyl ⁇ 6-[l-(2-acetylamino-2-methylpropyl)-2-ethoxymethyl-lH-imidazo[4,5- c]quinolin-7-yloxy]hexyl ⁇ carbamate (4.69 g, 8.44 mmol) to tert-butyl ⁇ 6-[l-(2- acetylamino-2-methylpropyl)-2-ethoxymethyl-5-oxido-lH-imidazo[4,5-c]quinolin-7- yloxy]hexyl ⁇ carbamate, obtained as a orange solid. The reaction was complete in one hour, and the product was used without purification.
• Part G The method described in Part I of Example 45 was used to convert the material from Part F to 4.85 g of tert-butyl ⁇ 6-[l-(2-acetylamino-2-methylpropyl)-4-amino-2- ethoxymethyl-lH-imidazo[4,5-c]quinolin-7-yloxy]hexyl ⁇ carbamate, obtained as an orange solid.
• Part ⁇ A modification of the method described in Part O of Example 2 was used to deprotect the material from Part G with hydrochloric acid in ethanol (100 mL of 3 M).
• Part i A modification of the method described in Part K of Example 45 was followed using N- ⁇ 2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-lH-imidazo[4,5-c]quinolin-l- yl]-l,l-dimethylethyl ⁇ acetamide (1.2 g, 2.5 mmol) as the starting material.
• the reaction was run in l-methyl-2-pyrrolidone (55 mL), and after completion, the reaction was poured into deionized water (400 mL) and stined over three days.
• the mixture was extracted with dichloromethane (3 x 200 mL), and the combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
• the residue was dissolved in diethyl ether (100 mL) and treated with a solution of hydrochloric acid in ethanol. A solid formed, and the diethyl ether was decanted. The solid was partitioned between dichloromethane and dilute ammonium hydroxide. The aqueous layer was separated and extracted with dichloromethane (3 x 100 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
• Part A The methods described in Parts A- ⁇ , M, and ⁇ of Example 2 were followed using
• Part B 7-Benzyloxy-2-ethoxymethyl-l-propyl-lH-imidazo[4,5-c]quinolin-4-amine (3.9 g, 9.99 mmol) was mixed with ethanol and added to a Pan flask charged with 10% palladium on carbon (0.390 g) in ethanol. The flask was placed under hydrogen pressure and shaken for 18 hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with warm DMF.
• Part C The method described in Part L of Example 2 was used to treat 4-amino-2- ethoxymethyl-l-propyl-lH-imidazo[4,5-c]quinolin-7-ol (1.89 g, 6.29 mmol) with cesium carbonate (4.10 g, 12.6 mmol) and tert-butyl 2-iodoethylcarbamate (1.79 g, 6.60 mmol).
• Part A The methods described in Parts E, F, and G of Example 1 were used to convert 7- benzyloxy-4-chloro-3-nitroquinoline, prepared in Parts A-D of Example 1, to 7-benzyloxy- 2-ethyl-l-(2-phenoxyethyl)-lH-imidazo[4,5-c]quinoline.
• 2-Phenoxyethylamine was used in lieu of isobutylamine in Part E, and triethyl orthopropionate was used in lieu of trimethyl orthobutyrate in Part G.
• Part B The method described in Part I of Example 1 was used to convert 7-benzyloxy-2- ethyl- 1 -(2-phenoxyethyl)- lH-imidazo[4,5-c] quinoline to 2-ethyl- 1 -(2-phenoxyethyl)- IH- imidazo [4,5-c] quinolin-7-ol.
• Part D The method described in Part M of Example 2 was used to oxidize 1- [2-ethyl- 1 -(2- phenoxyethyl)-lH-imidazo[4,5-c]quinolin-7-yloxy]-3,3-dimethylbutan-2-one (1.3 g, 3.0 mmol) to 1.4 g of l-[2-ethyl-5-oxido-l-(2-phenoxyethyl)-lH-imidazo[4,5-c]quinolin-7- yloxy]-3,3-dimethylbutan-2-one, which was isolated as an orange solid and used without purification.
• Part A The methods described in Parts A-D of Example 30 were used to convert 7- benzyloxy- ⁇ -(2-phenoxyethyl)quinoline-3 ,4-diamine to 2-ethyl-7-(2-mo ⁇ holin-4-yl-2- oxoethoxy)-l-(2-phenoxyethyl)-lH-imidazo[4,5-c]quinoline.
• Part D after the reaction mixture was filtered, the filtrate was allowed to stand for three days. Crystals formed and were isolated by filtration and washed with diethyl ether. The filtrate was concentrated under reduced pressure, and the resulting oil with triturated with a mixture of ethyl acetate and water.
• Part B The method described in Part E of Example 30 was used to convert 2-ethyl-7-(2- mo ⁇ holin-4-yl-2-oxoethoxy)-l-(2-phenoxyethyl)-lH-imidazo[4,5-c]quinoline (0.855 g, 1.86 mmol) to 0.92 g of 2-ethyl-7-(2-mo ⁇ holin-4-yl-2-oxoethoxy)-5-oxido-l-(2- phenoxyethyl)-lH-imidazo[4,5-c]quinoline.
• Part L The methods described in Parts L-N of Example 2 were used to treat l-(2- methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-7-ol.
• 2- (bromomethyl)tetrahydro-2 ⁇ -pyran was used as the alkylating agent.
• the crude product was recrystallized from acetonitrile to yield l-(2-methylpropyl)-2-propyl-7- (tetrahydropyran-2-ylmethoxy)-lH-imidazo[4,5-c]quinolin-4-amine as tan crystals, mp 126 °C (decomposition).
• Part C The method described in Part E of Example 52 was used to aminate the material from Part B.
• the crude product was recrystallized from acetonitrile to afford 0.242 g of 1- (2-methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-lH-imidazo[4,5-c]quinolin-4- amine as white needles, mp 178-182 °C.
• the prep ⁇ PLC fractions were analyzed using a Micromass LC-TOFMS, and the appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the desired compound.
• the table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt.
• Examples 93-129 The method described for Examples 57-92 was used to treat l-(2-methylpropyl)-7- (2-piperidin-4-ylethoxy)-2-propyl-lH-imidazo[4,5-c]quinolin-4-amine with acid chlorides.
• the table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt.
• Examples 130-161 The method described for Examples 57-92 was used to treat 8-(2-aminoethoxy)-2- ethoxymethyl-l-propyl-lH-imidazo[4,5-c]quinolin-4-amine with acid chlorides. The table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt. Examples 130-161
• Examples 162-189 The method described for Examples 57-92 was used to freat 7-(3-aminopropoxy)- l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]qu ⁇ nolin-4-amine with sulfonyl chlorides.
• the table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt.
• Examples 190-217 The method described for Examples 57-92 was used to freat l-(2-methylpropyl)-7- (2-piperidin-4-ylethoxy)-2-propyl-lH-imidazo[4,5-c]quinolin-4-amine with sulfonyl chlorides.
• the table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt.
• Examples 218-242 The method described for Examples 57-92 was used to treat 8-(2-aminoethoxy)-2- ethoxymethyl- 1 -propyl- 1 H-imidazo [4,5-c] quinolin-4-amine with sulfonyl chlorides .
• the table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt.
• Examples 243-284 The method described for Examples 57-92 was used to treat 7-(3-aminopropoxy)- l-(2-methylpropyl)-2-propyl-lH-imidazo[4,5-c]quinolin-4-amine with isocyanates or carbamoyl chlorides.
• the table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt.
• Examples 285-322 The method described for Examples 57-92 was used to treat l-(2-methylpropyl)-7- (2-piperidin-4-ylethoxy)-2-propyl-lH-imidazo[4,5-c]quinolin-4-amine with isocyanates or carbamoyl chlorides. The table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt. Examples 285-322
• Examples 323-365 The method described for Examples 57-92 was used to treat 8-(2-aminoethoxy)-2- ethoxymethyl-l-propyl-lH-imidazo[4,5-c]quinolin-4-amine with isocyanates or carbamoyl chlorides. The table below shows the structure made in each example and the observed accurate mass for the isolated trifluoroacetate salt. Examples 323-365
• Example 366 4-Amino-2-(2-methoxyethyl)- 1 -propyl- IH-imidazo [4,5-c] quinolin-7-yl isopropylcarbamate
• Part A The methods described in Parts A-I of Example 2 were followed using 3- benzyloxyaniline in lieu of 4-benzyloxyaniline and methoxypropionyl chloride in lieu of ethoxyacetyl chloride.
• 2-(2-Methoxyethyl)-l-propyl-lH-imidazo[4,5-c]quinolin-7-ol (2.0 g, 7.0 mmol), 4-(dimethylamino)pyridine (0.085 g, 0.70 mmol), and tetrahydrofuran (70 mL) were combined, and the mixture was cooled to 7 °C with an ice/water bath.
• Isopropyl isocyanate (0.689 mL, 7.01 mmol) was added dropwise to the mixture. After 20 minutes the cooling bath was removed and the reaction was stined for an additional 24 hours. Analysis by ⁇ PLC indicated that no product had formed. Di-butyltin dilaurate (1 drop) was added, and the reaction was siured at ambient temperature for 2.5 hours and then heated at reflux for 48 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane. The organic fraction was washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
• Part C The material from Part B was combined with N-(2- ⁇ [3-amino-7- (benzyloxy)quinolin-4-yl] amino ⁇ - 1 , 1 -dimethylethyl)-N-isopropylurea from another experiment, suspended in toluene, and concentrated under reduced pressure.
• the N-(2- ⁇ [3-amino-7- (benzyloxy)quinolin-4-yl] amino ⁇ - 1 , 1 -dimethylethyl)-N-isopropylurea from another experiment, suspended in toluene, and concentrated under reduced pressure.
• the N-(2- ⁇ [3-amino-7- (benzyloxy)quinolin-4-yl] amino ⁇ - 1 , 1 -dimethylethyl)-N-isopropylurea from another experiment, suspended in toluene, and concentrated under reduced pressure.
• Part G The material from Part F was converted into 4.20 g of tert-butyl 6- ⁇ [4-amino-2- (ethoxymethyl)- 1 -(2- ⁇ [(isopropylamino)carbonyl] amino ⁇ -2-methylpropyl)- 1H- imidazo[4,5-c]quinolin-7-yl]oxy ⁇ hexylcarbamate using the method described in Part I of Example 45.
• N-isopropylurea as a dark orange solid.
• Part i Isopropyl isocyanate (190 ⁇ L, 1.93 mmol) was added to a stirred solution of N- ⁇ 2- [4-amino-7-[(6-aminohexyl)oxy] -2-(ethoxymethyl)- IH-imidazo [4,5-c] quinolin- 1 -yl] -1,1- dimethylethyl ⁇ -N-isopropylurea (0.90 g, 1.75 mmol) in dichloromethane (50 mL) at 0 °C. After approximately 30 minutes, the solution was allowed to warm to room temperature.
• Acetyl chloride (180 ⁇ L, 2.53 mmol) was added to a stirred solution of N- ⁇ 2-[4- amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl ⁇ -N-isopropylurea (prepared as described in Parts A- ⁇ of Example 369, 1.18 g, 2.30 mmol) and triethylamine (0.64 mL, 4.60 mmol) in dichloromethane (100 mL) at 0 °C. After approximately 20 minutes, the solution was allowed to warm to room temperature and was stined overnight.
• Methanesulfonic anhydride (0.34 g, 1.93 mmol) was added to a stined solution of N- ⁇ 2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l- yl]-l,l-dimethylethyl ⁇ -N-isopropylurea (prepared as described in Parts A- ⁇ of Example
• the crude product was purified by flash chromatography (silica gel, elution with 10% methanol in dichloromethane) followed purification by chromatography on a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Virginia, USA) (silica gel, gradient elution with 0-40% CMA in chloroform where CMA is a solution of 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) to yield 0.31 g of N-(6- ⁇ [4- amino-2-(ethoxymethyl)- 1 -(2- ⁇ [(isopropylamino)carbonyl] amino ⁇ -2-methylpropyl)- 1H- imidazo[4,5-c]quinolin-7-yl]oxy ⁇ hexyl)methanesulfonamide as an off white solid, mp 190-194°C.
• Triethylamine 25.53 mL, 183.17 mmol was added to a solution of 7-benzyloxy- N 4 -[(2,2-dimethyl[l,3]dioxolan-4-yl)methyl]quinoline-3,4-diamine (55.60 g, 146.54 mmol) in dichloromethane (500 mL) at 0 °C.
• ethoxyacetyl chloride 22.45 g, 183.17 mmol
• reaction mixture was concenfrated under reduced pressure and the residue was added to a mixture of triethylamine (61.3 mL, 440 mmol) in ethanol (350 mL) and heated to reflux for 16 hours.
• the reaction mixture was concentrated under reduced pressure, extracted with dichloromethane (3 x 300 mL), washed with water (300 mL) and brine (300 mL) and dried over sodium sulfate.
• the crude material was purified by flash column chromatography (silica gel, eluted with 5% CMA in chloroform) and concentrated under reduced pressure to give 42.5 g of material as a brown solid.
• the mixture was cooled to 0 °C and/7-toluenesulfonyl chloride (4.04 g, 21.2 mmol) was added in portions.
• the reaction mixture was allowed to warm to room temperature and was stined for 16 hours, then was diluted with dichloromethane (200 mL) and washed with 2 M aqueous sodium carbonate (2 x 150 mL). The aqueous layer was back-extracted with dichloromethane (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.
• Examples 376-386 A reagent (0.10 mmol, 1.1 equivalents) from the table below was added to a test tube containing a solution of 3-[4-amino-7-(2-aminoethoxy)-2-(ethoxymethyl)-lH- imidazo[4,5-c]quinolin-l-yl]propane-l,2-diol dihydrochloride (43 mg, 0.09 mmol, prepared as described in Example 373) and NN-diisopropylethylamine (0.051 mL, 0.29 mmol) in NN-dimethylacetamide (1 mL). The test tubes were capped and shaken for 8 hours at room temperature and then two drops of water were added to each test tube.
• the solvent was removed by vacuum centrifugation.
• the compounds were purified by preparative high performance liquid chromatography (prep ⁇ PLC) using a Waters FractionLynx automated purification system.
• the prep ⁇ PLC 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 preparative liquid chromatography 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 reagent added to each test tube, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
• Part A A modification on the methods described in Parts A- ⁇ of Example 2 were used to prepare 2-(2-methoxyethyl)-l-propyl-lH-imidazo[4,5-c]quinolin-7-ol, with 3- benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of 4-benzyloxyaniline and ethoxyacetyl chloride, respectively.
• Example 388 4- ⁇ [4- Amino-2-(2-methoxyethyl)- 1 -propyl- IH-imidazo [4,5-c] quinolin-7-yl] oxy ⁇ -N- isopropylpiperidine- 1 -carboxamide
• Trimethylsilylisocyanate (0.225 mL, 1.67 mmol) was added dropwise to a slurry of
• Part A A modification on the methods described in Parts A- ⁇ of Example 2 were used to prepare 2-(2-methoxyethyl)-l-propyl-lH-imidazo[4,5-c]quinolin-7-ol, with 3- benzyloxyaniline and 3-methoxypropanoyl chloride used in lieu of 4-benzyloxyaniline and ethoxyacetyl chloride, respectively.
• Diisopropyl azodicarboxylate (2.07 mL, 10.5 mmol) was added dropwise to a slurry of 2-(2-methoxyethyl)-l-propyl-lH-imidazo[4,5- c]quinolin-7-ol (2.00 g, 7.01 mmol), triphenylphosphine (2.75 g, 10.5 mmol), and 3- (methylthio)propan-l-ol (1.08 mL, 10.5 mmol) in tetrahydrofuran (70 mL) at 0 °C. The solution was stined for 30 minutes at 0 °C, then at room temperature for 16 hours.

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