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WO2006028451A1 - 1-amino 1-h-imidazoquinolines - Google Patents

1-amino 1-h-imidazoquinolines Download PDF

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Publication number
WO2006028451A1
WO2006028451A1 PCT/US2004/028754 US2004028754W WO2006028451A1 WO 2006028451 A1 WO2006028451 A1 WO 2006028451A1 US 2004028754 W US2004028754 W US 2004028754W WO 2006028451 A1 WO2006028451 A1 WO 2006028451A1
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Prior art keywords
group
imidazo
amino
alkyl
quinolin
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Inventor
George W. Griesgraber
Karl J. Manske
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3M Innovative Properties Co
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3M Innovative Properties Co
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Priority to PCT/US2004/028754 priority Critical patent/WO2006028451A1/fr
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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention provides compounds of the Formulas 1-1 and II- 1 :
  • R 1 ', R 1 , R 2 , R 3 , R, R A , n, and m are as defined below; and pharmaceutically acceptable salts thereof.
  • the compounds of Formulas 1-1 and II- 1 are useful as immune response modifiers (IRMs) due to their ability to modulate 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.
  • IRMs immune response modifiers
  • 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.
  • 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.
  • 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 cytokine biosynthesis in animal cells, treating a viral disease in an animal, and/or treating a neoplastic disease in an animal by administering to the animal one or more compounds of the Formulas 1-1 and/or II- 1, and/or pharmaceutically acceptable salts thereof.
  • the present invention provides compounds of the Formulas 1-1 and II- 1:
  • R 1 ', Rj, R 2 , R 3 , R, R A , n, and m are as defined below; and pharmaceutically acceptable salts thereof.
  • the present invention provides compounds of the following Formula I-l:
  • Ri 1 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 1 is bonded; Ri is selected from the group consisting of:
  • R 2 is selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl,
  • R 3 is selected from the group consisting of: -Z'-RV, -Z'-X'-R t ', -Z'-X'-Y'-R ⁇ , and -Z'-X'-R 5 '; each R is independently selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino; n is an integer from 0 to 4; m is 0 or 1; with the proviso that when m is 1, then n is 0, 1, or 2; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl
  • R 5 is selected from the group consisting of:
  • X is C 2-20 alkylene
  • Y is selected from the group consisting Of -C(R 7 )-, -C(R 7 )O-, -S(O) 2 -, -S(O) 2 -N(R 6 )-, and -C(R 7 )-N(Rg)-; wherein R9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or Rg and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
  • Z is selected from the group consisting of -O- and -S(0)o -2 -;
  • A is selected from the group consisting of -CH(R 6 )-, -O-, -N(Rg)-, -N(Y-R 4 )-, and -N(X-N(Rg)-Y-R 4 )-;
  • a and b are independently integers from 1 to 4 with the proviso that when A is
  • a and b are independently integers from 2 to 4;
  • R 4 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
  • X 1 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 by 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 -, '
  • Z' is a bond or -O-
  • a 1 is selected from the group consisting Of-CH 2 -, -O-, -C(O)-, -S(O) 0-2 -, and -N(R 4 1 )-;
  • Q is selected from the group consisting of a bond, -C(R 7 )-, -C(R 7 )-C(R 7 )-, -S(O) 2 -, -C(R 7 )-N(R n )-W-, -S(O) 2 -N(R 11 )-, -C(R 7 )-O-, and -C(R 7 )-N(OR 12 )-;
  • V is selected from the group consisting Of -C(R 7 )-, -0-C(R 7 )-, -N(R ⁇ )-C(R 7 )-, and -S(O) 2 -;
  • R 12 is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of the following
  • each RA is independently selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, -NH 2 , -NH(alkyl), and
  • n is an integer from 0 to 4.
  • R 1 ' is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 ' is bonded;
  • Ri is selected from the group consisting of: -R 4 , -Y-R 4 , -X-R 5 , -X-N(Rs)-Y-R 4 ,
  • R 1 ' and Ri together with the nitrogen atom to which they are bonded can join to form a group selected from the group consisting of:
  • R 2 is selected from the group consisting of: hydrogen, , alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH, halogen,
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with
  • A is selected from the group consisting Of -CH(R 6 )-, -O-, -N(R 6 )-, -N(Y-R 4 )-, and -N(X-N(Re)-Y-R 4 )-;
  • X is C 2-2O alkylene
  • Y is selected from the group consisting Of -C(R 7 )-, -C(R 7 )-O-, -S(O) 2 -, -S(O) 2 -N(R 6 )-, and -C(Rv)-N(R 9 )-; wherein R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which Rg is bonded can join to form the group
  • Z is selected from the group consisting of -O- and -S(0)o -2 -; and a and b are independently integers from 1 to 4 with the proviso that when A is
  • a and b are independently integers from 2 to 4; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound selected from the group consisting of:
  • the compound or salt is selected from the group consisting of:
  • the compound or salt is N-(3- ⁇ [4-Amino-2-
  • the compound or salt is selected from the group consisting of: l-( ⁇ - ⁇ [4-Amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yl]amino ⁇ propyl)-3-isopropylurea;
  • Ri' is selected from the group consisting of alkoxyalkylenyl and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which
  • Ri' is bonded.
  • n is 0.
  • R 3 is selected from the group consisting of -Z'-RV, -Z'-X'-RV, and
  • R 3 is selected from the group consisting of hydroxy, 2-(pyridin-3-yl)ethyl, pyridinyl, (hydroxymethyl)pyridinyl, phenyl,
  • R 3 is selected from the group consisting of 2-(pyridin-3-yl)ethyl, pyridinyl,
  • R 1 ' is selected from the group consisting of alkoxyalkylenyl and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which Ri' is bonded.
  • n is 0.
  • Ri is ' selected from the group consisting Of-R 4 , -Y-R 4 , and -X-N(Re)-Y-R 4 wherein Y is -C(R 7 )-, -S(O) 2 -, or -C(R 7 )-N(R 9 )-.
  • Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, alkylaminocarbonyl, alkylaminocarbonylaminoalkylenyl, arylaminocarbonyl, (arylalkylenyl)ammoalkylenyl, heterocyclylcarbonylaminoalkylenyl, arylaminocarbonylaminoalkylenyl, heteroarylcarbonylaminoalkylenyl, and
  • Ri is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, 3-phenylpropyl, cinnamyl, furan-2- ylmethyl, and -CH 2 CH 2 CH 2 -NHRi 3 , wherein R 13 is selected from the group consisting of methylcarbonyl, isopropylcarbonyl, cyclopentylcarbonyl, tetrahydropyran-4-ylcarbonyl, methanesulfonyl, phenylsulfonyl, benzyl, ethylaminocarbonyl, isopropylaminocarbonyl, mo ⁇ holine-4-carbonyl, phenylaminocarbonyl, pyridm-3-ylcarbonyl, and pyridin-3
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, 2-methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, and 3- hydroxypropyl.
  • the present invention provides compounds of the following Formula VTI:
  • each R B is independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, and trifluoromethyl; n is an integer from 0 to 4; R 2 is selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl,
  • each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
  • Z is selected from the group consisting of -O- and -S(0)o -2 -; or a pharmaceutically acceptable salt thereof.
  • R 2 is selected from the group consisting of alkyl and alkenyl substituted by one or more substituents selected from the group consisting of -N(R 6 )-C(R 7 )-aryl, -N(Re)-S(O) 2 -aryl, -O-C(R 7 )-C 1-10 alkyl, -O-C(R 7 )-aryl, -0-C(R 7 )-N(R 6 )-CM O alkyl, and -O-C(R 7 )-N(R 6 )-aryl.
  • the present invention provides intermediate compounds of the following Formula IX:
  • Ri is selected from the group consisting of: -R 4 ,
  • R 1 ' and Ri together with the nitrogen atom to which they are bonded can join to form a group selected from the group consisting of:
  • R 2 is selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl,
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with
  • A is selected from the group consisting Of -CH(R 6 )-, -0-, -N(R 6 )-, -N(Y-R 4 )-, and -N(X-N(Re)-Y-R 4 )-;
  • X is C 2-20 alkylene
  • Y is selected from the group consisting Of-C(R 7 )-, -C(R 7 )-0-, -S(O) 2 -, -S(O) 2 -N(R 6 )-, and -C(Rz)-N(Rg)-; wherein R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which Rg is bonded can join to form the group
  • Z is selected from the group consisting of -O- and -S(0)o -2 -; and a and b are independently integers from 1 to 4 with the proviso that when A is
  • a and b are independently integers from 2 to 4; or a pharmaceutically acceptable salt thereof.
  • R 1 ' is selected from the group consisting of alkoxyalkylenyl and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 1 is bonded.
  • R 2 is selected from the group consisting of alkyl and alkenyl substituted by one or more substituents selected from the group consisting of -N(R 6 )-C(R 7 )-aryl, -N(Re)-S(O) 2 -aryl, -O-C(R 7 )-C M0 alkyl, -O-C(R 7 )-aryl, -O-C(R 7 )-N(R 6 )-C M0 alkyl, and -O-C(R 7 )-N(R 6 )-aryl.
  • the present invention also provides intermediate compounds of the following Formula X:
  • each R B is independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, and trifluoromethyl; n is an integer from 0 to 4; R 1 ' is hydrogen or alkyl; R 1 a is selected from the group consisting of:
  • Ri 1 and Rj 3 together with the nitrogen atom to which they are bonded can join to form a group selected from the group consisting of:
  • R 2a is selected from the group consisting of:
  • R t e is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 43 is a substituted alkyl group and the substituent contains a hetero
  • R 5 is selected from the group consisting of
  • A is selected from the group consisting Of -CH(R 6 )-, -0-, -N(Rg)-, -N(Y-R 4 )-, and -N(X-N(Re)-Y-R 4 )-;
  • X is C 2-20 alkylene; Y is selected from the group consisting Of -C(R 7 )-, -C(R 7 )-O-, -S(O) 2 -,
  • R 9 is selected from the group consisting of hydrogen, alkyl and arylalkylenyl, or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
  • — Z" is selected from the group consisting of -O- and -S(O) 2 -; and a and b are independently integers from 1 to 4 with the proviso that when A is
  • R 1 ' is selected from the group consisting of alkoxyalkylenyl and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which
  • R 1 ' is bonded.
  • the present invention provides intermediate compounds of the following Formula XLII:
  • R is selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino; l is O, I, or 2; R 2 is selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH, halogen, -N(Re) 2 ,
  • each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
  • R 2 is selected from the group consisting of alkyl and alkenyl substituted by one or more substituents selected from the group consisting of -N(R 6 )-C(R 7 )-aryl, -N(R 6 )-S(O) 2 -aryl, -0-C(R 7 )-Ci.io alkyl, -O-C(R 7 )-aryl, -O-C(R 7 )-N(R 6 )-Ci -10 alkyl, and -O-C(R 7 )-N(R 6 )-aryl.
  • 1 is 0 or 1. In certain of these embodiments, 1 is 1.
  • the present invention provides intermediate compounds of the following Formula XLIII:
  • R is selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino; 1 is 0, 1 or 2;
  • R 1 ' is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 1 is bonded;
  • Ri is selected from the group consisting of: -R 4 , -Y-R 4 , -X-R 5 ,
  • R 1 ' and Ri together with the nitrogen atom to which they are bonded can join to form a group selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with
  • R 5 is selected from the group consisting of
  • X is C 2-20 alkylene
  • Y is selected from the group consisting of -C(R 7 )-, -C(R 7 )-O-, -S(O) 2 -, -S(O) 2 -N(R 6 )-, and -C(R 7 )-N(R 9 )-; wherein Rg is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
  • Z is selected from the group consisting of -O- and -S(O) 0-2 -; and a and b are independently integers from 1 to 4 with the proviso that when A is -O-, -N(R 6 )-, -N(Y-R 4 )-, or -N(X-N(Re)-Y-R 4 )- then a and b are independently integers from 2 to 4; or a pharmaceutically acceptable salt thereof.
  • R 1 1 is selected from the group consisting of alkoxyalkylenyl and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which Ri' is bonded.
  • R 2 is selected from the group consisting of alkyl and alkenyl substituted by one or more substituents selected from the group consisting of -N(R 6 )-C(R 7 )-aryl, -N(R 6 )-S(O) 2 -aryl, -O-C(R 7 )-C 1-10 alkyl, -O-C(R 7 )-aryl, -O-C(R 7 )-N(R 6 )-Ci.i 0 alkyl, and -O-C(R 7 )-N(R 6 )-aryl.
  • 1 is 0 or 1. In certain of these embodiments, 1 is 0.
  • each one of the following variables e.g., R, RJ 1 , Ri, R 2 , R 3 , R A , RB, m, n, A, X, X 1 , Y, Y', and so on
  • each one of the following variables e.g., R, RJ 1 , Ri, R 2 , R 3 , R A , RB, m, n, A, X, X 1 , Y, Y', and so on
  • each of the resulting combinations of variables is an embodiment of the present invention.
  • R is selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino.
  • R is halogen or hydroxy.
  • R A is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, -NH 2 , -NH(alkyl), and -N(alkyl) 2 .
  • R B is selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, and trifluoromethyl.
  • R B is halogen or hydroxy.
  • R 1 ' is selected from the group consisting of alkoxyalkylenyl and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 ' is bonded.
  • R 1 1 is hydroxyalkylenyl.
  • R 1 1 is 2-hydroxyethyl.
  • Ri is selected from the group consisting Of -R 4 , -Y-R 4 , -X-R 5 , -X-N(Re)-Y-R 4 , -X-C(R 7 VN(Rg)-R 4 , -X-O-C(R 7 J-N(Re)-R 4 , -X-S(O) 2 -N(Re)-R 4 , and -X-O-R 4 .
  • Ri is selected from the group consisting of -R 4 , -Y-R 4 , -X-R 5 , -X-N(Re)-Y-R 4 , -X-C(R 7 VN(Re)-R 4 , and -X-O-R 4 ; and R 1 1 is selected from the group consisting of hydrogen and alkyl.
  • R 1 is selected from the group consisting Of -R 4 , -Y-R 4 , -X-R 5 , -X-N(Re)-Y-R 4 , -X-C(R 7 )-N(R 6 )-R 4 , and -X-O-R 4 .
  • Ri is selected from the group consisting Of -R 4 , -Y-R 4 , and -X-N(R 6 J-Y-R 4 wherein Y is -C(R 7 )-, -S(O) 2 -, or -C(R 7 J-N(R 9 J-.
  • Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylaminocarbonyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, and arylaminocarbonylaminoalkylenyl.
  • Ri is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, cinnamyl, furan-2-ylmethyl, and -CH 2 CH 2 CH 2 -NHRi 3 , wherein R 13 is selected from the group consisting of methanesulfonyl, phenylsulfonyl, benzyl, and phenylaminocarbonyl.
  • Ri is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylaminocarbonyl, alkylaminocarbonylaminoalkylenyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, heterocyclylcarbonylaminoalkylenyl, and arylaminocarbonylaminoalkylenyl.
  • R 1 is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, 3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and -CH 2 CH 2 CH 2 -NHRJ 3 , wherein R 13 is selected from the group consisting of methanesulfonyl, phenylsulfonyl, benzyl, isopropylaminocarbonyl, morpholine-4-carbonyl, and phenylaminocarbonyl.
  • R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, alkylaminocarbonyl, alkylaminocarbonylaminoalkylenyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, heterocyclylcarbonylaminoalkylenyl, arylaminocarbonylaminoalkylenyl, heteroarylcarbonylaminoalkylenyl, and heteroarylaminocarbonylamino
  • R 1 is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, 3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and -CH 2 CH 2 CH 2 -NHR 13 , wherein R 13 is selected from the group consisting of methylcarbonyl, isopropylcarbonyl, cyclopentylcarbonyl, tetrahydropyran-4-ylcarbonyl, methanesulfonyl, phenylsulfonyl, benzyl, ethylaminocarbonyl, isopropylaminocarbonyl, morpholine-4-carbonyl, phenylaminocarbonyl, pyridin-3-ylcarbonyl, and pyridin-3- ylaminocarbonyl.
  • R 13 is selected from
  • R 1 ' is selected from the group consisting of hydrogen and alkyl
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of -OH, -halogen, -N(R 6 ) 2 , -C(R 7 )-N(Rg) 2 , -S(O) 2 -N(Re) 2 , -N(Re)-C(R 7 )-C 1-10 alkyl, -N(Re)-S(O) 2
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of -OH, halogen, -N(Re) 2 , -C(R 7 )-N(R 6 ) 2 , -S(O) 2 -N(Re) 2 ,
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of -OH, halogen, -N(R 6 ) 2 , -C(Ry)-N(Re) 2 , -S(O) 2 -N(Re) 2 , -N(Re)-C(Ry)-Ci -I0 alkyl, -N(Re)-S(O) 2 -Cj -10 alkyl, -C(O)-Ci -I0 alkyl, -C(O)-O-C M0 alkyl, -N 3 , aryl, heteroaryl, heterocyclyl, -C(O)-ary
  • R 2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.
  • R 2 is selected from the group consisting of hydrogen, butyl, 2-methoxyethyl, and ethoxymethyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, propyl, butyl, 2-methoxyethyl, and ethoxymethyl.
  • R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, 2-methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.
  • R 3 is selected from the group consisting of -Z'-RV,
  • R 3 is selected from the group consisting of -Z'-RV, -Z-X-R 4 ', and -Z'-X'-Y'-R ⁇ .
  • R 3 is selected from the group consisting of hydroxyl, 2- (pyridin-3-yl)ethyl, pyridinyl, (hydroxymethyl)pyridinyl, phenyl, (hydroxymethyl)phenyl, ethoxyphenyl, (morpholine-4-carbonyl)phenyl, 3-(methanesulfonylamino)phenyl, 2-
  • R 3 is selected from the group consisting of 2-(pyridin-3-yl)ethyl, pyridinyl, (hydroxymethyl)pyridinyl, phenyl, (hydroxymethyl)phenyl, ethoxyphenyl, (morpholine-4-carbonyl)phenyl, 3-(methanesulfonylamino)phenyl, 2- (methanesulfonylamino)ethoxy, 3-(methanesulfonylamino)propoxy, and benzyloxy.
  • R 3 is selected from the group consisting of 2-(pyridin-3-yl)ethyl, pyridinyl, (hydroxymethyl) ⁇ yridmyl, ethoxyphenyl, (morpholine-4-carbonyl)phenyl, 2- (methanesulfonylamino)ethoxy, and benzyloxy.
  • R'" is R or R 3 when n is 1 , R or one R and one R 3 when n is 2, R or two R's and one R 3 when n is 3, or R when n is 4.
  • R'" is R or R 3 when n is 1 , R or one R and one R 3 when n is 2, or R when n is 3 or 4.
  • R"' is R 3 .
  • R 3 is selected from the group consisting of -Z'-RV, -Z'-X'-RV, and -Z'-X'-Y'-RV.
  • R'" is selected from the group consisting of hydroxyl, 2- (pyridin-3-yl)ethyl, pyridinyl, (hydroxymethyl)pyridinyl, phenyl, (hydroxymethyl)phenyl, ethoxyphenyl, (morpholine-4-carbonyl)phenyl, 3-(methanesulfonylamino)phenyl, 2- (methanesulfonylamino)ethoxy, 3-(methanesulfonylamino)propoxy, and benzyloxy.
  • R 1 " is selected from the group consisting of 2-(pyridin-3- yl)ethyl, pyridinyl, (hydroxymethyl)pyridinyl, phenyl, (hydroxymethyl)phenyl, ethoxyphenyl, (morpholine-4-carbonyl)phenyl, 3-(methanesulfonylamino)phenyl, 2- (methanesulfonylamino)ethoxy, 3-(methanesulfonylamino)propoxy, and benzyloxy.
  • R'" is selected from the group consisting of 2-(pyridin-3- yl)ethyl, pyridinyl, (hydroxymethyl)pyridinyl, ethoxyphenyl, (morpholine-4- carbonyl)phenyl, 2-(methanesulfonylamino)ethoxy, and benzyloxy.
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, o
  • R 4 is selected from the group consisting of C 1-6 alkyl, arylalkylenyl, and heterocyclyl.
  • R 4 is C 2-6 alkyl.
  • 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 wherein the alkyl, alkeny
  • R 4 ' is hydrogen, alkyl, aryl, arylalkylenyl, heteroaryl, or heteroarylalkylenyl wherein the aryl and heteroaryl groups are unsubstituted or substituted by one or more of hydroxyalkyl or alkoxy.
  • R 5 is selected from the group consisting of:
  • R 5 ' is selected from the group consisting of:
  • R 5 ' is .
  • V is
  • A' is -O- and c and d are each the integer 2.
  • R 6 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl.
  • R 6 is hydrogen.
  • R 8 is C 2-7 alkylene.
  • Rg is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
  • R 9 is hydrogen
  • R 9 and R 4 together with the nitrogen atom to which R 9 is bonded join to form the group
  • R 10 is C 3-8 alkylene.
  • Rn is selected from the group consisting of hydrogen, Ci -10 alkyl, C 2 - 10 alkenyl, Ci -10 alkoxyC 2- i 0 alkylenyl, and arylCi.io alkylenyl.
  • Rn is hydrogen.
  • Ri 2 is selected from the group consisting of hydrogen and alkyl.
  • A is selected from the group consisting of -CH(R 6 )-, -O-, -N(R 6 )-, -N(Y-R 4 )-, and -N(X-N(Re)-Y-R 4 )-.
  • A is -O-.
  • A' is selected from the group consisting Of-CH 2 -, -O-,
  • A' is -O-.
  • Q is selected from the group consisting of a bond, -C(R 7 )-, -C(R 7 )-C(R 7 )-, -S(O) 2 -, -C(RT)-NCRH)-W-, -S(O) 2 -N(R 11 )-, -C(R 7 )-O-, and -C(R 7 )-N(ORi 2 )-.
  • Q is -S(O) 2 -.
  • V is selected from the group consisting of -C(R 7 )-,
  • V is -C(R 7 )-.
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -.
  • X is C 2-2O alkylene.
  • X is C 2-4 alkylene.
  • 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 by arylene, heteroarylene, or heterocyclylene and optionally interrupted by one or more -O- groups.
  • X' is C 1-4 alkylene.
  • Y is selected from the group consisting Of -C(R 7 )-, -C(R 7 )-0-, -S(O) 2 -, -S(O) 2 -N(R 6 )-, and -C(R 7 J-N(R 9 )-; wherein R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
  • a and b are independently integers from 1 to 4 with the proviso that when A is -O-, -N(R 6 )-, -N(Y-R 4 )-, or -N(X-N(R 6 J-Y-R 4 )- then a and b are independently integers from 2 to 4.
  • Y is selected from -C(R 7 )-, -S(O) 2 -, -S(O) 2 -N(R 6 )-, and -C(R 7 J-N(R 9 )-.
  • Y is -C(R 7 )-, -S(O) 2 -, and -C(R 7 J-N(R 9 )-.
  • Y' is selected from the group consisting Of -S(OJo -2 -, -S(O) 2 -N(R 11 )-, -C(R 7 )-, -C(R 7 J-O-, -0-C(R 7 J-, -0-C(O)-O-, -N(R n J-Q-, -C(R 7 J-N(R 11 J-,
  • Y' is -S(O) 2 -N(Rn)- or -C(R 7 )-.
  • R n is hydrogen
  • Z is selected from the group consisting of -O- and -S(0)o -2 -. F° r certain embodiments, Z is -0-.
  • Z' is a bond or -0-.
  • Z' is a bond.
  • Z' is -0-.
  • a and b are independently integers from 1 to 4 with the proviso that when A is -O-, -N(R 6 )-, -N(Y-R 4 )-, or -N(X-N(R ⁇ )-Y-R 4 )- then a and b are independently integers from 2 to 4.
  • a and b are each the integer 2.
  • c and d are independently integers from 1 to 6 with the proviso that c + d is ⁇ 7, and when A 1 is -O- or -N(R 4 ')- then c and d are independently integers from 2 to 4.
  • c and d are each the integer 2.
  • n is an integer from 0 to 4. For certain embodiments, n is 0. For certain embodiments, n is 1. For certain embodiments, n is 1 , and R B is halogen or hydroxy.
  • n is 0, 1, or 2.
  • m is 0 or 1; with the proviso that when m is 1, then n is 0, 1, or 2.
  • n is 0 or 1.
  • m is 1 and n is 0.
  • m is 0, and n is 0.
  • n is 1.
  • R is halogen or hydroxy.
  • alkyl As used herein, the terms "alkyl,” “alkenyl,” “alkynyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms.
  • Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.
  • alkylene "-alkylene-”, “alkenylene”, “-alkenylene-”, “alkynylene”, and “-alkynylene-” are the divalent forms of the “alkyl”, “alkenyl 11 , and “alkynyl” groups defined above.
  • alkylenyl “alkenylenyl”, and “alkynylenyl” are used when “alkylene”, “alkenylene”, and “alkynylene", respectively, are substituted.
  • an arylalkylenyl group comprises an "alkylene” moiety to which an aryl group is attached.
  • haloalkyl is inclusive of alkyl groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix "halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • aryl as used herein includes carbocyclic aromatic rings or ring systems.
  • 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).
  • Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl,
  • heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
  • exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl, homopiperazinyl, and the like.
  • arylene is the divalent forms of the "aryl”, “heteroaryl”, and “heterocyclyl” groups defined above.
  • arylenyl is used when “arylene”, “heteroarylene”, and “heterocyclylene”, respectively, are substituted.
  • an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
  • acyl includes alkylcarbonyl and arylcarbonyl. In certain embodiments, “acyl” is alkanoyl or benzoyl.
  • each group is independently selected, whether explicitly stated or not.
  • each Re group is independently selected for the formula -N(Re) 2 .
  • each R 7 group is independently selected when an Ri and an R 2 group both contain an R 7 group.
  • each R 8 group is independently selected when more than -N- C(R 7 ) -N- C(R 7 ) one C R 8; group is present (i.e., R 5 and R 5 ' both contain a ⁇ V 8 group) each R 8 group is independently selected and each R 7 group is independently selected.
  • the invention is inclusive of the compounds described herein and salts thereof in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, solvates, polymorphs, and the like.
  • the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers.
  • step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula III is reacted with tert-butyl carbazate or an alternate carbazate to provide a carbazate compound of Formula IV.
  • the reaction can be carried out by adding tert-butyl carbazate to a solution of a compound of Formula III in a suitable solvent such as anhydrous dichloromethane in the presence of a base such as triethylamine.
  • the reaction can be run at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • Many compounds of Formula III are known or can be prepared using known synthetic methods, see for example, U.S. Patent Nos.
  • Terti ⁇ y-butyl carbazate is commercially available (for example, from Aldrich, Milwaukee, WI). Many alternate carbazate reagents (for example, benzyl carbazate) may be prepared using known synthetic methods.
  • step (2) of Reaction Scheme I a carbazate compound of Formula IV is reduced to provide a compound of Formula V.
  • the reduction can be carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon.
  • a platinum catalyst is preferred.
  • the reaction can be conveniently carried out on a Parr apparatus in a suitable solvent such as toluene and/or isopropanol.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • Other reduction processes may be used for the reduction in step (2).
  • an aqueous solution of sodium dithionite can be added to a solution or suspension of the compound of Formula IV in a suitable solvent such as ethanol or isopropanol.
  • a suitable solvent such as ethanol or isopropanol.
  • the reaction can be carried out at an elevated temperature, for example at reflux, or at ambient temperature.
  • a compound of Formula V is (i) reacted with an acyl halide of Formula R 2a C(O)Cl or R 2a C(O)Br and then (ii) cyclized to provide a IH- imidazo compound of Formula VI.
  • the acyl halide is added to a solution of a compound of Formula V in a suitable solvent such as anhydrous dichloromethane in the presence of a base such as triethylamine.
  • the reaction can be run at a reduced temperature, for example, 0° C, or at ambient temperature.
  • the product of part (i) is heated in an alcoholic solvent in the presence of a base.
  • step (3) can be carried out by reacting a compound of Formula V with a carboxylic acid or an equivalent thereof.
  • Suitable equivalents to carboxylic acid include orthoesters and 1,1-dialkoxyalkyl alkanoates.
  • the carboxylic acid or equivalent is selected such that it will provide the desired R 2a substituent in a compound of Formula VI.
  • triethyl orthoformate will provide a compound where R 2a is hydrogen
  • triethyl orthovalerate will provide a compound where R 2a is butyl.
  • the reaction can be run in the absence of solvent or in an inert solvent such as anhydrous toluene.
  • the reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
  • a catalyst such as pyridine hydrochloride can be included.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (4) of Reaction Scheme I the fert-butoxycarbonyl or alternate oxycarbonyl group is removed from a lH-imidazo compound of Formula VI by hydrolysis under acidic conditions to provide a lH-imidazo[4,5-c]quinolin-l-amine of Formula Vila or a salt (for example, hydrochloride salt) thereof.
  • a compound of Formula VI is dissolved in 1.5M HCl in ethanol and heated to reflux.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (5a) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-l-amine of Formula Vila or a salt thereof is treated with a ketone, aldehyde, or corresponding ketal or acetal thereof, under acidic conditions to provide a compound of Formula VIII.
  • a ketone is added to a solution of the hydrochloride salt of a compound of Formula Vila in a suitable solvent such as isopropanol in the presence of an acid or acid resin, for example, DOWEX W50-X1 acid resin.
  • the ketone, aldehyde, or corresponding ketal or acetal thereof, is selected with R; and R;, groups that will provide the desired Ri a substituent in a lH-imidazo[4,5-c]quinolin-l-amine compound of Formula IXa.
  • R groups that will provide the desired Ri a substituent in a lH-imidazo[4,5-c]quinolin-l-amine compound of Formula IXa.
  • acetone will provide a compound where Ri a is isopropyl
  • benzaldehyde will provide a compound where Ri a is benzyl.
  • the reaction is run with sufficient heating to drive off the water formed as a byproduct of the reaction.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • a compound of Formula VIII is reduced to provide a lH-imidazo[4,5-c]quinolin-l-amine compound of Formula IXa.
  • the reaction can be carried out by adding sodium borohydride to a solution of a compound of Formula VIII in a suitable solvent, for example, methanol.
  • a suitable solvent for example, methanol.
  • the reaction can be run at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • a lH-imidazo[4,5-c]quinolm ⁇ l- amine of Formula Vila can be treated with a ketone and a borohydride under acidic conditions to provide a lH-imidazo[4,5-c]quinolin-l-amine compound of Formula IXa.
  • the hydrochloride salt of a lH-imidazo[4,5-c]quinolin-l-arnine of Formula Vila dissolved in a suitable solvent such as 1,2-dichloroethane, can be treated with a ketone and sodium triacetoxyborohydride at room temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • a lH-imidazo[4,5-c]quinolin-l -amine compound of Formula IXa is oxidized to provide an N-oxide of Formula Xa using a conventional oxidizing agent that is capable of forming N-oxides.
  • the reaction is carried out by treating a solution of a compound of Formula DCa in a suitable solvent such as chloroform or dichloromethane with 3-chloroperoxybenzoic acid at ambient temperature.
  • a suitable solvent such as chloroform or dichloromethane
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • an N-oxide of Formula Xa is animated to provide a lH-imidazo[4,5-c]quinoline-l,4-diamine of the Formula Ia, which is a subgenus of compounds of the Formula 1-1.
  • the reaction is carried out in two parts.
  • a compound of Formula Xa is reacted with an acylating agent.
  • Suitable acylating agents include alkyl- or arylsulfonyl chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride, and/>-toluenesulfonyl chloride).
  • Suitable aminating agents include ammonia (e.g. in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate).
  • ammonia e.g. in the form of ammonium hydroxide
  • ammonium salts e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate.
  • the reaction can be carried out by dissolving a compound of Formula Xa in a suitable solvent such as dichloromethane, adding ammonium hydroxide to the solution, and then adding />-toluenesulfonyl chloride.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (7) the oxidation of step (7) and the amination of step (8) can be carried out sequentially without isolating the product of the oxidation to provide a IH- imidazo[4,5-c]quinoline-l,4-diamine of the Formula Ia.
  • step (7) after the IH- imidazo[4,5-c]quinolin-l-amine compound of Formula IXa is consumed by reaction with 3-chloroperoxybenzoic acid as described in step (7), the aminating and acylating agents are added to the reaction mixture as in step (8).
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme II a lH-imidazo compound of Formula VI is oxidized to provide an N-oxide of Formula XI using the method of step (7) in Reaction Scheme I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (2) of Reaction Scheme II an N-oxide of Formula XI is aminated using the method of step (8) in Reaction Scheme I to provide a 4-amino compound of the Formula XIIa.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (3) of Reaction Scheme II the fert-butoxycarbonyl or alternate oxycarbonyl group is removed from a 4-amino compound of the Formula XIIa using the method of step (4) in Reaction Scheme I to provide a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula XIIIa or a salt (for example, hydrochloride salt) thereof.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (4a) of Reaction Scheme II a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula XIIIa is treated with a ketone, aldehyde, or corresponding ketal or acetal thereof, using the method of step (5a) in Reaction Scheme I to provide a compound of Formula XIVa.
  • the ketone, aldehyde, or corresponding ketal or acetal thereof is selected with Ri and R U groups that will provide the desired Ri substituent in a lH-imidazo[4,5- c]quinoline-l,4-diamine compound of Formula Ib.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (5) of Reaction Scheme II a compound of Formula XIVa is reduced to provide a lH-imidazo[4,5-c]quinolin-l -amine compound of Formula Ib using the method of step (6) in Reaction Scheme I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • a lH-imidazo[4,5-c]quinoline- 1,4-diamine of Formula XIIIa can be treated with a ketone and a borohydride using the method of step (5b) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinolm-l- amine compound of Formula Ib, which is a subgenus of compounds of the Formula 1-1.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (1) of Reaction Scheme III a 4-chloro-3-nitroquinoline of Formula III is reacted with a hydrazino compound of Formula XVa to provide a compound of Formula XVI.
  • the reaction can be carried out by adding the hydrazino compound of Formula XVa to a solution of a compound of Formula III in a suitable solvent such as anhydrous dichloromethane in the presence of a base such as triethylamine.
  • the reaction can be run at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • Many hydrazino compounds of Formula XVa are commercially available; others can be readily prepared using known synthetic methods.
  • step (2) of Reaction Scheme III a compound of Formula XVI is reduced to provide a compound of Formula XVII using the methods of step (2) in Reaction Scheme I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (3) of Reaction Scheme III a compound of formula XVII is cyclized using the methods of step (3) in Reaction Scheme I to provide a lH-imidazo[4,5-c]quinolin-l- amine compound of Formula IXb.
  • the product of step (i) (described in step (3) of Reaction Scheme I) can be isolated to provide a compound of the following formula:
  • the product of part (i) can be refluxed in suitable solvent such as toluene in the presence of pyridine hydrochloride.
  • suitable solvent such as toluene
  • pyridine hydrochloride a suitable solvent
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (4) of Reaction Scheme III a lH-imidazo[4,5-c]quinolin-l -amine compound of Formula IXb is oxidized to provide an N-oxide of Formula X using the method of step (7) in Reaction Scheme I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (5) of Reaction Scheme III an N-oxide of Formula X is aminated using the method of step (8) in Reaction Scheme I to provide a lH-imidazo[4,5-c]quinoline-l,4- diamine of the Formula Ic, which is a subgenus of compounds of the Formula I- 1.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (4) the oxidation of step (4) and the amination of step (5) can be carried out sequentially without isolating the product of the oxidation to provide a IH- imidazo[4,5-c]quinoline-l,4-diamine of the Formula Ic.
  • step (4) after the IH- imidazo[4,5-c]quinolin-l-amine compound of Formula IXb is consumed by reaction with
  • step (1) of Reaction Scheme IV a 2,4-dichloro-3-nitroquinoline of Formula XVIII is reacted with tert-butyl carbazate or an alternate carbazate to provide a carbazate compound of Formula XIX.
  • the reaction can be carried out by adding tert-butyl carbazate or an alternate carbazate to a solution of a 2,4-dichloro-3-nitroquinoline of Formula XVIII in a suitable solvent such as anhydrous dichloromethane in the presence of a base such as triethylamine.
  • the reaction can be run at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • Many quinolines of Formula XVIII are known or can be prepared using known synthetic methods (see for example, Andre et al., U.S. Patent No. 4,988,815 and references cited therein).
  • step (2) of Reaction Scheme IV a carbazate compound of Formula XIX is reduced to provide a 2-chloroquinolin-3 -amine of Formula XX using the method of step (2) in Reaction Scheme I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (3) of Reaction Scheme IV a 2-chloroquinolin-3 -amine of Formula XX is reacted with an acyl halide of formula R 2 C(O)Cl or R 2 C(O)Br, or a carboxylic acid or equivalent thereof, using the methods of step (3) in Reaction Scheme I to provide a 4- chloro-lH-imidazo[4,5-c]quinoline of Formula XXI.
  • the carboxylic acid or equivalent is selected such that it provides the desired R 2 substituent in compounds of Formula XXI.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (4) of Reaction Scheme IV the tert-butoxycarbonyl or alternate oxycarbonyl group is removed from a 4-chloro-lH-imidazo[4,5-c]quinoline of Formula XXI using the method of step (4) of Reaction Scheme I to provide a 4-chloro-lH- imidazo[4,5-c]quinolin-l-amme of Formula XXII or a salt thereof.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (5a) of Reaction Scheme IV a 4-chloro-lH-imidazo[4,5-c]quinolin-l- amine of Formula XXII or a salt thereof is treated with a ketone, aldehyde, or corresponding ketal or acetal using the method of step (5a) of Reaction Scheme I to provide a compound of Formula XXIII.
  • the ketone, aldehyde, or corresponding ketal or acetal thereof, is selected with R; and R U groups that will provide the desired Ri substituent in a 4-chloro-lH-imidazo[4,5-e]quinolm-l-amine compound of Formula XXTVa.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (6) of Reaction Scheme IV a compound of Formula XXIII is reduced using the method of step (6) in Reaction Scheme I to provide a 4-chloro-lH-imidazo[4,5- c]quinolin-l -amine compound of Formula XXIVa.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (5b) of Reaction Scheme IV a 4-chloro-lH-imidazo[4,5- c]quinolin-l -amine of Formula XXII can be treated with a ketone and a borohydride using the method of step (5b) in Reaction Scheme I to provide a 4-chloro-lH-imidazo[4,5- c]quinolin-l -amine compound of Formula XXIVa.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • a 4-chloro-lH-imidazo[4,5-c]quinolm-l-amine of Formula XXTVa is aminated to provide a lH-imidazo[4,5-c]qumoline-l,4-diamine of Formula Id, which is a subgenus of compounds of the Formula 1-1.
  • the reaction is carried out by heating (e.g., 125-175°C) a compound of Formula XXTVa under pressure in a sealed reactor in the presence of a solution of ammonia in an alkanol.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme V a 4-chloro-lH-imidazo[4,5-c]quinoline of Formula XXI is animated, using the method of step (7) in Reaction Scheme IV, to provide a 4-amino compound of the Formula XII.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (2) of Reaction Scheme V the or alternate oxycarbonyl group is removed from a 4-amino compound of the Formula XII using the method of step (4) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula XIII or a salt thereof.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (3a) of Reaction Scheme V a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula XIII or a salt thereof is treated with a ketone, aldehyde, or corresponding ketal or acetal using the method of step (5a) of Reaction Scheme I to provide a compound of
  • 1,4-diamine of Formula XIII or a salt thereof can be treated with a ketone and a borohydride using the method of step (5b) in Reaction Scheme I to provide a IH- imidazo[4,5-c]quinoline-l,4-diamine compound of Formula Id.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (1) of Reaction Scheme VI a 2,4-dichloro-3-nitroquinoline of Formula XVIII is reacted with a hydrazino compound of Formula XV, using the method of step (1) in Reaction Scheme III, to provide a compound of Formula XXV.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (2) of Reaction Scheme VI a compound of Formula XXV is reduced using the method of step (2) in Reaction Scheme I to provide a compound of Formula XXVI.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (3) of Reaction Scheme VI a compound of Formula XXVI is reacted with an acyl halide of formula R 2 C(O)Cl or R 2 C(O)Br, or a carboxylic acid or equivalent thereof using the methods of step (3) in Reaction Scheme I to provide a 4-chloro-lH- imidazo[4,5-c]quinolm-l-amine compound of Formula XXIV.
  • the carboxylic acid or equivalent is selected such that it provides the desired R 2 substituent in a compound of Formula XXIV.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (4) of Reaction Scheme VI a 4-chloro-lH-imidazo[4,5-c]quinolin-l-amine compound of Formula XXIV is aminated using the method of step (7) in Reaction Scheme IV to provide a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula Ie, which is a subgenus of compounds of the Formula 1-1.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (1) of Reaction Scheme VII a lH-imidazo[4,5-c]quinolin-l-amine of Formula VTIa or a salt thereof is treated with a ketal or acetal, containing a protected amino group, using the method of step (5a) of Reaction Scheme I to provide a compound of Formula XXVII.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • the amino ketal or acetal is selected with Rj' and X groups that will provide the desired Ri 1 and X groups in a lH-imidazo[4,5-c]quinolin-l,4-diamine of Formula XXX, XXXI, or XXXII, which are subgenera of compounds of the Formula 1-1.
  • Rj' and X groups that will provide the desired Ri 1 and X groups in a lH-imidazo[4,5-c]quinolin-l,4-diamine of Formula XXX, XXXI, or XXXII, which are subgenera of compounds of the Formula 1-1.
  • tert-butyl (3,3-diethoxypropyl)carbamate will provide a compound where Ri 1 is hydrogen and X is ethylene.
  • the amino group of an amino ketal or acetal can be protected with a fert-butoxycarbonyl or an alternate oxycarbonyl group.
  • l-amino-3,3- diethoxypropane can be reacted with di-tert-butyl dicarbonate in a suitable solvent such as tetrahydrofuran (THF) in the presence of triethylamine to provide tert-butyl (3,3- diethoxypropyl)carbamate.
  • a compound of Formula XXVII is reduced using the method of step (6) in Reaction Scheme I to provide a compound of Formula XXVIII, which is a subgenus of compounds of the Formula IX.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (3) of Reaction Scheme VTI a compound of Formula XXVIII is oxidized to provide an N-oxide of Formula XXIX using the method of step (7) in Reaction Scheme I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (4) of Reaction Scheme VII an ⁇ -oxide of Formula XXIX is aminated using the method of step (8) in Reaction Scheme I to provide a lH-imidazo[4,5- c]quinoline-l,4-diamine of the Formula XXX, which is a subgenus of compounds of the Formula 1-1.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (5) of Reaction Scheme VII a the tert-butoxycarbonyl or alternate oxycarbonyl group is removed from a lH-imidazo[4,5-c]quinoline-l,4-diamine of the Formula XXX using the method of step (4) of Reaction Scheme I to provide a IH- imidazo[4,5-c]quinoline-l,4-diamine of the Formula XXXI, which is a subgenus of compounds of the Formula 1-1.
  • the product or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • a lH-imidazo[4,5-c]qumoline-l,4-diamine of the Formula XXXI is converted to a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula XXXII using conventional methods.
  • a lH-imidazo[4,5-c]quinoline-l,4- diamine of the Formula XXXI can react with an acid chloride of Formula R 4 C(O)Cl to provide a compound of Formula XXXII in which Y is -C(O)-.
  • a IH- imidazo[4,5-c]quinoline-l,4-diamine of the Formula XXXI can react with sulfonyl chloride of Formula R 4 S(O) 2 Cl or a sulfonic anhydride of Formula (R 4 S(O) ⁇ 2 O to provide a compound of Formula XXXII in which Y is -S(O) 2 -.
  • Numerous acid chlorides of Formula R 4 C(O)Cl, sulfonyl chlorides of Formula R 4 S(O) 2 Cl, and sulfonic anhydrides of Formula (R 4 S(O) ⁇ 2 O are commercially available; others can be readily prepared using known synthetic methods.
  • the reaction can be conveniently carried out by adding the acid chloride of Formula R 4 C(O)Cl, sulfonyl chloride of Formula R 4 S(O) 2 Cl, or sulfonic anhydride of Formula (R 4 S(O) ⁇ 2 O to a cooled solution of a lH-imidazo[4,5-c]quinoline- 1 ,4-diamine of the Formula XXXI and a base such as triethylamine in a suitable solvent such as chloroform, dichloromethane, or acetonitrile.
  • the reaction can be carried out at ambient temperature or at a sub-ambient temperature such as O 0 C.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a suitable solvent such as dichloromethane or chloroform.
  • the reaction can be carried out at ambient temperature or at a sub-ambient temperature such as O 0 C.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • each Rc is independently selected from the group consisting of hydroxy, alkyl, and alkoxy; and R ⁇ and R 2b are a subset of Ri and R 2 , respectively, as defined above, which do not include those groups that one skilled in the art would recognize as being susceptible to reduction under the acidic hydrogenation conditions in step (1).
  • susceptible groups include, for example, alkenyl, alkynyl, and aryl groups, and groups bearing nitro substituents.
  • step (1) of Reaction Scheme VIII a lH-imidazo[4,5-c]quinolin-4-amine of Formula If is reduced to provide a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine of Formula Ua, which is a subgenus of compounds of the Formula II- 1.
  • the reaction can be conveniently carried out by suspending or dissolving a compound of Formula If in trifluoiOacetic acid, adding platmum(IV) oxide, and hydrogenating under an atmosphere of hydrogen.
  • the reaction can be carried out in a Parr apparatus.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Step (1) the amino group of a compound of Formula XXXIII may be acylated to provide a compound of Formula XXXTV.
  • the reaction may be conveniently carried out by reacting a compound of Formula XXXIII with an alkyl malonyl chloride in the presence of a base such as triethylamine in a suitable solvent such as methylene chloride.
  • a compound of Formula XXXTV may be cyclized to provide a compound of Formula XXXV.
  • the reaction may be conveniently carried out by adding a solution of a compound of Formula XXXIV in a suitable solvent such as THF to a suspension of sodium hydride (or other base capable of removing a malonyl methylene proton) in a suitable solvent such as THF.
  • the reaction may be run at an elevated temperature, for example the reflux temperature.
  • the product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.
  • a compound of Formula XXXV may be hydrolyzed and decarboxylated to provide a compound of Formula XXXVI.
  • the reaction may be carried out by conventional methods, for example, by combining a compound of Formula XXXV with an acid, such as hydrochloric acid, with heating.
  • the product may be isolated using conventional methods.
  • a compound of Formula XXXVI may be nitrated to provide a compound of Formula XXXVII.
  • the reaction may be carried out under conventional nitration conditions, such as by heating a compound of Formula
  • XXXVI in the presence of nitric acid, preferably in a solvent such acetic acid.
  • a solvent such as acetic acid.
  • the product or a pharmaceutically acceptable salt thereof may be isolated using conventional methods.
  • a compound of Formula XXXVII may be chlorinated to provide a 2,4-dichloro-3-nitro-5,6,7,8-tetrahydroquinoline of Formula XXXVIII.
  • the reaction may be carried out by combining a compound of Formula
  • XXXVII with a conventional chlorinating agent (e.g., phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, or phosphorus pentachloride), optionally in solvent such as NN-dimethylformamide (DMF) or methylene chloride, with heating (e.g., at the reflux temperature).
  • a conventional chlorinating agent e.g., phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, or phosphorus pentachloride
  • solvent such as NN-dimethylformamide (DMF) or methylene chloride
  • heating e.g., at the reflux temperature
  • step (6) of Reaction Scheme IX a 2,4-dichloro-3-nitro-5,6,7,8- tetrahydroquinoline of Formula XXXVIII may be reacted with a hydrazino compound of Formula XV (H 2 N-N(R 1 1 XR 1 ), using the method of step (1) in Reaction'scheme III, to provide a compound of Formula XXXIX.
  • the product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.
  • a compound of Formula XXXIX may be reduced using the method of step (2) in Reaction Scheme I to provide a compound of Formula XL.
  • the product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.
  • a compound of Formula XL may be reacted with an acyl halide of formula R 2 C(O)Cl or R 2 C(O)Br, or a carboxylic acid or equivalent thereof using the methods of step (3) in Reaction Scheme I to provide a 4-chloro-lH- imidazo[4,5-c]quinolin-l -amine compound of Formula XLI.
  • the carboxylic acid or equivalent may be selected such that it provides the desired R 2 substituent in a compound of Formula II- 1.
  • the product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.
  • a 4-chloro-lH-imidazo[4,5-c]qumolin-l-amine compound of Formula XLI may be animated using the method of step (7) in Reaction Scheme IV to provide a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula II- 1.
  • the product or a pharmaceutically acceptable salt thereof may be isolated by conventional methods.
  • compounds of the invention are prepared according to Reaction Scheme X, wherein R, Rj 3 , R 2a , and 1 are as defined above; Hal is chloro, bromo, or iodo; R 3a is -ZVR 4 1 , -Z'-X'-RV, -Z-X-T-R 4 ', or -Z'-X'-Rj'; wherein R 4 1 , Y 1 , X 1 , and R 5 ' are as defined above; and Z' is a bond.
  • step (1) of Reaction Scheme X a 4-chloro-3-nitroquinoline of Formula XLIV is converted to a carbazate of Formula XLV according to the method described in step (1) of Reaction Scheme I.
  • Compounds of Formula XLIV can be readily prepared using known synthetic routes; see for example, U.S. Patent Nos. 4,689,338 (Gerster), 5,367,076 (Gerster), 6,331,539 (Crooks et al.), 6,451,810 (Coleman et al.), 6,541,485 (Crooks et al.) and the documents cited therein.
  • steps (2) and (3) of Reaction Scheme X a nitro-substituted quinoline of Formula
  • XLV is first reduced to an amino-substituted quinoline of Formula XLVI, which is then cyclized to a lH-imidazoquinoline of Formula XLVII.
  • Steps (2) and (3) of Reaction Scheme X can be carried out as described for steps (2) and (3) of Reaction Scheme I.
  • step (4) of Reaction Scheme X the fert-butoxycarbonyl group of a IH- imidazoquinoline of Formula XLVII is hydrolyzed under acidic conditions to provide a lH-imidazo[4,5-c]quinolin-l-amine of Formula VIIb or a pharmaceutically acceptable salt thereof.
  • the reaction is conveniently carried out as described in step (4) of Reaction Scheme I.
  • the lH-imidazo[4,5-c]quinolin-l-amine of Formula VIIb is then converted to a lH-imidazo[4,5-c]quinolin-l-amine of Formula IXc using either a two-step procedure as shown in steps (5a) and (6) of Reaction Scheme X or a one-step procedure as shown in step (5b).
  • the two-step procedure, in which a compound of Formula VIIIb is isolated, can be carried out as described in steps (5a) and (6) of Reaction Scheme I.
  • step (5a) the ketone, aldehyde, or corresponding ketal or acetal thereof, is selected with Rj and R;; groups that will provide the desired Ri a substituent in a lH-imidazo[4,5-cJqumolin-l- amine compound of Formula IXc.
  • Step (5b) of Reaction Scheme X can be carried out as described for step (5b) of Reaction Scheme I.
  • steps (7) and (8) of Reaction Scheme X a lH-imidazo[4,5-c]quinolin-l-amine of Formula IXc is first oxidized to an N-oxide of Formula Xb, which is then aminated to provide a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula Ig, which is a subgenus of the compounds of the Formula 1-1.
  • Steps (7) and (8) of Reaction Scheme X can be carried out according to the procedures described in steps (7) and (8) of Reaction Scheme I.
  • Step (9) of Reaction Scheme X can be carried out using known palladium- catalyzed coupling reactions such as Suzuki coupling, Stille coupling, Sonogashira coupling, and the ⁇ eck reaction.
  • a lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula Ig undergoes Suzuki coupling with a boronic acid of Formula R 33 -B(OH) 2 , an anhydride thereof, or a boronic acid ester of Formula R 3a -B(O-alkyl) 2 to provide an IH- imidazo[4,5-c]quinoline-l,4-diamine of Formula I-lb, a subgenus of Formula 1-1, wherein R 3a is -Z-R 4 ', -Z'-X'-R A ', -Z'-X'-Y'-RV, or -Z-X-R 5 '; -Z' is a bond; -X'- is alkenylene
  • the coupling is carried out by combining a compound of Formula Ig with a boronic acid or an ester or anhydride thereof in the presence of palladium (II) acetate, triphenylphosphine, and abase such as sodium carbonate in a suitable solvent such as r ⁇ -propanol.
  • the reaction can be carried out at an elevated temperature (e.g., 80-100 0 C).
  • Numerous boronic acids of Formula R 33 -B(OH) 2 , anhydrides thereof, and boronic acid esters of Formula R 3a -B(O-alkyl) 2 are commercially available; others can be readily prepared using known synthetic methods. See, for example, Li, W. et al, J. Org. Chem., 67, 5394-5397 (2002).
  • the product of Formula I-lb or a pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • the Heck reaction can also be used in step (9) of Reaction Scheme X to provide compounds of Formula I-lb, wherein R 3a is -Z'-X'-RV or -Z'-X'-Y'-RV; -Z' is a bond; -X'- is alkenylene optionally terminated by arylene or heteroarylene; and R 4 ' and Y' are as defined above.
  • the Heck reaction is carried out by coupling a lH-imidazo[4,5- c]quinoline-l,4-diamine of Formula Ig with a vinyl-substituted arylene or heteroarylene compound.
  • arylene or heteroarylene compounds such as 2- vinylpyridine, 3-vinylpyridine, and 4-vinylpyridine
  • the reaction is conveniently carried out by combining the lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula Ig and the vinyl- substituted compound in the presence of palladium (II) acetate, triphenylphosphine or tri- ort/ ⁇ o-tolylphosphine, and a base such as triethylamine in a suitable solvent such as acetonitrile or toluene.
  • the reaction can be carried out at an elevated temperature such as 100-120 °C under an inert atmosphere.
  • the compound or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • compounds of the invention can be prepared according to Reaction Scheme XI where R, Ri a , R 2a , and 1 are as defined above; Boc is tert- butoxycarbonyl; R 3b is -Z'-RV, -Z'-X'-RV, -Z'-X'-Y'-RV, or -ZVJC-R 5 1 ; X 1 , Y 1 , and R 4 1 are as defined above; and Z 1 is -O-.
  • a benzyloxyaniline of Formula XLVIII is treated with the condensation product generated from 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid) and triethyl orthoformate to provide an imine of Formula XLEK.
  • the reaction is conveniently carried out by adding a solution of a benzyloxyaniline of Formula XLVIII to a heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an elevated temperature such as 45 0 C.
  • the product can be isolated using conventional methods.
  • step (2) of Reaction Scheme XI an imine of Formula XLIX undergoes thermolysis and cyclization to provide a benzyloxyquinolin-4-ol of Formula L.
  • the reaction is conveniently carried out in a heat transfer fluid such as DOWTHERM A heat transfer fluid at a temperature between 200 and 250 0 C.
  • DOWTHERM A heat transfer fluid at a temperature between 200 and 250 0 C.
  • the product can be isolated using conventional methods.
  • step (3) of Reaction Scheme XI a benzyloxyquinolin-4-ol of Formula L is nitrated under conventional nitration conditions to provide a benzyloxy-3-nitroquinolin-4- ol of Formula LI.
  • the reaction is conveniently carried out by adding nitric acid to the benzyloxyquinolin-4-ol of Formula L in a suitable solvent such as propionic acid and heating the mixture at an elevated temperature such as 125 0 C.
  • a suitable solvent such as propionic acid
  • the product can be isolated using conventional methods.
  • a benzyloxy-3-nitroquinolin-4-ol of Formula LI is chlorinated using conventional chlorination chemistry to provide a benzyloxy-4-chloro- 3-nitroquinoline of Formula LII.
  • the reaction is conveniently carried out by treating the benzyloxy-3-nitroquinolin-4-ol of Formula LI with phosphorous oxychloride in a suitable solvent such as DMF.
  • the reaction can be carried out at ambient temperature or at an elevated temperature such as 100 0 C, and the product can be isolated using conventional methods.
  • step (5) of Reaction Scheme XI abenzyloxy-4-chloro-3-nitroquinoline of Formula LII is converted to a carbazate of Formula LIII.
  • the reaction is conveniently carried out as described in step (1) of Reaction Scheme I.
  • steps (6) and (7) of Reaction Scheme XI a nitro-substituted quinoline of Formula LIII is first reduced to an amino-substituted quinoline of Formula LIV, which is then cyclized to a benzyloxy-lH-imidazo[4,5-c]quinoline of Formula LV.
  • Steps (6) and (7) of Reaction Scheme XI can be carried out as described for steps (2) and (3) of Reaction Scheme I.
  • step (8) of Reaction Scheme XI the Boc group of abenzyloxy-lH-imidazo[4,5- c]quinoline of Formula LV is hydrolyzed under acidic conditions to provide a benzyloxy- lH-imidazo[4,5-c]quinolin-l-amine of Formula XLIIa or a pharmaceutically acceptable salt thereof.
  • the reaction is conveniently carried out as described in step (4) of Reaction Scheme I.
  • the benzyloxy-lH-imidazo[4,5-c]quinolin-l-amine of Formula XLIIa is then converted to a benzyloxy-lH-imidazo[4,5-c]quinolin-l-amine of Formula XLIIIa using either a two-step procedure as shown in steps (9a) and (10) of Reaction Scheme XI or a one-step procedure as shown in step (9b).
  • the two-step procedure, in which a compound of Formula LVI is isolated, can be carried out as described in steps (5a) and (6) of Reaction Scheme I.
  • Step (9a) of Reaction Scheme XI can be carried out as described for step (5b) of Reaction Scheme I.
  • a benzyloxy-lH-imidazo[4,5- c]quinolin-l -amine of Formula XLIIIa is first oxidized to anN-oxide of Formula LVII, which is then aminated to provide a benzyloxy-lH-imidazo[4,5-c]quinoline-l,4-diamine of Formula LVIII, which is a subgenus of the compounds of the Formula 1-1.
  • Steps (11) and (12) of Reaction Scheme XI can be carried out according to the procedures described in steps (7) and (8) of Reaction Scheme I.
  • step (13) of Reaction Scheme XI the benzyl group of a benzyloxy-lH- imidazo[4,5-c]quinoline-l,4-diamine of Formula LVIII is cleaved to provide a hydroxy- lH-imidazo[4,5-c]qumoline-l,4-diamine of Formula Di.
  • 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 product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (14) of Reaction Scheme XI a hydroxy-lH-imidazo[4,5-c]quinoline-l,4- diamine of Formula Ih is converted to an ether-substituted lH-imidazo[4,5-c]quinoline- 1,4-diamine of Formula I- Ic (a subgenus of compounds of Formula 1-1) using a Williamson-type ether synthesis.
  • the reaction is effected by treating a compound of Formula Ih with an alkyl halide of Formula HaIIdC-R 4 1 , Halide-X'-Y'-RV, HaMe-X-R 4 ', or Halide-X'-R 5 ' in the presence of a base.
  • the reaction is conveniently carried out by combining the alkyl halide with a compound of Formula Ih in a solvent such as DMF in the presence of a suitable base such as cesium carbonate.
  • a suitable base such as cesium carbonate.
  • the reaction can be carried out at ambient temperature or at an elevated temperature, for example 65 0 C or 85 0 C.
  • the reaction can be carried out by treating a solution of a compound of Formula Di in a solvent such as DMF with sodium hydride and then adding the alkyl halide.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Halide-RV Halide-X'-RV
  • Halide-X'-Y'-RV Numerous reagents of Formulas Halide-RV, Halide-X'-RV, and Halide-X'-Y'-RV are commercially available, for example, bromo-substituted ketones, esters, and heterocycles.
  • reagents of Formulas HaMe-R 4 ', Halide-X'-Y'-RV, or Halide-X'-Rs' can be prepared using conventional synthetic methods; for example, a bromo-substituted acid halide of Formula ClC(O)-X'-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-X-C(O)-N(Rn)-R 4 1 or
  • the reaction can be run at a sub-ambient temperature such as -25 0 C, and the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Reagents of Formula I-X'-NH-C(O)-O-C(CH 3 ) 3 can be prepared in two steps from amino alcohols of Formula H0-X'-NH 2 , many of which are commercially available or readily prepared by known synthetic methods.
  • An amino alcohol of Formula HO-X-NH 2 is first protected with a tert-butoxy carbonyl group by treating the amino alcohol with di- tert-hutyl dicarbonate in the presence of a base such as aqueous sodium hydroxide in a suitable solvent such as tetrahydrofiiran.
  • the resulting hydroxyalkylcarbamate of Formula HO-X'-NH-C(O)-O-C(CH 3 ) 3 is then treated with a solution of iodine, triphenylphosphine, and imidazole at ambient temperature in a suitable solvent such as dicMoromethane.
  • a suitable solvent such as dicMoromethane.
  • the product of Formula 1-X-NH-C(O)-O-C(CHa) 3 can be isolated using conventional methods.
  • Step (14) of Reaction Scheme XI can alternatively be carried out by treating a hydroxy- lH-imidazo [4, 5-c]qumoline-l,4-diamine of Formula Hi with an alcohol of Formula ⁇ O-X'-Y'-RV, ⁇ 0-X'-R 5 ', HO-X'-RV, or HO-R 4 ' under Mitsunobu reaction conditions.
  • an alcohol of Formula ⁇ O-X'-Y'-RV, ⁇ 0-X'-R 5 ', HO-X'-RV, or HO-R 4 ' 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-X'- V-R 4 ', H0-X'-R 5 ', HO-X'-Rj', or HO-R 4 ' to a solution of a compound of Formula Ih in a suitable solvent such as tetrahydrofuran and then slowly adding diisopropyl azodicarboxylate or diethyl azodicarboxylate.
  • the reaction can be carried out at ambient temperature or at a sub-ambient temperature, such as O 0 C.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Compounds of Formula I- Ic, wherein R 3b is -O-X'-NH-C(O)-O-C(CH 3 ) 3 can be prepared by treating compounds of Formula Ih with alcohols such as ter/-butyl N-(4- hydroxybutyl)carbamate and N-(5-hydroxypentyl)carbamate under Mitsunobu conditions or with alkyl halides of Formula I-X'- ⁇ H-C(O)-O-C(CH 3 ) 3 in a Williamson- type ether synthesis.
  • alcohols such as ter/-butyl N-(4- hydroxybutyl)carbamate and N-(5-hydroxypentyl)carbamate under Mitsunobu conditions
  • alkyl halides of Formula I-X'- ⁇ H-C(O)-O-C(CH 3 ) 3 in a Williamson- type ether synthesis.
  • compounds of Formula I- Ic can be prepared according to Reaction Scheme XII, in which R, R la , R 2a , R 31 ,, and 1 are as defined above.
  • step (1) of Reaction Scheme XII the benzyl group of a benzyloxy-lH-imidazo[4,5-c]quinolin-l- amine of Formula XLIIa is cleaved to provide a hydroxy-lH-imidazo[4,5-c]quinolin-l- amine of Formula IXd.
  • step (2) of Reaction Scheme XII a hydroxy-lH-imidazo[4,5- cjquinolin-1 -amine of Formula IXd is converted to an ether-substituted lH-imidazo[4,5- c]quinolin-l -amine of Formula LEX.
  • steps (3) and (4) of Reaction Scheme XII an ether-substituted lH-imidazo[4,5-c]quinolin-l-amine of Formula LIX is first oxidized to an N-oxide of Formula LX, which is then aminated to provide an ether-substituted IH- imidazo[4,5-c]quinoline-l,4-diamine of Formula I- Ic, which is a subgenus of the compounds of Formula 1-1.
  • Steps (1), (2), (3), and (4) of Reaction Scheme XII can be carried out as described in steps (13), (14), (11), and (12), respectively, of Reaction Scheme XI.
  • compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount or “effective amount” means an amount of the compound sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, cytokine inhibition, 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 to the subject.
  • 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 of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds 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.
  • additional immune response modifiers antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.
  • Compounds of the invention have been shown to induce, and certain compounds of the invention may inhibit, the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
  • Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon- ⁇ (IFN- ⁇ ) and/or tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN- ⁇ , TNF- ⁇ , IL-I, IL-6, IL-IO and IL- 12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and neoplastic diseases.
  • IFN- ⁇ interferon- ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-6 tumor necrosis factor- ⁇
  • IL-IO interleukins
  • the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • the animal to which the compound 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 may provide therapeutic treatment.
  • the compound may be administered to the animal prior to the animal acquiring the disease so that administration of the compound may provide a prophylactic treatment.
  • compounds of the invention may 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 may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
  • T H I T helper type 1
  • T H 2 T helper type 2
  • TNF- ⁇ tumor necrosis factor- ⁇
  • the invention provides a method of inhibiting TNF- ⁇ biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • the animal to which the compound 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 may provide therapeutic treatment.
  • the compound may be administered to the animal prior to the animal aquiring the disease so that administration of the compound may provide a prophylactic treatment.
  • the compound or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant.
  • the compound 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 herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus (RSV), a coronavirus (e.g., SARS), a papovavirus, (e.g., papillomaviruses, such as those that cause genital warts, common warts, or plantar warts),
  • bacterial diseases such as, for example, diseases resulting from infection by bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococci, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
  • infectious diseases such as chlamydia, fungal diseases, such as, for example, candidiasis, aspergillosis, histoplasmonsis, cryptococcal meningitis, or parasitic diseases, such as, for example, malaria, Pneumocystis carnii pneomonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection;
  • neoplastic diseases such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, aenal cell leukemia, Karposi's sarcoma, melanoma, renal cell carcinoma, leukemias, such as, for example, myelogeous leukemia, chronic lymphocytic leukemia, and multiple myeloma, non-
  • Hodgkin's lymphoma cutaneous T-cell lymphoma, B-cell lymphoma, hairy cell leukemia, and other cancers;
  • atopic, and autoimmune diseases such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, systemic lupus erythematosis, essential thrombocythaemia, multiple sclerosis, Ommen's syndrome, discoid lupus, alopecia areata, inhibition of keloid formation and other types of scarring, and enhancing wound healing, including chronic wounds.
  • atopic dermatitis or eczema eosinophilia
  • asthma allergy
  • allergic rhinitis systemic lupus erythematosis
  • essential thrombocythaemia erythematosis
  • multiple sclerosis multiple sclerosis
  • Ommen's syndrome discoid lupus
  • alopecia areata, inhibition of keloid formation and other types of scarring, and enhancing wound healing, including chronic wounds.
  • IRMs identified herein also 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; recombinant proteins; and the like, for use in connection with, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, and hepatitis C, influenza A and influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningococcal and pneumo
  • IRMs identified herein may also be particularly helpful in individuals having compromised immune function.
  • IRM compounds may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
  • one or more of the above diseases or types of diseases for example, a viral disease or a neoplastic disease may be treated in an animal in need thereof (having the disease) by administering a therapeutically effective amount of a compound or salt of Formula I- 1 , II- 1 , any of the embodiments described herein, or a combination thereof to the animal.
  • An animal may also be vaccinated by administering an effecive amount of a compound or salt of Formula 1-1, II- 1, any of the embodiments described herein, or a combination thereof to the animal as a vaccine adjuvant.
  • An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-I, IL-6, IL-IO and IL- 12 that is increased over the 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 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 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.
  • a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt described herein to the animal.
  • a method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt described herein to the animal.
  • a method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt described herein to the animal.
  • a method of vaccinating an animal comprising administering an effective amount of a compound or salt described herein to the animal as a vaccine adjuvant.
  • N-benzyl(2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)amine (427 mg, 1.29 mmol) in 20 mL Of CH 2 Cl 2 was treated with MCPBA (77% max., 325 mg, 1.41 mmol). After stirring for 3 h, the reaction was quenched with saturated NaHCO 3 solution and extracted into CH 2 Cl 2 . The organic portion was washed with saturated NaHCO 3 solution, H 2 O and brine. The organic was dried over Na 2 SO 4 , filtered and concentrated to give N-benzyl(2-butyl-5-oxido-lH-imidazo[4,5-c]quinolin-l-yl)amine (393 mg) as a light brown foam.
  • N-benzylidene-(2-ethoxymethy- lH-imidazo[4,5-c]quinolin- 1 - yl)amine (1.00 g, 3.03 mmol) in 50 mL of MeOH was treated with NaBH 4 (458 mg, 12.1 mmol). After stirring for 1.5 h, the reaction mixture was concentrated, then treated with saturated NaHCO 3 solution, and extracted into CHCl 3 . The organic portion was washed with H 2 O and brine and dried over Na 2 SO 4 . The resulting solution was filtered and concentrated to give N-benzyl-(2-ethoxymethy-lH-imidazo[4,5-c]quinolin-l-yl)amine (1.01 g) as a tan solid.
  • N-Cyclohexyl-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-amine (0.51 g, 1.57 mmol) was placed in a 200 niL round bottom flask, purged with N 2 and dissolved in dichloromethane (25 mL). MCPBA (0.484 g, 1.96 mmol, 77% max) was added over a 5 min period. The reaction was stirred at room temperature under N 2 . After 2 h, analysis by thin layer chromatography (TLC) (SiO 2 , 95:5 chloroform:methanol) showed complete conversion. The solution was diluted with dichloromethane (15 mL) and 2% sodium carbonate solution (15 mL).
  • N-Cyclohexyl-2-(ethoxymethyl)-5-oxido-lH-imidazo[4,5-c]quinolin-l-amine (0.425 g, 1.25 mmol) was placed in a 100 mL round bottom flask and dissolved in dichloromethane (20 mL). Ammonium hydroxide solution (10 mL) was added and the mixture was stirred vigorously. The stirred mixture was chilled in an ice water bath. Aw- ⁇ -toluenesulfonyl chloride (0.250 g, 1.31 mmol) was added over 5 min. After 30 min of stirring at 0 0 C TLC (SiO 2 , 95:5 chloroform:methanol) showed complete conversion.
  • the mixture was warmed to room temperature and then diluted with dichloromethane (25 mL) and water (10 mL). The mixture was transferred to a separatory funnel and the phases separated. The organic portion was washed sequentially with 2% sodium carbonate solution (15 mL), water (15 mL) and brine (15 mL), dried over Na 2 SO 4 , filtered and then concentrated to yield an orange/tan foamy solid.
  • the material was purified by column chromatography (40 g SiO 2 , 95:5 chloroform:methanol) to yield the product as an off white solid. The off-white solid was dissolved in 3 mL of a 9:1 chloroform:methanol mixture.
  • a small spatula tip full of activated carbon (DARCO G 60-100 mesh) was added and the mixture was stirred at room temperature for 3 h.
  • the mixture was filtered through a short column of SiO 2 (5 g) eluting with 9:1 chloroform:methanol.
  • the filtrate was concentrated to yield a glassy solid.
  • the glassy solid was triturated in 15 mL diethyl ether for 2 h to provide a white solid. The solid was collected by vacuum filtration and rinsed with diethyl ether.
  • Part B A suspension of 4-(2,2-dimethylhydrazino)-3-nitroquinoline (5.33 g, 23.0 mmol) in 125 mL of acetonitrile was treated with 5% platinum on carbon (0.45 g, 0.11 mmol) and the mixture was shaken under an atmosphere of hydrogen (3.8 x 10 5 Pa). After 5 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with 80:20 acetonitrile:MeOH. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in CH 2 Cl 2 , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 4-(2,2-dimethylhydrazino)quinolin-3-amine (4.64 g) as a red foam.
  • N-(morpholin-4-yl)(3-nitroquinolin-4-yl)amine (4.54 g, 16.6 mmol) in 150 mL of toluene was treated with 5% platinum on carbon (0.65 g, 0.17 mmol) and the mixture was shaken under an atmosphere of hydrogen (3.8 x 10 5 Pa). After 15 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with 4: 1 toluene:MeOH. The filtrate was concentrated under reduced pressure to yield N 4 - (morpholin-4-yl)quinoline-3,4-diamine (4.06 g) as a red foam.
  • the dried HCl salt was dissolved in 75 mL of water and treated with 50% NaOH solution until the p ⁇ of the water was 12-13.
  • the free base of the product precipitated out and was triturated in the basic water for 30 min while being cooled in an ice water bath.
  • the solid was collected by vacuum filtration and dried under vacuum to give 4.64 g of 2-propyl-lH-imidazo[4,5-c]quinolin-l -amine as a tan granular solid.
  • the reaction mixture was treated with/>-toluenesulfonyl chloride (1.85 g, 9.70 mmol) over 5 min. The reaction was allowed to come to ambient temperature. After 30 min, the reaction mixture was diluted with 50 mL of chloroform and 30 mL of water and the phases were separated. The organic portion was washed with 5% Na 2 CO 3 solution (30 mL), water (30 mL) and brine (30 mL). The organic portion was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to yield a light brown foam.
  • the reaction mixture was treated withp-toluenesulfonyl chloride (1.13 g, 5.94 g) over 5 min and allowed to warm to ambient temperature. After 30 min, the reaction mixture was diluted with 50 mL of CHCl 3 and 25 mL of water. An undissolved solid between the phases was filtered off, saved, and the phases were separated. The organic portion was washed with saturated NaHCO 3 solution (30 mL), water (30 mL) and brine (30 mL). The organic portion was then dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to yield a tan/orange solid. A high-performance liquid chromatography (HPLC) analysis of the filtered solid matched that of the solid from the concentrated organic extracts.
  • HPLC high-performance liquid chromatography
  • reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in water), water (2 mL) and palladium(II) acetate (3.1 mg, 0.014 mmol). Again the head-space of the reaction flask was purged and back-filled with nitrogen (3X). The reaction was heated to 100° C. After 17 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown solid. The solid was dissolved and partitioned between 15 mL of water and 15 mL of chloroform and then separated. The aqueous portion was extracted with chloroform (2 X 15 mL).
  • 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.
  • the oil was dissolved in 200 mL of 1-butanol and treated with pyridinium/>- toluenesulfonate (0.25 g, 1.0 mmol). The mixture was heated to 135 0 C under an atmosphere of nitrogen. After 20 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 250 mL Of CHCl 3 and washed with saturated NaHCO 3 solution (75 mL), water (75 mL) and brine (75 mL). The organic portion was then dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give an orange/brown oil.
  • the reaction mixture was poured into saturated aqueous sodium thiosulfate and stirred until solution became colorless.
  • the organic layer was separated and washed sequentially with saturated aqueous sodium thiosulfate, water, and brine; dried over anhydrous magnesium sulfate; filtered; and concentrated under reduced pressure to a pale yellow oil.
  • the oil was purified by flash column chromatography (eluting with 80:20 hexanes: ethyl acetate) to a pale yellow oil which slowly crystallizes upon standing to afford 16.2 g of tert-butyl 3-iodopropylcarbamate as a yellow solid.
  • the mixture was diluted with 25 mL CHCl 3 , mixed and then separated. The organic portion was washed with H 2 O (15 mL) and brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to yield a tan foam.
  • the foam was purified by chromatography (SiO 2 , 96:4 CHCl 3 : methanol (MeOH)) to yield a light tan solid. The solid was dissolved in boiling 2-propanol (IPA), cooled to ambient temperature and then water was added until an off-white solid precipitated from solution.
  • IPA 2-propanol
  • the foam was purified by chromatography (SiO 2 , 30% (80:18:2 CHCl 3 MeOH: cone, ammonium hydroxide (NH 4 OH)) in CHCl 3 ) to give an off-white solid.
  • the filter pad was washed with additional 4: 1 CHCl 3 :MeOH (1% TFA).
  • the clear colorless filtrate was concentrated under reduced pressure to yield a white semi ⁇ solid.
  • the material was suspended in 15 mL OfH 2 O and treated with 50% NaOH solution until the pH of the liquid reached 13. The material was triturated with the basic H 2 O for 2 h. An off white solid was collected by vacuum filtration and dried.
  • reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in H 2 O), H 2 O (2 mL) and palladium (II) acetate (3.1 mg, 0.014 mmol). Again the headspace of the reaction flask was purged and back-filled with nitrogen (3X). The reaction was heated to 100 0 C. After 17 h, the reaction was cooled to ambient temperature and concentrated under reduced pressure to yield a brown solid. The solid was partitioned between 15 mL of H 2 O and 15 mL of CHCl 3 and then separated. The aqueous portion was extracted with CHCl 3 (2 X 15 mL).
  • reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in H 2 O), H 2 O (2 mL), and palladium (II) acetate (3.1 mg, 0.014 mmol). Again the headspace of the flask was purged and back filled with nitrogen (3X). The reaction mixture was heated to 100 0 C. After 16 h, the reaction mixture was concentrated under reduced pressure to yield a brown solid. The solid was partitioned between CHCl 3 (45 mL) and H 2 O (15 mL) and separated.
  • reaction mixture was then treated with triphenylphosphine (11 mg, 0.041 mmol), sodium carbonate (1.66 mL, 3.31 mmol, 2 M solution in H 2 O), H 2 O (2 mL), and palladium (II) acetate (3.1 mg, 0.014 mmol). Again the headspace of the flask was purged and back-filled with nitrogen (3X). The reaction mixture was heated to 100 0 C. After 16 h, the reaction mixture was concentrated under reduced pressure to yield a brown solid. The solid was partitioned between CHCl 3 (45 mL) and H 2 O (15 mL) and separated.
  • the reaction mixture was treated with potassium vinylfluoroborate (0.695 g, 5.19 mmol) and dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.069 g, 0.094 mmol) and the head-space purged and backfilled as before.
  • the reaction was heated to 100 0 C. After 16 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of CHCl 3 and washed with 5% Na 2 CO 3 solution (15 mL). There was a thick emulsion that did not fully separate.
  • Part B A suspension of palladium (II) acetate (0.067 g, 0.30 mmol) and tri-o- tolylphosphine (0.271 g, 0.891 mmol) in 10 mL of MeCN was placed in a 50 mL heavy wall glass pressure flask and placed under an atmosphere of nitrogen. The mixture was stirred until homogeneous.
  • the solid was purified by chromatography (SiO 2 , 20-50% (80: 18:2 CHCl 3 :MeOH:NH 4 ⁇ H) in CHCl 3 ) to yield N 1 -isopropyl-2-propyl-7-(2- ⁇ yridin-3-yl- vmyl)-lH-imidazo[4,5-c]qumoline-l,4-diamine (0.97 g) as a light yellow solid.
  • 2-Ethyl-N 1 -isopropyl-lH-imidazo[4,5-c]quinoline-l,4-diamine was prepared in 5 steps from tert-butyl N-(3-aminoquinolin-4-yl)hydrazinecarboxylate in analogous fashion to the preparation of N 1 -Isopropyl-2-propyl-lH-imidazo[4,5-c]quinoline-l,4-diamine (Example 16). Triethyl orthopropionate was used in lieu of trimethyl orthobutyrate.
  • the oil was suspended in a minimum amount OfH 2 O and treated with 50% NaOH solution until the pH of the liquid was 12-13.
  • the mixture was extracted with CH 2 Cl 2 (3 X 15 mL).
  • the combined organic extracts were washed with brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to yield an off-white solid.
  • the solid was purified by chromatography (SiO 2 , 15- 20% (80:18:2 CHCl 3 :MeOH:NH 4 OH) in CHCl 3 ) to yield a white solid.
  • the filtrate was concentrated under reduced pressure to yield a clear, colorless oil.
  • the oil was suspended in 25 mL OfH 2 O and treated with 50% NaOH until the pH of the liquid reached 13. A white solid precipitated. The solid was triturated in the basic solution for 15 min and then filtered to give a white solid.
  • the solid was treated with 6 M aqueous hydrochloric acid (20 mL) to form a white suspension that was stirred at 50 0 C for 2 hours. The mixture was allowed to cool to room temperature and was adjusted to p ⁇ 7 with 50% aqueous sodium hydroxide solution. A white solid was isolated by filtration, washed with water, and dried under vacuum.
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formula I- Id and the following Ri, R 2 , and R 3 substituents, wherein each line of the table represents a specific compound.
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formulas (Ii, lib, Ij, or Ik) and the following Ri and R 2 substituents, wherein each line of the table is matched with Formula Ii, lib, Ij, or Ik to represent a specific compound.
  • cytokine induction An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon and tumor necrosis factor ( ⁇ ) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. in “Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
  • ⁇ interferon and tumor necrosis factor
  • PBMC Peripheral blood mononuclear cells
  • HISTOP AQUE-1077 Blood is diluted 1 : 1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced Salts Solution (HBSS).
  • DPBS Dulbecco's Phosphate Buffered Saline
  • HBSS Hank's Balanced Salts Solution
  • the PBMC layer is collected and washed twice with DPBS or HBSS and resuspended at 4 x 10 6 cells/mL in RPMI complete.
  • the PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells.
  • the compounds are generally tested at concentrations ranging from 30-0.014 ⁇ M.
  • test compound is added at 60 ⁇ M to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells.
  • the PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (30-0.014 ⁇ M).
  • the final concentration of PBMC suspension is 2 x 10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere. Separation:
  • the plates are centrifuged for 10 minutes at 1000 rpm ( ⁇ 200 x g) at 4 0 C.
  • the cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to sterile polypropylene tubes. Samples are maintained at -30 to -70 0 C until analysis.
  • the samples are analyzed for interferon ( ⁇ ) by ELISA and for tumor necrosis factor ( ⁇ ) by ELISA or IGEN Assay.
  • Interferon ( ⁇ ) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL.
  • Tumor necrosis factor ( ⁇ ) (TNF) concentration is determined using ELISA kits available from Biosource International, Camarillo, CA. Alternately, the TNF concentration can be determined by ORIGEN M-Series Immunoassay and read on an IGEN M-8 analyzer from IGEN International, Gaithersburg, MD. The immunoassay uses a human TNF capture and detection antibody pair from Biosource International,
  • Certain compounds of the invention may modulate cytokine biosynthesis by inhibiting production of tumor necrosis factor ⁇ (TNF- ⁇ ) when tested using the method described below.
  • TNF- ⁇ tumor necrosis factor ⁇
  • the mouse macrophage cell line Raw 264.7 is used to assess the ability of compounds to inhibit tumor necrosis factor- ⁇ (TNF- ⁇ ) production upon stimulation by lipopolysaccharide (LPS).
  • TNF- ⁇ tumor necrosis factor- ⁇
  • LPS lipopolysaccharide
  • Blood Cell Preparation for Culture Raw cells are harvested by gentle scraping and then counted.
  • the cell suspension is brought to 3 x 10 5 cells/mL in RPMI with 10 % fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • Cell suspension 100 ⁇ L is added to 96-well flat bottom sterile tissues culture plates (Becton Dickinson Labware, Lincoln Park, NJ).
  • the final concentration of cells is 3 x 10 4 cells/well.
  • the plates are incubated for 3 hours. Prior to the addition of test compound the medium is replaced with colorless RPMI medium with 3 % FBS.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells.
  • Compounds are tested at 5 ⁇ M.
  • LPS Lipopolysaccaride from Salmonella typhimurium, Sigma-Aldrich
  • EC 70 concentration as measured by a dose response assay.
  • test compound l ⁇ l
  • the plates are mixed on a microtiter plate shaker for 1 minute and then placed in an incubator. Twenty minutes later the solution of LPS (1 ⁇ L, EC 70 concentration ⁇ 10 ng/ml) is added and the plates are mixed for 1 minute on a shaker. The plates are incubated for 18 to 24 hours at 37 0 C in a 5 % carbon dioxide atmosphere.
  • TNF- ⁇ Analysis Following the incubation the supernatant is removed with a pipet. TNF- ⁇ concentration is determined by ELISA using a mouse TNF- ⁇ kit (from Biosource International, Camarillo, CA). Results are expressed in pg/mL. TNF- ⁇ expression upon LPS stimulation alone is considered a 100% response.
  • Raw cells are harvested by gentle scraping and then counted.
  • the cell suspension is brought to 4 x 10 5 cells/mL in RPMI with 10 % FBS.
  • Cell suspension 250 ⁇ L is added to 48-well flat bottom sterile tissues culture plates (Costar, Cambridge, MA). The final concentration of cells is 1 x 10 5 cells/well. The plates are incubated for 3 hours.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells.
  • Compounds are tested at 0.03, 0.1, 0.3, 1, 3, 5 and 10 ⁇ M. LPS
  • test compound 200 ⁇ l
  • the plates are mixed on a microtiter plate shaker for 1 minute and then placed in an incubator. Twenty minutes later the solution of LPS (200 ⁇ L, EC 7O concentration ⁇ 10 ng/ml) is added and the plates are mixed for 1 minute on a shaker. The plates are incubated for 18 to 24 hours at 37 0 C in a 5 % ⁇ arbon dioxide atmosphere.
  • TNF- ⁇ concentration is determined by ELISA using a mouse TNF- ⁇ kit (from Biosource International, Camarillo, CA). Results are expressed in pg/mL. TNF- ⁇ expression upon LPS stimulation alone is considered a 100% response.

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Abstract

L'invention concerne des composés de 1-amino 1-H--imidazoquinoline, des compositions pharmaceutiques contenant les composés, des intermédiaires, et des méthodes de conception et d'utilisation desdits composés en tant qu'immunomodulateurs, dans la modulation de la biosynthèse de la cytokine chez des animaux et dans le traitement de maladies, notamment, des maladies virales et néoplasiques.
PCT/US2004/028754 2004-09-03 2004-09-03 1-amino 1-h-imidazoquinolines Ceased WO2006028451A1 (fr)

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