WO2007079086A1 - Composés imidazo cycliques substitués par des groupements pyrazoloalkyle et méthodes - Google Patents

Composés imidazo cycliques substitués par des groupements pyrazoloalkyle et méthodes Download PDF

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WO2007079086A1
WO2007079086A1 PCT/US2006/049307 US2006049307W WO2007079086A1 WO 2007079086 A1 WO2007079086 A1 WO 2007079086A1 US 2006049307 W US2006049307 W US 2006049307W WO 2007079086 A1 WO2007079086 A1 WO 2007079086A1
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alkyl
group
aryl
hydrogen
heteroaryl
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PCT/US2006/049307
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English (en)
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David S. Hays
Tushar A. Kshirsagar
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Coley Pharmaceutical Group, Inc.
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Publication of WO2007079086A1 publication Critical patent/WO2007079086A1/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
    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • IRMs immune response modifiers
  • the compounds or salts of Formula I are useful as IRMs due to their ability to modulate cytokine biosynthesis (e.g., induce the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals.
  • the ability to modulate cytokine biosynthesis 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 invention further provides pharmaceutical compositions containing an effective amount of a compound of Formula I and methods of inducing cytokine biosynthesis in an animal, treating a viral infection or disease and/or treating a neoplastic disease in an animal by administering an effective amount of a compound of Formula I to the animal.
  • the present invention provides compounds of the following Formula I:
  • X, Rj, RA, RB, RAU RBI, Ra. Rb, Rc, R ⁇ , Gi, m, and n are as defined below; and pharmaceutically acceptable salts thereof.
  • the present invention provides a compound of the following Formula I:
  • R 1 is selected from the group consisting of: ,
  • X is selected from the group consisting of -CH(Ra)- and -CH(R. 3 )-alkylene-;
  • R 2 is selected from the group consisting of R 2a and R 2b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl;
  • R2b is selected from the group consisting Of -CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH-C(O)-C, ⁇ alkyl, and -CH 2 -NH-C(O)-N(R') ⁇ wherein each R' is independently hydrogen, methyl or ethyl; RA and RB taken together form either a fused aryl ring that is unsubstituted or substituted by one or more R 3 groups, or a fused 5 to 7 membered saturated ring that is unsubstituted or substituted by one or more R 0 groups; or R A and R B taken together form either a fused heteroaryl ring that is unsubstituted or substituted by one or more R b groups, or a 5 to 7 membered saturated ring containing one heteroatom selected from the group consisting of N and S, and that is unsubstituted or substituted
  • Ri a> Ri bs and R] C are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(0)o- 2 -alkyl, -S(0)o- 2 -aryl,
  • each of R ⁇ and Rj 0 can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of R ⁇ and Ri c can be -N(Rg) 2 or -N(Rs)-Q-R 7 ;
  • R 3 is selected from the group consisting of alkyl, alkoxy, fluoro, chloro, and trifluoromethyl;
  • Rb is selected from the group consisting of alkyl, alkoxy, hydroxy, fluoro, chloro, and trifluoromethyl;
  • R 0 is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl
  • R3 is selected from the group consisting of hydrogen and C 1-4 alkyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl;
  • R 5 is selected from the group consisting of hydrogen and alkyl
  • R 7 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 consist
  • Rs is selected from the group consisting of hydrogen, C MO alkyl, C 2 .io alkenyl, hydroxy-Cj-io alkylenyl, Ci -1O alkoxy-Ci-n) alkylenyl, aryl-Ci-io alkylenyl, and heteroaryl-Ci-io alkylenyl;
  • Q is selected from the group consisting of a bond, -C(R ⁇ )-, -C(Ro)-C(Rg)-, -S(O) 2 -, -C(Rs)-N(Rs)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(Re)-S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • Ri is selected from the group consisting of:
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R 3 )-alkylene-;
  • R 2 is selected from the group consisting of R 2a and R ⁇ b wherein: R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; and
  • R 2b is selected from the group consisting of -C ⁇ -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 33 -CH 2 -NH-C(O)-Ci -4 alkyl > and -CH 2 -NH-C(O)-N(R')R' wherein each R' is independently hydrogen, methyl or ethyl;
  • R la , Ri b , and R lc are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting
  • each of Rib and R 10 can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of R ⁇ and Rj 0 can be -N(Rs) 2 or -N(Rs)-Q-R 7 ;
  • Ra is selected from the group consisting of alkyl, alkoxy, fluoro, chloro, and trifluoromethyl; n is 0, 1, 2, 3, or 4;
  • R3 is selected from the group consisting of hydrogen and Ci ⁇ alkyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl
  • Rs is selected from the group consisting of hydrogen, C M0 alkyl, C2-ioalkenyl, hydroxy-Ci-ioalkylenyl, Ci-ioalkoxy-Ci.jo alkylenyl, aryl-Ci-ioalkylenyl, and heteroaryl-Ci-io alkylenyl;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Re)-C(Ro)-, -S(O) 2 -, -CCRe)-N(Rg)-W-, -S(O) 2 -N(R 8 )-, -C(R 6 )O-, -C(R 6 )-S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • Ri is selected from the group consisting of:
  • X is selected from the group consisting of -CH(Rs)- and -CH(R. 3 )-alkylene-;
  • R 2 is selected from the group consisting of R 28 and R 2 b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl;
  • R2b is selected from the group consisting of -CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH-C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R' is independently hydrogen, methyl or ethyl;
  • R 1 a , Rib, and R 1 c are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consist
  • each of R ⁇ and Ri c can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of R ⁇ and Ri 0 can be -N(Rs) 2 or -N(Rs)-Q-R 7 ;
  • R 0 is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl; n is O, 1, 2, 3, or 4;
  • R3 is selected from the group consisting of hydrogen and C1.4 alkyl
  • R4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl
  • R5 is selected from the group consisting of hydrogen and alkyl
  • R 7 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;
  • Rs is selected from the group consisting of hydrogen, C I - I Q alkyl, C 2- io alkenyl, hydroxy-Ci-ioalkylenyl, Ci-joalkoxy-Ci-io alkylenyl, aryl-Ci-ioalkylenyl, and heteroaryl-Ci.io alkylenyl;
  • Q is selected from the group consisting of a bond, -C(Re)-, -C(Re)-C(Re)-, -S(O) 2 -, -C(Re)-N(Rs)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(Re)-S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • Ri is selected from the group consisting of:
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R 3 )-alkylene-;
  • R 2 is selected from the group consisting of R 28 and R 2b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxy alkylenyl;
  • R 2b is selected from the group consisting of -CH2-NH-SO2-CH3, -CH 2 -NH-SO 2 -CH 2 CH 35 -CH 2 -NH-C(O)-C walkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R 1 is independently hydrogen, methyl or ethyl;
  • Ri a, Rib, and Ri c are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(0)o -2 -alkyl, -S(0)o -2 -aryl, -NH-S(O) 2 -alkyl, -NH-S(O) 2 -aryl, haloalkoxy, halogen, cyano, nitro, aryl
  • each of R ⁇ and Ri c can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of R ⁇ and Rj 0 can be -N(Rs) 2 or -N(Rs)-Q-R 7 ;
  • Rb is selected from the group consisting of alkyl, alkoxy, hydroxy, fluoro, chloro, and trifluoromethyl; m is O, 1, 2, or 3;
  • R 3 is selected from the group consisting of hydrogen and C M alkyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl
  • R 5 is selected from the group consisting of hydrogen and alkyl
  • R 7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • R is selected from the group consisting of:
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R 3 )-alkylene-;
  • R 2 is selected from the group consisting of R 2a and R 2 b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl;
  • R 2b is selected from the group consisting Of-CH 2 -NH-SO 2 -CHs, -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH-C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R' is independently hydrogen, methyl or ethyl; Ri a , Ri b , and Rj 0 are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:
  • each of R ⁇ and Ri c can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of Rib and Rj c can be -N(Rs)2 or -N(Rs)-Q-R 7 ;
  • R 0 is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
  • m is O, 1, 2, or 3;
  • R.3 is selected from the group consisting of hydrogen and Ci -4 alkyl
  • R4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl
  • R-5 is selected from the group consisting of hydrogen and alkyl
  • R 7 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;
  • alkyl C 2 -10 alkenyl, hydroxy-Ci-ioalkylenyl, alkylenyl, aryl-Ci-ioalkylenyl, and heteroaryl-Ci-io alkylenyl;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Re)-C(Rg)-, -S(O) 2 -, -C(Re)-N(Rg)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(Re)-S-, and -C(Re)-N(OR 5 )-; and W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; d or a pharmaceutically acceptable salt thereof.
  • Ri is selected from the group consisting of:
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R 3 )-alkylene-;
  • R 2 is selected from the group consisting of R 2a and R 2b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl;
  • R 2 b is selected from the group consisting of -CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 35 -CH 2 -NH-C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R 1 is independently hydrogen, methyl or ethyl;
  • RAI and RBI are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(Rs) 2 ;
  • R-Ia 9 Rib, and Ri 0 are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(0)o- 2 -alkyl,
  • each of Rib and Ri c can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of Ri b and Ri 0 can be -N(Rs) 2 or -N(Rs)-Q-R 7 ;
  • Ra is selected from the group consisting of hydrogen and C 1 -4 alkyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl;
  • Rs is selected from the group consisting of hydrogen and alkyl
  • R 7 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
  • Rs is selected from the group consisting of hydrogen, Cj-io alkyl, C 2-1O alkenyl, hydroxy-Ci-ioalkylenyl, Ci-ioalkoxy-Cj-ioalkylenyl, aryl-Cj-ioalkylenyl, and heteroaryl-Ci-io alkylenyl;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Re)-C(R 6 )-, -S(O) 2 -, -C(Rg)-N(Rs)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(R 6 )S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of the following Formula XI, which is a prodrug:
  • Gi is selected from the group consisting of: -C(O)-R", ⁇ -aminoacyl, ⁇ -aminoacyl- ⁇ -aminoacyl, -C(O)-O-R", -C(O)-N(R"')R",
  • R" and R" 1 are independently selected from the group consisting of C M0 alkyl, C3.7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C ⁇ .$ alkyl, C ⁇ alkoxy, aryl, heteroaryl, aryl-Ci- 4 alkylenyl, heteroaryl-Ci- 4 alkylenyl,. halo-Ci-4 alkylenyl, halo-Ci- 4 alkoxy, -O-C(O)-CH 3 ,
  • R"' can also be hydrogen
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids
  • Yi is selected from the group consisting of hydrogen, Ci- ⁇ alkyl, and benzyl
  • Yo is selected from the group consisting of C 1. 6 alkyl, carboxy-Ci-6 alkylenyl, amino-C ⁇ alkylenyl, mono-iV-Ci-galkylamino-C M alkylenyl, and di-iV,JV-Ci. 6 alkylamino-C t . 4 alkylenyl; and
  • Y 2 is selected from the group consisting of mono-N-Ci.6 alkylamino, di-N,N-C ⁇ ⁇ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, and
  • Ri is selected from the group consisting of:
  • X is selected from the group consisting of -CH(Ra)- and -CH(R 3 )-alkylene-;
  • R2 is selected from the group consisting OfR 28 and R2b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl;
  • R 2 b is selected from the group consisting Of-CH 2 -NH-SO 2 -CHs, -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH-C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R' is independently hydrogen, methyl or ethyl; R A and R B taken together form either a fused aryl ring that is unsubstituted or substituted by one or more R a groups, or a fused 5 to 7 membered saturated ring that is unsubstituted or substituted by one or more R 0 groups; or R A and R B taken together form either a fused heteroaryl ring that is unsubstituted or substituted by one or more Rb groups, or a 5 to 7 membered saturated ring containing one heteroatom selected from the group consisting of N and S, and that is unsubstituted or substituted by one
  • Ri a , Ri b , and Rj c are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(O) 0-2 -alkyl,
  • each of Ri b and R 10 can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of R] b and Ri c can be -N(Rs) 2 or -N(Rs)-Q-R 7 ;
  • R a is selected from the group consisting of alkyl, alkoxy, fluoro, chloro, and trifluoromethy 1 ;
  • Rb is selected from the group consisting of alkyl, alkoxy, hydroxy, fluoro, chloro, and trifluoromethyl;
  • Rc is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
  • R3 is selected from the group consisting of hydrogen and Ci -4 alkyl;
  • R4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl;
  • Rs is selected from the group consisting of hydrogen and alkyl
  • R 7 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; nitro; hydroxy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; (dialkylamino)alkyleneoxy; and, in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;
  • Rg is selected from the group consisting of hydrogen, C no alkyl, C2-10 alkenyl, hydroxy-Ci.io alkylenyl, Ci-ioalkoxy-Ci-ioalkylenyl, aryl-Cno alkylenyl, and heteroaryl-C 1 -i 0 alkylenyl;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Rg)-C(R 6 )-, -S(O) 2 -, -C(Re)-N(Rg)-W-, -S(O) 2 -N(Rg)-, -C(Re)-O-, -C(Re)-S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • the present invention provides an intermediate compound of Formula XII:
  • Ri is selected i from the group consisting of:
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R 3 )-alkylene-;
  • R2 is selected from the group consisting of R 2a and R 2b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; and R 2b is selected from the group consisting of -CH 2 -NH-SO 2 -CH 3 ,
  • Rib and Ri c are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino,
  • R 1 b and Ri c can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of Rib and Ri c can be -N(Rs) 2 or -N(Rs)-Q-R 7 ;
  • R a is selected from the group consisting of alkyl, alkoxy, fluoro, chloro, and trifluoromethyl ;
  • n is O, 1, 2, 3, or 4;
  • R 3 is selected from the group consisting of hydrogen and Ci -4 alkyl;
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl; Rs is selected from the group consisting of hydrogen and alkyl;
  • R 7 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;
  • Rg is selected from the group consisting of hydrogen, Ci.10 alkyl, C 2- io alkenyl, hydroxy-Ci_io alkylenyl, C MO alkoxy-Ci-io alkylenyl, aryl-Ci -io alkylenyl, and heteroaryl-Ci-10 alkylenyl;
  • Q is selected from the group consisting of a bond, -C(Re)-, -C(Re)-C(R 6 )-, -S(O) 2 -, -C(Re)-N(Rs)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(Re)-S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • the present invention provides an intermediate compound of Formula XIII:
  • Ri is selected from the group consisting of: ,
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R3)-alkylene-;
  • R 2 is selected from the group consisting of R 2a and R 2b wherein:
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl;
  • R 2b is selected from the group consisting Of-CH 2 -NH-SO 2 -CHa, -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH-C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R f is independently hydrogen, methyl or ethyl;
  • R AI and RBI are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and
  • Ri b , and Ri c are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl. arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino,
  • each of Rib and Ri c can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of Rjb and Ri c can be -N(Rs) 2 or -N(Rs)-Q-R 7 ;
  • R 3 is selected from the group consisting of hydrogen and C M alkyl;
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl;
  • R 5 is selected from the group consisting of hydrogen and alkyl
  • R 7 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 consist
  • R. 8 is selected from the group consisting of hydrogen, Ci-io alkyl, C 2 -io alkenyl, hydroxy-Ci-ioalkylenyl, Ci.ioalkoxy-Ci-ioalkylenyl, aryl-Ci.joalkylenyl, and heteroaryl-Ci-io alkylenyl;
  • Q is selected from the group consisting of a bond, -C(Rg)-, -C(Rg)-C(R 6 )-,
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • the present invention provides an intermediate compound of Formula XIV:
  • Rj is selected from the group consisting of:
  • X is selected from the group consisting of -CH(R 3 )- and -CH(R 3 )-alkylene-;
  • R 2 is selected from the group consisting OfR 23 and R 2 b wherein: R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; and
  • R. 2b is selected from the group consisting of -CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH 1 C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R 1 is independently hydrogen, methyl or ethyl;
  • Ri a, Ri b» and Ri c are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroary lalky leny 1 , heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(O) 0-2 -alkyl,
  • each of R ⁇ and Rj 0 can be further independently selected from the group consisting of halogen, -N(R 5 ) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of R ⁇ and R lc can be -N(Rs) 2 or -N(R 5 )-Q-R 7 ;
  • R 3 is selected from the group consisting of alkyl, alkoxy, fiuoro, chloro, and trifiuoromethyl; n is O, 1, 2, 3, or 4;
  • R 3 is selected from the group consisting of hydrogen and C 1 - 4 alkyl
  • R4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl
  • R 5 is selected from the group consisting of hydrogen and alkyl
  • R 7 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;
  • Q is selected from the group consisting of a bond, -C(Re)-, -C(Re)-C(Re)-, -S(O) 2 -, -C(Re)-N(Rg)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(Re)-S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • the present invention provides an intermediate compound of Formula XV:
  • Ri is selected from the group consisting of:
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R 3 )-alkylene-;
  • R 2 is selected from the group consisting of R 2 a and R2b wherein: -
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl;
  • R 2b is selected from the group consisting Of-CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 35 -CH 2 -NH-C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R' ⁇ 1 wherein each R' is independently hydrogen, methyl or ethyl; Ri a> Rib, and R lc are each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of: hydroxy, alky
  • each of R ⁇ and Ri 0 can be further independently selected from the group consisting of halogen, -N(Rs) 2 , and -N(Rs)-Q-R 7 ; and with the further proviso that only one of R ⁇ and Rj 0 can be -N(Rs) 2 or -N(Rs)-Q-R?;
  • R b is selected from the group consisting of alkyl, alkoxy, hydroxy, fluoro, chloro, and trifluoromethyl;
  • m is O, 1, 2, or 3;
  • R 3 is selected from the group consisting of hydrogen and CM alkyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl
  • R 5 is selected from the group consisting of hydrogen and alkyl
  • R 7 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;
  • Rs is selected from the group consisting of hydrogen, Ci-ioalkyl, C2-10 alkenyl, hydroxy-Ci- t oalkylenyl, Ci-ioalkoxy-Ci_ioalkylenyl, aryl-Ci. 10 alkylenyl, and heteroaryl-Ci-ioalkylenyl;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Ro)-C(Rg)-, -S(O) 2 -, -C(Re)-N(Rg)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(R ⁇ )-S-, and -C(Re)-N(OR 5 )-; and
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; or a pharmaceutically acceptable salt thereof.
  • alkyl As used herein, the terms “alkyl,” “alkenyl,” “alkynyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, e.g., cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 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 alkenylene
  • alkynylene are the divalent forms of the “alkyl”, “alkenyl”, and “alkynyl” groups defined above.
  • the terms, “alkylenyl”, “alkenylenyl”, and “alkynylenyl” are use when “alkylene”, “alkenylene”, and “alkynylene", respectively, are substituted.
  • an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached.
  • hydroxyalkylenyl, haloalkylenyl, and haloalkyleneoxy have the same meaning as hydroxyalkyl, haloalky 1, and haloalkoxy, respectively.
  • haloalkyl is inclusive of 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 5 N).
  • heteroaryl includes a ring or ring system that contains 2-12 carbon atoms, 1-3 rings, 1-4 heteroatoms, and O,
  • heteroaryl includes one ring that contains 2-5 carbon atoms, 1-3 heteroatoms, and O, S, and N as the heteroatoms.
  • exemplary 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-oxidopyrid
  • heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
  • heterocyclyl includes a ring or ring system that contains 2-12 carbon atoms, 1-3 rings, 1-4 heteroatoms, and O, S, and N as the heteroatoms.
  • heterocyclyl includes one or two rings that contain 2-9 carbon atoms or 2-5 carbon atoms, 1-3 heteroatoms, and O, S, and N as the heteroatoms.
  • heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1 ,1- dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1,4- oxazepanyl, homopiperazinyl (diazepanyl), 1 ,3-dioxolanyl, aziridinyl, azetidinyl, dihydroisoquinolin-( 1 H)-yl, octahydroisoquinolin-( 1 H)-yl, dihydroquinolin-(2#)-yl, octahydroquinolin-(2H)-yl ⁇ dihydr
  • heterocyclyl includes bicylic and tricyclic heterocyclic ring systems. Such ring systems include fused and/or bridged rings and spiro rings. Fused rings can include, in addition to a saturated or partially saturated ring, an aromatic ring, for example, a benzene ring. Spiro rings include two rings joined by one spiro atom and three rings joined by two spiro atoms.
  • heterocyclyl contains a nitrogen atom
  • the point of attachment of the heterocyclyl group may be the nitrogen atom
  • arylene is the divalent forms of the "aryl”, “heteroaryl”, and “heterocyclyl” groups defined above.
  • arylenyl is used when “arylene”, “heteroarylene”, and “heterocyclylene”, respectively, are substituted.
  • an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
  • fused aryl ring includes fused carbocyclic aromatic rings or ring systems.
  • fused aryl rings examples include benzo, naphtho, fluoreno, and indeno.
  • fused heteroaryl ring includes the fused forms of 5 or 6 membered aromatic rings that contain one heteroatom selected from S and N. Examples of fused heteroaryl rings include pyrido and thieno.
  • fused 5 to 7 membered saturated ring includes rings which are fully saturated except for the bond where the ring is fused, for example a cyclohexene ring and a tetrahydropyridine ring (when one nitrogen atom is present).
  • each group is independently selected, whether explicitly stated or not.
  • each R4 group is independently selected for the formula -C(O)-N(R4) 2
  • each R' group is independently selected.
  • the invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, prodrugs, and the like.
  • isomers e.g., diastereomers and enantiomers
  • salts e.g., sodium bicarbonate
  • solvates e.g., sodium bicarbonate
  • polymorphs e.g., sodium bicarbonate
  • prodrugs e.g., sodium bicarbonate
  • the term “compound” includes any or all of such forms, whether explicitly stated or not (although at times, “salts" are explicitly stated).
  • prodrug means a compound that can be transformed in vivo to yield an immune response modifying compound, including any of the salt, solvated, polymorphic, or isomeric forms described above.
  • the prodrug itself, may be an immune response modifying compound, including any of the salt, solvated, polymorphic, or isomeric forms described above.
  • the transformation may occur by various mechanisms, such as through a chemical (e.g., solvolysis or hydrolysis, for example, in the blood) or enzymatic biotransformation.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • Ri, R 2 , Ria, Rib, Ric Rs, R ⁇ , Gi, Q, X, and so on in any of its embodiments can be combined with any one or more of the other variables in any of their embodiments and associated with any one of the formulas described herein, as would be understood by one of skill in the art.
  • Each of the resulting combinations of variables is an embodiment of the present invention.
  • the fused aryl ring is unsubstituted.
  • the fused aryl ring is benzo.
  • the fused 5 to 7 membered saturated ring is a cyclohexene ring.
  • the fused heteroaryl ring is unsubstituted.
  • the ring is pyrido.
  • the ring is unsubstituted.
  • the ring is tetrahydropyrido.
  • R AI and R BI are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(Rs) 2 .
  • RAI and R BI are independently selected from the group consisting of hydrogen and alkyl.
  • RAI and RB 1 are each methyl.
  • n is 0, 1, 2, 3, or 4.
  • n is 0, 1, or 2.
  • n is 0 or 1.
  • n is 0.
  • the compound selected from the group consisting of Formulas IV, V, and VI, or a pharmaceutically acceptable salt thereof is the compound of Formula IV or a pharmaceutically acceptable salt thereof.
  • the compound selected from the group consisting of Formulas VII, VII, and IX, or a pharmaceutically acceptable salt thereof is the compound of Formula VII or a pharmaceutically acceptable salt thereof.
  • m is 0, 1, 2, or 3.
  • m is 0, or 1.
  • m is 0.
  • m is 0.
  • R 2 is selected from the group consisting OfR 28 , R 2b> and R 2c wherein R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; R 2 b is selected from the group consisting Of -CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH-C(O)-C M alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R' is independently hydrogen, methyl or ethyl; and R2 C is -NH 2 .
  • R 2 is selected from the group consisting of R 2a and R 2b wherein R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl; and R 2b is selected from the group consisting Of-CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 3 ,
  • each R 1 is independently hydrogen, methyl or ethyl.
  • R 2 is R 2a .
  • R 2a is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
  • R 2a is selected from the group consisting of hydrogen, CM alkyl, C M alkyl-O-C] 4 alkylenyl, and hydroxyCi- 4 alkylenyl.
  • R 2a is selected from the group consisting of methyl, ethyl, «-propyl, «-butyl, methoxymethyl, ethoxymethyl, 2- methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.
  • R 2a is selected from the group consisting of methyl, ethyl, w-propyl, and n-butyl.
  • R 28 is selected from the group consisting of methoxymethyl, ethoxymethyl, and 2-methoxyethyl.
  • R 2a is selected from the group consisting of hydroxymethyl and 2- hydroxyethyl.
  • R 2b is selected from the group consisting Of-CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-SO 2 -CH 2 CH 3 , -CH 2 -NH-C(O)-C ⁇ alkyl, and -CH 2 -NH-C(O)-N(R')R' wherein each R' is independently hydrogen, methyl or ethyl.
  • R 2b is -CH 2 -NH-SO 2 -CH 3 or -CH 2 -NH-SO 2 -CH 2 CH 3 .
  • R 2b is -CH 2 -NH-C(O)-C M alkyl.
  • R 2b is -CH 2 -NH-C(O)-N(R')R' wherein each R 1 is independently hydrogen, methyl or ethyl.
  • X is selected from the group consisting Of-CH(R 3 )- and -CH(R 3 )-alkylene-.
  • X is C 1 - 4 alkylene.
  • X is -CH 2 -.
  • R 1 is selected from the group consisting of:
  • Ri is .
  • Ri is
  • Ri 3 , R, b , and Ri c are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(O) 0 - 2 -alkyl
  • Rj 3 , Rib 5 and Rj c are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl, wherein alkyl, aryl, and heteroaryl are each unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl.
  • not more than one of Ri a , Rib, and Ri c is aryl or heteroaryl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl.
  • At least one of Ri 3 , Rib, and Ri 0 is other than hydrogen.
  • one of Ri a , Ru,, and Ri c is hydrogen.
  • R] 0 is hydrogen.
  • Rj 3 and R ⁇ are independently selected from the group consisting of Ci .4 alkyl and aryl which is unsubstituted or substituted by one or more substituents independently selected from fluoro and chloro
  • Ri c is hydrogen.
  • R 1 a and Rib are each independently selected from the group consisting of methyl, 4-fluorophenyl, and 4- chlorophenyl.
  • Ri 8 is C 1 ⁇ alkyl
  • Rj b is aryl which is unsubstituted or substituted by one or more substituents independently selected from fluoro and chloro
  • R 1C is hydrogen
  • Ri 3 is aryl which is unsubstituted or substituted by one or more substituents independently selected from fluoro and chloro
  • Rib is CM alkyl
  • Ri c is hydrogen.
  • aryl is 4-fluorophenyl or 4-chlorophenyl
  • C M alkyl is methyl.
  • R ⁇ or Rj 0 is -N(Rs)-Q-R 7 ; wherein R 5 is hydrogen or C 1-4 alkyl, Q is -C(O)-, -S(O) 2 -, or -C(O)-N(R 8 ), Re is hydrogen or CM alkyl, and R 7 is alkyl, aryl, heteroaryl, or heterocyclyl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl; alkoxy; hydroxyalkyl; haloalkyl; halogen; nitro; hydroxy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; hetero
  • Ri c is -N(Rs)-Q-R 7
  • R] a and R ⁇ are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl, wherein alkyl, aryl, and heteroaryl are each unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl.
  • R ⁇ is -N(R 5 )-Q-R 7
  • Rj 3 and Ri c are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl, wherein alkyl, aryl, and heteroaryl are each unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, and haloalkyl.
  • Ri b or R] 0 is -N(Rs)-Q-R 7 , or where R ⁇ b is -N(R 5 )-Q-R 7 , or where Ri distortion is -N(R 5 )-Q-R 7 , R 5 is hydrogen, Q is -C(O)- or -S(O) 2 -, and R 7 is C 1.3 alkyl.
  • -N(R 5 )-Q-R 7 is methylsulfonylamino, methylcarbonylamino,or cyclopropylcarbonylamino.
  • R" and R'" are independently selected from the group consisting of Ci-ioalkyl, C 3 . 7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, Ci- ⁇ alkyl, CM alkoxy, aryl, heteroaryl, aryl-Ci- 4 alkylenyl, heteroaryl-C M alkylenyl, halo-Ci-4 alkylenyl, halo-C M alkoxy, -0-C(O)-CH 3 , -C(O)-O-CH 3 , -C(O)-NH 2 , -0-CH 2 -C(O)-NH 2 , -NH 2 , and -S(O) 2 -NH 2
  • Yi is selected from the group consisting of hydrogen, Ci -6 alky 1, and benzyl;
  • Yo is selected from the group consisting of Ci ⁇ alkyl, carboxy-Q. 6 alkylenyl, amino-Ci-4 alkylenyl, mono-N-Ci.6alkylamino-Ci-4 alkylenyl, and di- ⁇ iV-Ci.6 alkylamino-Ci_ 4 alkylenyl; and Y 2 is selected from the group consisting of mono-TV-Ci-e alkylamino, di- ⁇ iV-C 1-6 alky lamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, and 4-C1-4 alkylpiperazin-1-yl.
  • Gj is selected from the group consisting of -C(O)-R", ⁇ -aminoacyl, and -C(O)-O-R".
  • Gi is selected from the group consisting of -C(O)-R", ⁇ -amino-C 2 .i 1 acyl, and -C(O)-O-R".
  • ⁇ - Amino-C 2 -i 1 acyl includes ⁇ -amino acids containing a total of at least 2 carbon atoms and a total of up to 11 carbon atoms, and may also include one or more heteroatoms selected from the group consisting of O, S, and N.
  • R 2 is hydroxyalkylenyl, for example, hydroxyC 1.4 alkylenyl, hydroxymethyl, or 2- hydroxyethyl
  • the hydrogen of the hydroxy group is replaced by G 2 to form a prodrug wherein G 2 is selected from the group consisting Of-X 2 -C(O)-R", ⁇ -aminoacyl, ⁇ - aminoacyl- ⁇ -aminoacyl, -X 2 -C(O)-O-R", -C(O)-N(R'")R", and -S(O) 2 -R".
  • X 2 is selected from the group consisting of a bond; -CH 2 -O-; -CH(CH 3 )-O-; -C(CH 3 ) 2 -O-; and, in the case of -X 2 -C(O)-O-R", -CH 2 -NH-; R" and R'" are independently selected from the group consisting of Cj.ioalkyl, C 3 .
  • R'" can also be hydrogen
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L- amino acids.
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from a naturally occuring amino acid selected from the group consisting of racemic, D-, and L- amino acids.
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from an amino acid found in proteins, wherein the the amino acid is selected from the group consisting of racemic, D-, and L-amino acids.
  • G 2 is selected from the group consisting of ⁇ -amino-C 2 -s alkanoyl, C 2 -6 alkanoyl, Ci- 6 alkoxycarbonyl, and C 1-6 alkylcarbamoyl.
  • each R' is independently hydrogen, methyl or ethyl.
  • one R 1 is hydrogen, and the other R 1 is methyl.
  • one R' is methyl, and the other R' is methyl.
  • R a is selected from the group consisting of alkyl, alkoxy, fluoro, chloro, and trifluoromethyl.
  • R b is selected from the group consisting of alkyl, alkoxy, hydroxy, fluoro, chloro, and trifluoromethyl.
  • R 0 is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl.
  • R 3 is selected from the group consisting of hydrogen and CM alkyl.
  • R 3 is hydrogen.
  • R 3 is methyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, hydroxyalkylenyl, and arylalkylenyl.
  • R 4 is hydrogen or C 1 ⁇ alkyl.
  • R 4 is hydrogen.
  • R 5 is selected from the group consisting of hydrogen and alkyl.
  • R 5 is hydrogen
  • R 5 is C 1-4 alkyl.
  • Re O
  • Re S.
  • R 7 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy;
  • R 7 is alkyl, aryl, heteroaryl, or heterocyclyl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl; alkoxy; hydroxyalkyl; haloalkyl; halogen; nitro; hydroxy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; (dialkylamino)alkyleneoxy; and, in the case of alkyl and heterocyclyl, oxo.
  • R 7 is C1. 3 alkyl.
  • R 7 is methyl.
  • R 7 is cyclopropyl.
  • Rg is selected from the group consisting of hydrogen, C 1 - I o alkyl, C 2 .ioalkenyl, hydroxy-Ci-joalkylenyl, Cj-io alkoxy-Ci-ioalkylenyl, aryl-Ci.ioalkylenyl, and heteroaryl-Cnoalkylenyl.
  • Rs is hydrogen or C 1 .4 alkyl.
  • Rs is hydrogen.
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Rs)-C(R 6 )-, -S(O) 2 -, -C(Re)-N(Rg)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(R 6 )S-, and -C(Rs)-N(OR 5 )-.
  • Q is -C(O)-, -S(O) 2 -, or -C(O)-N(R 8 ).
  • Q is -C(O)- or -S(O) 2 -.
  • Q is -C(O)-.
  • Q is -S(O) 2 -.
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -.
  • W is a bond.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, and XI and a pharmaceutically acceptable carrier.
  • the present invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, and XI or a pharmaceutical composition comprising a therapeutically effective amount of any one of the above embodiments of Formulas I, II, III, IV, V.
  • the cytokine is selected from the group consisting of IFN- ⁇ , TNF - ⁇ , IL-6, IL-IO, and IL- 12.
  • the cytokine is IFN- ⁇ or TNF- ⁇ .
  • the cytokine is IFN- ⁇ .
  • the present invention provides a method of treating a viral disease in an animal in need thereof comprising administering a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas
  • the present invention provides a method of treating a neoplastic disease in an animal in need thereof comprising administering a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X 5 and XI or a pharmaceutical composition comprising a therapeutically effective amount of any one of the above embodiments of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, and XI to the animal.
  • Compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin, USA) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R. Katritsky, Otto Meth- Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v. 1- 6, Pergamon Press, Oxford, England, (1995); Barry M. Trost and Ian Fleming,
  • reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates.
  • EXAMPLES section below For more detailed description of the individual reaction steps, see the EXAMPLES section below.
  • Other synthetic routes may be used to synthesize the compounds of the invention.
  • specific starting materials and reagents are depicted in the reaction schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional methods well known to those skilled in the art.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, terf-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9- fluorenylmethoxycarbonyl (Fmoc).
  • Suitable hydroxy protecting groups include acetyl and silyl groups such as the terf-butyl dimethylsilyl group.
  • Such techniques may include, for example, all types of chromatography (high performance liquid chromatography (HPLC), column chromatography using common absorbents such as silica gel, and thin layer chromatography), recrystallization, and differential (i.e., liquid- liquid) extraction techniques.
  • HPLC high performance liquid chromatography
  • column chromatography using common absorbents such as silica gel
  • thin layer chromatography such as silica gel
  • recrystallization i.e., differential (i.e., liquid- liquid) extraction techniques.
  • compounds of the invention can be prepared according to Reaction Scheme I wherein R a , Ri, R 2a> X 3 and n are as defined above.
  • step (1) of Reaction Scheme I a 2,4-dichloro-3-nitroquinoline of Formula XX is reacted with an amine of Formula Ri-X-NH 2 to provide a compound of Formula XXI.
  • the reaction can be carried out by adding the amine to a solution of the compound of Formula XX in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine.
  • the reaction can be run at ambient temperature or at an elevated temperature such as, for example, 45 0 C.
  • Many compounds of Formula XX are known or can be prepared using known synthetic methods, see for example U.S. Patent No.
  • Amines of Formula R 1 -X-NH 2 can be prepared using known synthetic methods, including those methods described in more detail below.
  • step (2) of Reaction Scheme I a 2-chloro-3-nitroquinoline of Formula XXI is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula XXII.
  • the reduction can be carried out by adding an aqueous solution of sodium dithionite to a solution or suspension of the compound of Formula XXI in a suitable solvent such as ethanol, isopropanol, acetonitrile, or mixtures thereof.
  • the reaction can be carried out at an elevated temperature, for example, at reflux, or at ambient temperature.
  • a 2-chloroquinoline-3,4-diamine of Formula XXII is (i) reacted with an acyl halide of Formula R 23 C(O)Cl or R 23 C(O)Br and then (ii) cyclized to provide a 4-chloro-lH-imidazo[4,5-c]quinoline of Formula XXIII.
  • the acyl halide is added to a solution of the compound of Formula XXII in a suitable solvent such as acetonitrile or anhydrous dichloromethane in the presence of a base such as triethylamine.
  • the reaction can be run at a sub-ambient temperature, for example, 0° C, or at ambient temperature.
  • a sub-ambient 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.
  • the product of part (i) is refluxed in ethanol in the presence of excess triethylamine or is heated with methanolic ammonia.
  • step (3) can be carried out by reacting a compound of Formula XXII 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 XXIII.
  • 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 utilized.
  • step (4) of Reaction Scheme I a 4-chloro-lH-imidazo[4,5-c]quinoline of Formula XXIII is reacted with ammonia to provide a 4-amino-lH-imidazo[4,5-c]quinoline of Formula lie.
  • the reaction can be carried out by adding a solution of ammonia in a suitable solvent such as methanol to the compound of Formula XXIII and heating the reaction mixture at an elevated temperature such as 150 °C.
  • the reaction can be carried out in a pressure vessel.
  • R 2a is hydroxyalkylenyl
  • a methoxy- or ethoxyalkylenyl group which can be installed by using a methoxy or ethoxy- substituted carboxylic acid equivalent, for example methoxyacetyl chloride, 3- methoxypropionyl chloride, or ethoxyacetyl chloride, in step (3).
  • the dealkylation can be carried out by treating a compound wherein R 28 is methoxy- or ethoxyalkylenyl with boron tribromide in a suitable solvent such as dichloromethane at a sub-ambient temperature such as 0 0 C.
  • a suitable solvent such as dichloromethane
  • an acetoxy substituted carboxylic acid equivalent for example, acetoxyacetyl chloride
  • hydrolysis of the ester group to reveal a hydroxy group can be carried out using conventional methods.
  • intermediates of the Formula Rj-X-NH 2 can be prepared according to Reaction Scheme II wherein Ri a , R ⁇ 3 and R lc are as defined above.
  • step (1) of Reaction Scheme II a pyrazole carboxylate of the Formula XXIV is reduced to provide an alcohol of Formula XXV.
  • the reduction can be carried out by treating a solution of the pyrazole carboxylate of Formula XXIV in tetrahydrofuran (THF) with lithium aluminum hydride.
  • THF tetrahydrofuran
  • the reduction can be carried out at ambient temperature or at a sub-ambient temperature, such as 0 0 C.
  • Pyrazole carboxylates of Formula XXIV can be prepared using known synthetic methods, including those methods described in more detail below.
  • step (2) of Reaction Scheme II an alcohol of Formula XXV is converted to an azide of Formula XXVI. The conversion can be carried out in two parts.
  • a solution of an alcohol of Formula XXV in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of a base such as triethylamine to provide a sulfonic acid ester.
  • the reaction can be carried out at a sub-ambient temperature, such as -30 0 C.
  • a solution of an alcohol of Formula XXV in a suitable solvent such as dichloromethane is treated with thionyl chloride to provide a chloride.
  • the reaction can be carried out at ambient temperature.
  • a solution of the sulfonic acid ester or of the chloride in a suitable solvent such as N 1 N- dimethylformamide (DMF) is treated with sodium azide.
  • the reaction can be carried out at ambient temperature.
  • step (3) of Reaction Scheme II an azide of Formula XXVI is reduced to provide an am ⁇ nomethyl substituted pyrazole of Formula XXVII.
  • the reduction can be carried out using conventional methods such as, for example, catalytic hydrogenation, treatment with triphenylphosphine in the presence of water, and reduction with silicon hydrides catalyzed by organotin reagents.
  • intermediates of the Formula Ri-X-NH 2 can be prepared according to Reaction Scheme III wherein Ri 3 , Ri b , and R] C are as defined above.
  • a pyrazole carboxylate of Formula XXIV is converted to a pyrazole carboxamide of Formula XXVIII.
  • the reaction can be carried out by animating a pyrazole carboxylate of Formula XXIV.
  • the amination can be carried out by adding ammonium hydroxide to a solution of the pyrazole carboxylate of Formula XXrV in a suitable solvent such as methanol and heating at an elevated temperature, such as 100 0 C.
  • the reaction can be carried out in a pressure vessel.
  • step (1) can be carried out in three parts.
  • a pyrazole carboxylate of Formula XXIV is hydrolyzed to provide a pyrazole carboxylic acid.
  • the ester hydrolysis can be carried out under basic conditions by combining a solution of the pyrazole carboxylate of Formula XXIV in a suitable solvent such as methanol or ethanol with a solution of lithium hydroxide or sodium hydroxide in water.
  • the reaction can be carried out at ambient temperature.
  • a pyrazole carboxylic acid is converted to a pyrazole acid chloride.
  • the reaction can be carried out by treating a solution of the pyrazole carboxylic acid in a suitable solvent such as dichloromethane with oxalyl chloride.
  • a suitable solvent such as dichloromethane
  • the reaction can be carried out at ambient temperature.
  • the acid chloride is treated with ammonium hydroxide at a sub-ambient temperature, such as 0 0 C, to provide a pyrazole carboxamide of Formula XXVIII.
  • the conversion of the carboxylic acid to a pyrazole carboxamide of Formula XXVIII can be carried out under coupling conditions by adding 1-hydroxybenzotriazole and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to a solution of the carboxylic acid in a suitable solvent such as DMF at ambient temperature and then adding concentrated ammonium hydroxide.
  • a pyrazole carboxamide of Formula XXVIII is reduced to provide an aminomethyl substituted pyrazole of Formula XXVII.
  • the reduction can be carried out using conventional methods, for example, by treating a solution of the pyrazole carboxamide of Formula XXVIII in a suitable solvent such as THF with lithium aluminum hydride or borane.
  • pyrazole carboxylate intermediates can be prepared according to Reaction Scheme IV wherein Ru and Ri b are as defined above, hal is Br or I, and Ri d is defined below.
  • step (1) of Reaction Scheme IV a methyl ketone of Formula XXIX undergoes a Claisen condensation with diethyl oxalate to afford a 1,3-diketone of Formula XXX.
  • step (2) of Reaction Scheme IV a 1,3-diketone of Formula XXX is treated with a hydrazine of Formula Ri a NHNH 2 to provide the isomeric pyrazoles of Formulas XXXI and XXXII.
  • the reaction can be carried out by slowly adding the hydrazine to a solution of the salt of a compound of Formula XXX in a suitable solvent such as ethanol or acetic acid.
  • the reaction can be carried out at ambient temperature.
  • the isomers can be separated using conventional methods.
  • pyrazole carboxylate of Formula XXXI or XXXII is halogenated to provide a pyrazole of Formula XXXIII or XXXIV.
  • Bromination can be carried out by adding bromine to a solution of the pyrazole carboxylate of Formula XXXI or XXXII and potassium acetate in acetic acid.
  • the reaction can be carried out at ambient temperature.
  • Iodination can be carried out by adding iodine monochloride to a mixture of the pyrazole carboxylate of Formula XXXI or
  • XXXIII or XXXIV undergoes known palladium-catalyzed coupling reactions such as the Suzuki coupling and the Heck reaction.
  • a compound of Formula XXXIII or XXXIV undergoes known palladium-catalyzed coupling reactions such as the Suzuki coupling and the Heck reaction.
  • a compound of Formula XXXIII or XXXIV undergoes known palladium-catalyzed coupling reactions such as the Suzuki coupling and the Heck reaction.
  • XXXIV undergoes Suzuki coupling with a boronic acid of Formula Ri d -B(OH) 2 , an anhydride thereof, or a boronic acid ester of Formula Rid-B(O-alkyl)2; wherein R 1 d is aryl, heteroaryl, arylalkylenyl, or heteroarylalkylenyl each of which can be unsubstituted or substituted as defined in Ri c above.
  • Numerous boronic acids of Formula R I J-B(OH) 2 , anhydrides thereof, and boronic acid esters of Formula Ria-B(O-alkyl) 2 are commercially available; others can be readily prepared using known synthetic methods.
  • the Heck reaction can also be used in Reaction Scheme IV to provide compounds of Formula XXXV or XXXVI, wherein Ri a is alkenyl or substituted alkenyl such as, for example, arylalkenyl or heteroary alkenyl.
  • Several of these vinyl-substituted compounds are commercially available; others can be prepared by known methods.
  • the Suzuki coupling and Heck reaction can be carried out according to any of the methods described in U.
  • the alkenyl or substituted alkenyl group can be reduced to provide an alkyl or substituted alkyl group.
  • the reduction can be carried out by hydrogenation according to the methods described in U. S. Patent Application Publication No. 2004/0147543 (Hays et al.).
  • Compounds of Formula XXXV or XXXVI, wherein Rj d is an alkynylene or a substituted alkynylene can be prepared by palladium catalyzed coupling reactions such as the Stille coupling or Sonogashira coupling.
  • Formula XXXV or XXXVI wherein R ld is -NH-C(O)-alkyl, -NH-SO 2 -alkyl, or -NH-SO 2 -aryl.
  • the reaction can be carried out by combining a compound of Formula XXXIII or XXXIV and an amide or sulfonamide of Formulas NH 2 -C(O)-alkyl, NH2-SO 2 -alkyl, or NH 2 -SO 2 -aryl in the presence of copper (I) iodide, potassium phosphate, and racemic trans- 1,2-diaminocyclohexane in a suitable solvent such as 1,4- dioxane.
  • the reaction can be carried out at an elevated temperature such as 110 0 C.
  • Many amides and sulfonamides of these formulas are commercially available; others can be made by conventional methods.
  • These reaction conditions can also be used to couple a compound of Formula XXXIII or XXXIV with a wide variety of nitrogen-containing heterocycles to provide a compound of Formula XXXV or XXXVI wherein Ri a is -heterocyclyl wherein the heterocyclyl is attached to the pyrazole ring through a nitrogen atom.
  • certain of these compounds of Formula XXXV or XXXVI wherein Ri a is -heterocyclyl wherein the heterocyclyl is attached to the pyrazole ring through a nitrogen atom can be prepared using a palladium-mediated coupling, which can be carried out by combining a compound of the Formula XXXIII or XXXIV and the nitrogen- containing heterocyclyl compound in the presence of tris(dibenzylideneacetone)dipalladium ⁇ ( ⁇ )-2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl, sodium tert-butoxide, and a suitable solvent such as toluene.
  • a palladium-mediated coupling which can be carried out by combining a compound of the Formula XXXIII or XXXIV and the nitrogen- containing heterocyclyl compound in the presence of tris(dibenzylideneacetone)dipalladium ⁇
  • the reaction can be carried out at an elevated temperature such as 80 0 C.
  • the synthetic methods described in International Publication No. WO 2005/123080 (Merrill et al.) filed June 15, 2005 can also be used. These reaction conditions can also be used to prepare compounds wherein
  • Ri d is -NH-R 5 .
  • intermediates of the Formula R 1 -X-NH 2 can be prepared according to Reaction Scheme V wherein Ri 8 , Ric, Rs, R7, and Q are as defined above.
  • step (1) of Reaction Scheme V a nitrile of Formula XXXVII is reacted with diethyl oxalate in the presence of ethanolic sodium ethoxide to afford a cyano ketone of Formula XXXVIII.
  • the reaction can be carried out at ambient temperature and the product isolated as the sodium salt.
  • step (2) of Reaction Scheme V a cyano ketone of Formula XXXVIII is reacted with a hydrazine of formula Rj 3 NHNH 2 to afford an aminopyrazole of Formula XXXIX.
  • the reaction can be carried out in a suitable solvent system such as a mixture of ethanol and acetic acid at elevated temperature, such as the reflux temperature of the solvent system.
  • an aminopyrazole of Formula XXXIX is derivatized using conventional methods to provide a compound of Formula XL.
  • a compound of Formula XXXIX can react with an acid chloride of Formula R 7 C(O)Cl or acid anhydride of Formula [R 7 C(O)] 2 O to provide a compound of Formula XL in which Q is -C(O)-.
  • a compound of Formula XXXIX can react with sulfonyl chloride of Formula R 7 S(O) 2 Cl or a sulfonic anhydride of Formula (R 7 S(0) 2 ) 2 O to provide a compound of Formula XL in which Q is -S(O) 2 -.
  • sulfonyl chloride of Formula R 7 S(O) 2 Cl or a sulfonic anhydride of Formula (R 7 S(0) 2 ) 2 O to provide a compound of Formula XL in which Q is -S(O) 2 -.
  • Formula R 7 C(O)Cl, sulfonyl chlorides of Formula R 7 S(O) 2 Cl, and sulfonic anhydrides of Formula (R 7 S(O)2)2 ⁇ are commercially available; others can be readily prepared using known synthetic methods.
  • the reaction can be carried out by adding the acid chloride, sulfonyl chloride, or sulfonic anhydride to a solution of the compound of Formula XXXIX in a suitable solvent such as chloroform, dichloromethane, or DMF.
  • a base such as triethylamine or N, N-diisopropylethyl amine can be added.
  • Sulfamides of Formula XL where Q is -S(O ⁇ -N(Rg)-, can be prepared by reacting a compound or salt of Formula XXXIX with sulfuryl chloride to generate a sulfamoyl chloride in situ, and then reacting the sulfamoyl chloride with an amine of formula HN(Re)R 7 .
  • sulfamides of Formula XL can be prepared by reacting a compound of Formula XXXIX with a sulfamoyl chloride of Formula R 7 (Rg)N-S(O) 2 Cl.
  • the reaction can be carried out by adding the isocyanate, isothiocyanate, carbamoyl chloride, or sulfonyl isocyanate to a solution of the compound of Formula XXXIX in a suitable solvent such as DMF or chloroform.
  • a suitable solvent such as DMF or chloroform.
  • a base such as triethylamine or N, N- diisopropylethylamine can be added.
  • step (4) of Reaction Scheme V compound of Formula XL is alkylated to provide a compound of Formula XLI.
  • the introduction of an R 5 alkyl group may be achieved by treatment with an alkyl bromide or iodide as described in Wise, L. D. et ah, J. Med. Chem.y 29, pp. 1628-1637, (1986).
  • R 5 is hydrogen
  • step (4) is omitted.
  • steps (5) through (7) of Reaction Scheme V a compound of Formula XLI is converted to an aminomethyl substituted pyrazole of Formula XLII using the methods of steps (1) through (3) respectively of Reaction Scheme II.
  • intermediates of the Formula Ri-X-NH 2 can be prepared according to Reaction Scheme VI wherein Rj 8 and Ri c are as defined above and Rs 3 , Rs b , and R 5c are alkyl.
  • step (1) of Reaction Scheme VI an aminopyrazole of Formula XXXIX is converted to an amide of Formula XLIII.
  • the reaction can be carried out as described in step (3) of Reaction Scheme V.
  • step (2) of Reaction Scheme VI an amide of Formula XLIII is alkylated to provide a compound of Formula XLIV.
  • the reaction can be carried out as described in step (4) of Reaction Scheme V.
  • step (3) of Reaction Scheme VI both the amide and the ester groups of a compound of Formula XLIV are reduced to provide a compound of Formula XLV.
  • the reduction can be carried out by treating a solution of a compound of Formula XLIV in a suitable solvent such as THF with lithium aluminum hydride.
  • the reaction can be carried out at an elevated temperature, such as the reflux temperature of the solvent.
  • steps (4) and (5) of Reaction Scheme VI a compound of Formula XLV is converted to an aminomethyl substituted pyrazole of Formula XLVI using the methods of steps (2) and (3) respectively of Reaction Scheme II.
  • intermediates of the Formula R 1 -X-NH 2 can be prepared according to Reaction Scheme VII wherein Ri 3 , R 1 c , R5, Rsb, Rs c R ⁇ , and Q are as defined above.
  • Aminopyrazole carboxylates of Formula XLVII are known and can be prepared by conventional methods, such as those found in Chenard, B. L. J. Org. Chem., 49, pp. 1224- 1227, (1984) or Lee, H. H. et al, J. Org. Chem., 54, pp. 428-431, (1989).
  • Aminopyrazole carboxylates of Formula XLVII can be converted to compounds of Formula XLVIII using the methods described in Reaction Scheme V.
  • aminopyrazole carboxylates of Formula XLVII can be converted to compounds of Formula XLIX using the methods described in Reaction Scheme VI.
  • intermediates of the Formula Ri-X-NH 2 can be prepared according to Reaction Scheme VIII wherein Ri 9 , Rn,, Rs, Rs b , Rs c R 7 , and Q are as defined above.
  • Aminopyrazole carboxylates of Formula L are known and can be prepared by conventional methods, such as those found in Yuan, J. et al., Bioorg. Med. Chem. Lett., 12, pp. 2133-2136. Aminopyrazole carboxylates of Formula L can be converted to compounds of Formula LII using the methods described in Reaction Scheme V. Alternatively, aminopyrazole carboxylates of Formula L can be converted to compounds of Formula LI using the methods described in Reaction Scheme VI. Reaction Scheme VIII
  • intermediates of the Formula Rj-X-NH 2 can be prepared according to Reaction Scheme IX wherein Ri a , Rib, R 5 , Rs b , Rs c R7, and Q are as defined above.
  • Aminopyrazole carboxylates of Formula LIII are known and can be prepared by conventional methods, such as those found in Yuan, J. et al, Bioorg. Med Chem. Lett., 12, pp. 2133-2136. Aminopyrazole carboxylates of Formula LIII can be converted to compounds of Formula LIV using the methods described in Reaction Scheme VI. Alternatively, aminopyrazole carboxylates of Formula LIII can be converted to compounds of Formula LV using the methods described in Reaction Scheme V.
  • intermediates of the Formula R1-X-NH2 can be prepared according to Reaction Scheme X wherein Ri 3 , Rit » and Ri 0 are as defined above.
  • Pyrazole carboxylates of Formula LVI are known and can be prepared by conventional methods such as those found in Menozzi, G., et ah, J. Heterocycl. Chem., 24, pp. 1669-1676, (1987), Huppatz, J. L., Aust. J. Chem., 36, pp. 135-137, (1983), and Rojahn, C. A., Arch. Pharm., 264, pp. 337-347 (1926). They can be converted to aminomethyl substituted pyrazoles of Formula LVII using the methods described in Reaction Schemes II and III. Reaction Scheme X
  • intermediates of the Formula Ri-X-NH 2 can be prepared according to Reaction Scheme XI wherein Rj 8 , Ri b , and Ri c are as defined above.
  • Pyrazole carboxylates of Formula LVIII are known and can be prepared by conventional methods such as those found in Menozzi, G., et al., J. Heterocycl. Chem., 24, pp. 1669-1676, (1987), and Huppatz, J. L., Aust. J. Chem., 36, pp. 135-137, (1983). They can be converted to aminomethyl substituted pyrazoles of Formula LIX using the methods described in Reaction Schemes II and III.
  • intermediates of the Formula R 1 -X-NH 2 can be prepared according to Reaction Scheme XII wherein Rj 3 , Rib, Rs, Rsb, Rsc R7, and Q are as defined above.
  • Aminopyrazole carboxylates of Formula LX are known and can be prepared by conventional methods, such as those found in Senda, S. et al, Chem. Pharm. Bull, 20, pp. 391-398, (1972). Aminopyrazole carboxylates of Formula LX can be converted to compounds of Formula LXII using the methods described in Reaction Scheme V. Alternatively, aminopyrazole carboxylates of Formula LX can be converted to compounds of Formula LXI using the methods described in Reaction Scheme VI.
  • intermediates of the Formula R1-X-NH 2 can be prepared according to Reaction Scheme XIII wherein R ⁇ a , Ri b , R 5 , Rs b , Rs c R 75 and Q are as defined above.
  • Aminopyrazole carboxylates of Formula LXIII are known and can be prepared by conventional methods, such as those found in Senda, S. et ah, Chem. Pharm. Bull, 20, pp. 391-398, (1972) and in Pitt, G. R. W. et a!., Bioorg. Med. Chem. Lett., 14, pp. 4585-4589,
  • Aminopyrazole carboxylates of Formula LXIII can be converted to compounds of Formula LXV using the methods described in Reaction Scheme V.
  • aminopyrazole carboxylates of Formula LXIII can be converted to compounds of Formula LXIV using the methods described in Reaction Scheme VI.
  • intermediates of the Formula Rj-X-NH 2 can be prepared according to Reaction Scheme XIV wherein Rj 3 , Rn 3 , and Ri 0 are as defined above.
  • an alcohol of Formula XXV is oxidized to provide an aldehyde of Formula LXVI.
  • the oxidation can be carried out using conventional methods, such as for example, treatment with manganese dioxide or pyridinium chlorochromate, or Swern conditions.
  • step (2) of Reaction Scheme XIV an aldehyde of Formula LXVI is converted to a nitrile of Formula LXVII.
  • the reaction can be carried out by treating the aldehyde of Formula LXVI with diethyl cyanomethylphosphonate and sodium hydride.
  • step (3) of Reaction Scheme XIV a nitrile of Formula LXVII is reduced to provide an aminopropyl substituted compound of Formula LXVIIL
  • the reduction can be carried out by treating a nitrile of Formula LXVII with lithium aluminum hydride.
  • intermediates of the Formula Ri-X-NH 2 can be prepared according to Reaction Scheme XV wherein Ri a> Rib, and Ri c are as defined above.
  • an aldehyde of Formula LXVI is homologated to provide an aldehyde of Formula LXIX.
  • the reaction can be carried out in two parts. In part (i) the aldehyde of Formula LXVI is treated with methoxymethylenetriphenylphosphorane and a base such as n-butyllithium to provide a vinyl ether. In part (ii) the vinyl ether is hydrolyzed under acidic conditions to provide the aldehyde of Formula LXIX.
  • step (2) of Reaction Scheme XV an aldehyde of Formula LXIX is converted to a nitrile of Formula LXX.
  • the reaction can be carried out by treating the aldehyde of Formula LXIX with diethyl cyanomethylphosphonate and sodium hydride.
  • step (3) of Reaction Scheme XV a nitrile of Formula LXX is reduced to provide an aminobutyl substituted compound of Formula LXXL
  • the reduction can be carried out by treating a nitrile of Formula LXX with lithium aluminum hydride.
  • intermediates of the Formula Ri -X-NHa can be prepared according to Reaction Scheme XVI wherein R] 3 , Ru,, and Rj 0 are as defined above.
  • step (1) of Reaction Scheme XVI an aldehyde of Formula LXIX is reduced to " "- provide an alcohol of Formula LXXII.
  • the reduction can be carried out using conventional methods, for example, by treating a solution of the aldehyde of Formula LXIX in ethanol with sodium borohydride.
  • step (2) of Reaction Scheme XVI an alcohol of Formula LXXII is converted to an azide of Formula LXIII using the methods described in step (2) of Reaction Scheme II.
  • step (3) of Reaction Scheme XVI an azide of Formula LXXIII is reduced to provide an aminoethyl substituted pyrazole of Formula LXXIV using the methods described in step (3) of Reaction Scheme II.
  • Reaction Scheme XVI
  • compounds of the invention can be prepared according to
  • step (1) of Reaction Scheme XVII a 4-chloro-3-nitro[l,5]naphthyridine of Formula LXXV is reacted with an amine of Formula Ri-X-NH 2 to provide a 3- nitro[l,5]naphthyridin-4-amine of Formula LXXVI.
  • the reaction can be carried out using the method described in step (1) of Reaction Scheme I.
  • Compounds of Formula LXXV and their preparation are known; see, for example, U.S. Patents Nos. 6,194,425 (Gerster) and 6,518,280 (Gerster).
  • step (2) of Reaction Scheme XVII a 3-nitro[l,5]naphthyridin-4-amine of Formula LXXVI is reduced to provide a [l,5]naphthyridin-3,4-diamine of Formula LXXVII.
  • the reduction can be carried out using the method described in step (2) of
  • step (3) of Reaction Scheme XVII a [l,5]naphthyridin-3,4-diamine of Formula LXXVII is cyclized to provide a lH-imidazo[4,5-c][l,5]naphthyridine of Formula LXXVIII.
  • the cyclization can be carried out using the methods described in step (3) of Reaction Scheme I.
  • a lH-imidazo[4,5-c][l,5]naphthyridine of Formula LXXVIII is oxidized to provide a lH-imidazo[4,5-c][l,5]naphthyridine-5N-oxide of Formula LXXIX using a conventional oxidizing agent capable of forming N-oxides.
  • the reaction can be carried out by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula LXXVIII in a solvent such as dichloromethane or chloroform. The reaction can be carried out at ambient temperature.
  • a 5iV-oxide of Formula LXXIX is aminated to provide a lH-imidazo[4,5-c][l,5]napthyridin-4-amine of Formula IVe.
  • Step (5) can be carried out by the activation of an N-oxide of Formula LXXIX by conversion to an ester and then reacting the ester with an aminating agent.
  • Suitable activating agents include alkyl- or arylsulfonyl chlorides such as benzenesulfonyl chloride, methanesulfonyl chloride, or/7-toluenesulfonyl chloride.
  • Suitable aminating agents include ammonia, in the form of ammonium hydroxide, for example, and ammonium salts such as ammonium carbonate, ammonium bicarbonate, and ammonium phosphate.
  • the reaction can be carried out by adding ammonium hydroxide to a solution of the iV-oxide of Formula
  • LXXIX in a suitable solvent such as dichloromethane or chloroform and then adding p- toluenesulfonyl chloride or benzenesulfonyl chloride.
  • the reaction can be carried out at ambient temperature.
  • Steps (4) and (5) of Reaction Scheme XVII may be carried out as a one-pot procedure by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula LXXVIII in a solvent such as dichloromethane or chloroform and then adding ammonium hydroxide and p-toluenesulfonyl chloride or benzenesulfonyl chloride without isolating the iV-oxide compound of Formula LXXIX.
  • a solvent such as dichloromethane or chloroform
  • the animation reaction in step (5) of Reaction Scheme XVII can alternatively be carried out by treating a 5iV-oxide of Formula LXXIX with trichloroacetyl isocyanate followed by hydrolysis of the resulting intermediate to provide a compound of Formula IVe.
  • the reaction is carried out in two steps by (i) adding trichloroacetyl isocyanate to a solution of a 5iV-oxide of Formula LXXIX in a solvent such as dichloromethane and stirring at ambient temperature to provide an isolable amide intermediate.
  • a solution of the intermediate in methanol is treated with a base such as sodium methoxide or ammonium hydroxide at ambient temperature.
  • compounds of the invention can be prepared according to
  • step (1) of Reaction Scheme XVIII a 2,4-dichloro-3-nitropyridine of Formula LXXX is reacted with an amine of Formula Ri-X-NH 2 to provide a 2-chloro-3- nitropyridine of Formula LXXXI.
  • the reaction can be carried out using the method described in step (1) of Reaction Scheme I.
  • Many 2,4-dichloro-3-nitropyridines of the Formula LXXX are known and can be readily prepared using known synthetic methods. (See, for example, Dellaria et al., U.S. Pat. No.
  • step (2) of Reaction Scheme XVIII a 2-chloro-3 -nitropyridine of Formula LXXXI is reacted with 6/s-(4-methoxybenzyl)amine to provide an N- ⁇ 2-[bis-(4- methoxybenzyl)amino] -3 -nitropyridine of Formula LXXXII.
  • the reaction can be carried out by adding the Z>/-?-(4-methoxybenzyl)amine to a solution of a compound of Formula LXXXI in a suitable solvent such as toluene in the presence of a base such as triethyl amine.
  • the reaction can be carried out at an elevated temperature (about 90 0 C).
  • step (3) of Reaction Scheme XVIII an ⁇ - ⁇ 2-[ ⁇ «-(4-methoxybenzyl)amino]-3- nitropyridine of Formula LXXXII is reduced to provide an N 2 -[bis-(4- methoxybenzyl)]pyridine-2,3,4-triamine of Formula LXXXIII.
  • the reduction can be carried out using the method described in step (2) of Reaction Scheme I.
  • step (4) of Reaction Scheme XVIII an N 2 -[6/s-(4-methoxybenzyl)]pyridine- 2,3,4-triamine of Formula LXXXIII is cyclized to provide an iV-[ ⁇ /.s-(4-methoxybenzyl)]- l/f-imidazo[4 5 5-c]pyridin-4-amine of Formula LXXXIV.
  • the cyclization can be carried out using the methods described in step (3) of Reaction Scheme I.
  • step (5) of Reaction Scheme XVIII the 4-methoxybenzyl groups on an N-[bis- (4-methoxybenzyl)]-li_r-imidazo[4 5 5-c]pyridin-4-amine of Formula LXXXIV are removed by acid hydrolysis to provide a lH-imidazo[4,5-c]pyridin-4-amine of Formula Xe.
  • the reaction can be carried out by treating a compound of Formula LXXXIV with trifluoroacetic acid.
  • the reaction can be carried out at ambient temperature.
  • the ⁇ /_?-(4-methoxybenzyl)amino group may be installed at a later point in the synthesis, e.g. after cyclization.
  • compounds of the invention can be prepared according to Reaction Scheme XIX wherein R 0 , Ri, R 23 , X, and n are as defined above.
  • a 2,4-dihydroxy-3-nitrotetrahydroquinoline.of Formula LXXXV is chlorinated to provide a 2,4-dichloro-3-nitrotetrahydroquinoline of Formula LXXXVI.
  • the reaction can be carried out by combining a compound of Formula LXXXV with a conventional chlorinating agent (e.g., phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, or phosphorus pentachloride), optionally in a solvent such as DMF or dichloromethane.
  • a conventional chlorinating agent e.g., phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, or phosphorus pentachloride
  • a solvent such as DMF or dichloromethane.
  • Some 2,4-dihydroxy-3-nitrotetrahydroquinolines of Formula LXXXV are known;
  • a 2,4-dichloro-3-nitrotetrahydroquinoline of Formula LXXXVI is then converted to a tetrahydro-l//-imidazo[4,5-c]quinolin-4-amine of Formula VIIe using the methods described in steps (1) through (4) of Reaction Scheme I.
  • compounds of the invention can be prepared according to Reaction Scheme XX wherein R a , Ri, R 2b , X, and n are as defined above.
  • step (1) of Reaction Scheme XX 5 a 4-chloro-3-nitroquinoline of Formula LXXXVII is reacted with an amine of Formula R]-X-NH 2 to provide a 3-nitroquinolin-4- amine of Formula LXXXVIII.
  • the reaction can be carried out using the method described in step (1) of Reaction Scheme I.
  • step (2) of Reaction Scheme XX a 3-nitroquinolin-4-amine of Formula LXXXVIII is reduced to provide a quinolin-3,4-diamine of Formula LXXXIX.
  • the reduction can be carried out using the method described in step (2) of Reaction Scheme I.
  • step (3) of Reaction Scheme XX a quinolin-3,4-diamine of Formula LXXXIX is reacted with chloroacetyl chloride to provide a 2-chloromethyl-lH-imidazo[4,5- c]quinoline of Formula XC.
  • the reaction can be carried out using the method described in step (3) of Reaction Scheme I.
  • step (4) of Reaction Scheme XX a 2-chlorornethyl-lH-imidazo[4,5-c]quinoline of Formula XC is treated with potassium phthalimide to provide a phthalimide-substituted lH-imidazo[4,5-c]quinoline of Formula XCI.
  • the reaction can be carried out by combining potassium phthalimide and a compound of Formula XC in a suitable solvent such as DMF. The reaction can be carried out at ambient temperature.
  • a phthalimide-substituted lH-imidazo[4,5- cjquinoline of Formula XCI is deprotected to provide a 2-aminomethyl-lH-imidazo[4,5- c]quinoline of Formula XCII.
  • the phthalimide protecting group can be removed by adding hydrazine to a suspension of the compound of Formula XCI in a suitable solvent such as ethanol. The reaction can be carried out at ambient temperature.
  • step (6) of Reaction Scheme XX the amino group of a 2-aminomethyl-lH- imidazo[4,5-c]quinoline of Formula XCII is derivatized to provide a lH-imidazo[4,5- c]quinoline of Formula XCIII.
  • the derivatization can be carried out using the methods described in step (3) of Reaction Scheme V.
  • steps (7) and (8) of Reaction Scheme XX a lH-imidazo[4,5-cr]quinoline of
  • Formula XCIII is oxidized and then aminated to provide a lH-imidazo[4,5-c]quinolin-4- amine of Formula Hf using the methods described in steps (4) and (5) of Reaction Scheme XVII.
  • aminoalkyl substituted pyrazoles described above can be used to prepare IH- imidazo[l,7]naphthyridin-4-amines and lH-imidazo[l,8]naphthyridin-4-amines of the invention using the general methods described in U.S. Patent No. 6,194,425 (Gerster).
  • R 2 is -N ⁇ 2
  • Compounds of the invention can also be prepared using variations in the synthetic routes shown in Reaction Schemes I through XX that would be apparent to one of skill in the art.
  • the pyrazole carboxylates of Formulas LVI and LVIII can be reduced to the corresponding alcohols using the method of step (1) of Reaction Scheme II and the alcohols can be converted to the corresponding chain extended aminoalkyl substituted pyrazoles using the methods of Reaction Schemes XIV, XV, and XVI.
  • Prodrugs can be prepared in a variety of ways.
  • a compound wherein R 2a is hydroxyalkylenyl can be converted into a prodrug by replacing the hydrogen of the hydroxy group with G2 wherein G 2 is selected from the group consisting Of-X 2 -C(O)-R", ⁇ -aminoacyl, ⁇ -aminoacyl- ⁇ -aminoacyl, -X 2 -C(O)-O-R", -C(O)-N(R"')R", and -S(O) 2 -R".
  • X 2 is selected from the group consisting of a bond;
  • R" and R'" are independently selected from the group consisting of Ci-ioalkyl, 0 3 .
  • R'" can also be hydrogen
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids.
  • a compound wherein R b or R 0 is hydroxy may also be converted to an ester, an ether, a carbonate, or carbamate.
  • prodrugs are esters made from carboxylic acids containing one to six carbon atoms, unsubstituted or substituted benzoic acid esters, or esters made from naturally occurring L-amino acids.
  • Prodrugs can also be made from a compound containing an amino group by conversion of the amino group to a functional group such as an amide, carbamate, urea, ami dine, or another hydrolyzable group using conventional methods.
  • R" and R'" are each independently Ci-io alkyl, C 3-7 cycloalkyl, phenyl, or benzyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, C] -6 alkyl, CM alkoxy, aryl, heteroaryl, arylCi_ 4 alkylenyl, heteroarylCi- 4 alkylenyl, haloCi ⁇ alkyl, haloCi-4 alkoxy, -0-C(O)-CH 3 , -C(O)-O-CH 3 , -C(O)-NH 2 , -0-CH 2 -C(O)
  • compositions of the invention contain a therapeutically effective amount of a compound or salt described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount and “effective amount” mean an amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral activity.
  • cytokine induction cytokine induction
  • immunomodulation antitumor activity
  • antiviral activity cytokine induction
  • amount of compound or salt used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound or salt, the nature of the carrier, and the intended dosing regimen.
  • compositions of the invention will contain sufficient active ingredient or prodrug to provide a dose of about 100 nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg). preferably about 10 micrograms per kilogram ( ⁇ g/kg) to about 5 mg/kg, of the compound or salt to the subject.
  • the method includes administering sufficient compound to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • dosage forms such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
  • These dosage forms can be prepared with conventional pharmaceutically acceptable carriers and additives using conventional methods, which generally include the step of bringing the active ingredient into association with the carrier.
  • the compounds or salts of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts described herein may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.
  • Cytokines whose production may be induced by the administration of compounds or salts of the invention generally include interferon- ⁇ (IFN- ⁇ ) and tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (IL).
  • Cytokines whose biosynthesis may be induced by compounds or salts of the invention include IFN- ⁇ , TNF- ⁇ , IL-I, IL-6, IL-10 and IL-12, and a variety of other cytokines.
  • the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of the invention to the animal.
  • the animal to which the compound or salt is administered for induction of cytokine biosynthesis may have a disease as described infra, for example a viral disease or a neoplastic disease, and administration of the compound or salt may provide therapeutic treatment.
  • the compound or salt may be administered to the animal prior to the animal acquiring the disease so that administration of the compound or salt may provide a prophylactic treatment.
  • compounds or salts described herein can affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
  • the compounds or salts may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, the compounds or salts may cause proliferation and differentiation of B-lymphocytes. Compounds or salts described herein can also have an effect on the acquired immune response.
  • T H O cytokine IFN- ⁇ may be induced indirectly and the production of the T helper type 2 (TH2) cytokines IL- 4, IL-5 and IL- 13 may be inhibited upon administration of the compounds or salts.
  • the compound or salt or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant.
  • the compound or salt or composition and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.
  • Conditions for which compounds or salts or compositions identified herein may be used as treatments include, but are not limited to:
  • viral diseases such as, for example, diseases resulting from infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
  • 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., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum
  • a coronavirus e.g., SARS
  • a papovavirus e.g., papillomaviruses, such as those that cause genital warts, common warts, or plantar warts
  • a hepadnavirus e.g., hepatitis B virus
  • a flavivirus e.g., hepatitis C virus or Dengue virus
  • a retrovirus e.g., a lentivirus such as HIV
  • bacterial diseases such as, for example, diseases resulting from infection by bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aero
  • infectious diseases such as chlamydia, fungal diseases including but not limited to candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic diseases including but not limited to malaria, Pneumocystis carnii pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosome infection;
  • neoplastic diseases such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemias including but not limited to acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous
  • T-cell lymphoma T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers;
  • atopic diseases such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
  • diseases associated with wound repair such as, for example, inhibition of keloid formation and other types of scarring (e.g., enhancing wound healing, including chronic wounds).
  • a compound or salt identified herein may be useful as a vaccine adjuvant for use in conjunction with any material that raises either humoral and/or cell mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or bacterial immunogens; toxoids; toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; autologous vaccines; recombinant proteins; and the like, for use in connection with, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilus influenza b, tuberculosis, meningo
  • Compounds or salts identified herein may be particularly helpful in individuals having compromised immune function.
  • compounds or salts may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
  • one or more of the above diseases or types of diseases for example, a viral disease or a neoplastic disease may be treated in an animal in need thereof (having the disease) by administering a therapeutically effective amount of a compound or salt of the invention to the animal.
  • An animal may also be vaccinated by administering an effective amount of a compound or salt described herein, as a vaccine adjuvant.
  • a method of vaccinating an animal comprising administering an effective amount of a compound or salt described herein to the animal as a vaccine adjuvant.
  • An amount of a compound or salt effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-I, IL-6, IL-10 and IL- 12 that is increased (induced) over a background level of such cytokines.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments the induction or inhibition of cytokine biosynthesis may be performed by administering a compound or salt in a dose outside this range.
  • the method includes administering sufficient compound or salt or composition to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • the invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or salt of the invention to the animal.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
  • the precise amount that is effective for such treatment will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • An amount of a compound or salt effective to treat a neoplastic ⁇ condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg. In other embodiments, the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments either of these methods may be performed by administering a compound or salt in a dose outside this range.
  • the method includes administering sufficient compound or salt to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • pre HPLC normal high performance flash chromatography
  • COMBIFLASH an automated high-performance flash purification product available from Teledyne Isco, Inc., Lincoln, California, USA
  • HORIZON HPFC an automated high-performance flash purification product available from Biotage, Inc, Charlottesville, Virginia, USA
  • INTELLIFLASH Flash Chromatography System an automated flash purification system available from AnaLogix, Inc, Burlington, Wisconsin, USA.
  • the eluent used for each purification is given in the example.
  • the solvent mixture 80/18/2 v/v/v chloroform/methanol/concentrated ammonium hydroxide (CMA) was used as the polar component of the eluent.
  • CMA was mixed with chloroform in the indicated ratio.
  • Ethyl l-(4-fluorophenyl)-5-methyl-lH-pyrazole-3-carboxylate (10.58 g, 42.6 mmol) was dissolved in THF (25 mL) and added via syringe to an ice-cold solution of LiAlH 4 (42.6 mL of a 1 M solution in THF). The ice bath was removed; the reaction was stirred for 30 minutes, cooled again in an ice bath, and then quenched by the addition of water (1.6 mL), 4N sodium hydroxide (1.6 mL) and water (4.8 mL).
  • the organic layer was dried over magnesium sulfate, filtered, and concentrated to 10.19 g of orange oil that crystallized upon standing.
  • the solid was dissolved in DMF (35 mL) and treated with sodium azide (5.08 g, 78.2 mmol). After 3 hours, water (140 ml) was added, and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to 11.0 g of dark oil.
  • Ethyl l-(4-fluorophenyl)-3-methyl-l//-pyrazole-5-carboxylate (prepared in Part A of Example 1) was converted to 2-chloro-iV 4 - ⁇ [l-(4-fluorophenyl)-3-methyl-lH r -pyrazol-5- yl]methyl ⁇ quinoline-3,4-diamine using the methods of Example 1, Parts B-E and obtained as a stock solution in acetonitrile. This stock solution was used in the subsequent steps.
  • reaction mixture was concentrated, and the resulting solid was slurried in 2 M sodium carbonate and then collected by filtration.
  • the filter cake was washed with water, dried on suction, and then purified by prep ⁇ PLC (silica cartridge, eluting with 10% to 50% CMA in chloroform). Recrystallization from acetonitrile, followed by drying (98 0 C, 45 mtorr, 3.5 hours) afforded 390 mg of l- ⁇ [l-(4- fluorophenyl)-3-methyl-l/- r -pyrazol-5-yl]methyl ⁇ -2-methyl-li/-imidazo[4,5-c]quinolin-4- amine as a white solid, mp 246-248 0 C.
  • Example 18 The method described in Example 18 was used to convert 2-(ethoxymethyl)-l- ⁇ [l ⁇
  • Example 20 1 - ⁇ [5-(4-Fluorophenyl)- 1 -methyl- lH-pyrazol-3-yl]methyl ⁇ - 1 H-imidazo[4,5-c]quinolin-4- amine
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formula (Ha, Ilia, IVa, Vila, or Xa), an Rj a substituent, an Rib substituent, and an R 2 a-i substituent shown in the following table, wherein each line of the table is matched with the Formula (Ha, Ilia, IVa, Vila, or Xa) to represent a specific embodiment.
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formula (lib, IHb, IVb, VIIb, or Xb), an Ri 3 substituent, an Ri b substituent, and an R 23 - I substituent shown in the following table, wherein each line of the table is matched with the Formula (lib, HIb, IVb, VIIb, or Xb) to represent a specific embodiment.
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formula (Hc, HIc, IVc, VIIc, or Xc), an Rj 3 substiruent, an Rib substiruent, and an R2b-i substiruent shown in the following table, wherein each line of the table is matched with the Formula (Hc, IHc, IVc, VIIc, or Xc) to represent a specific embodiment.
  • Formula (Hc, HIc, IVc, VIIc, or Xc) an Rj 3 substiruent, an Rib substiruent, and an R2b-i substiruent shown in the following table, wherein each line of the table is matched with the Formula (Hc, IHc, IVc, VIIc, or Xc) to represent a specific embodiment.
  • Certain exemplary compounds including some of those described above in the Examples, have the following Formula (Hd, HId, IVd, VIId, or Xd), an Rj 3 substituent, an Rib substituent, and an R 2b -i substituent shown in the following table, wherein each line of the table is matched with the Formula (Hd, HId, IVd 3 VIId, or Xd) to represent a specific embodiment.
  • cytokine induction An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon ( ⁇ ) and tumor necrosis factor ( ⁇ ) (IFN- ⁇ and TNF- ⁇ , respectively) secreted into culture media as described by Testerman et. al. in “Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
  • ⁇ interferon
  • ⁇ tumor necrosis factor
  • PBMC Peripheral blood mononuclear cells
  • HISTOPAQUE- 1077 Sigma, St. Louis, MO
  • Ficoll-Paque Plus Amersham Biosciences Piscataway, NJ
  • Blood is diluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced Salts Solution (HBSS).
  • DPBS Dulbecco's Phosphate Buffered Saline
  • HBSS Hank's Balanced Salts Solution
  • PBMC whole blood is placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, FL) centrifuge frit tubes containing density gradient medium.
  • the PBMC layer is collected and washed twice with DPBS or HBSS and re-suspended at 4 x 10 6 cells/mL in RPMI complete.
  • the PBMC suspension is added to 96 well flat bottom sterile tissue culture plates containing an equal volume of RPMI complete media containing test compound.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells.
  • the compounds are generally tested at concentrations ranging from 30-0.014 ⁇ M. Controls include cell samples with media only, cell samples with DMSO only (no compound), and cell samples with reference compound.
  • test compound is added at 60 ⁇ M to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells.
  • the PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (usually 30-0.014 ⁇ M).
  • the final concentration of PBMC suspension is 2 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 0 C in a 5% carbon dioxide atmosphere.
  • IFN- ⁇ concentration is determined with a human multi-subtype colorimetric sandwich ELISA (Catalog Number 41105) from PBL Biomedical Laboratories, Piscataway, NJ. Results are expressed in pg/mL.
  • the TNF- ⁇ concentration is determined by ORIGEN M-Series Immunoassay and read on an IGEN M-8 analyzer from BioVeris Corporation, formerly known as IGEN International, Gaithersburg, MD.
  • the immunoassay uses a human TNF- ⁇ capture and detection antibody pair (Catalog Numbers AHC3419 and AHC3712) from Biosource International, Camarillo, CA. Results are expressed in pg/mL.
  • the data output of the assay consists of concentration values of TNF- ⁇ and IFN- ⁇ (y-axis) as a function of compound concentration (x-axis).
  • the reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro- ⁇ , ⁇ - dimethyl-lH-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91) and the expected area is the sum of the median dose values from the past 61 5 experiments.
  • the minimum effective concentration is calculated based on the background- subtracted, reference-adjusted results for a given experiment and compound.
  • the minimum effective concentration ( ⁇ molar) is the lowest of the tested compound concentrations that induces a response over a fixed cytokine concentration for the tested 0 cytokine (usually 20 pg/mL for IFN- ⁇ and 40 pg/mL for TNF- ⁇ ).
  • the maximal response is the maximal amount of cytokine (pg/ml) produced in the dose-response.
  • PBMC Peripheral blood mononuclear cells
  • HISTOP AQUE-1077 Sigma, St. Louis, MO
  • Ficoll-Paque Plus Amersham Biosciences Piscataway, NJ
  • Whole blood is placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, FL) centrifuge frit tubes containing density gradient 5 medium.
  • the PBMC layer is collected and washed twice with DPBS or HBSS and re- suspended at 4 x 10 6 cells/mL in RPMI complete (2-fold the final cell density).
  • the PBMC suspension is added to 96-well flat bottom sterile tissue culture plates.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • Controls include cell samples with media only, cell samples with DMSO only (no compound), and cell samples with a reference compound 2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro- ⁇ , ⁇ -dimethyl- lH-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91) on each plate.
  • test compound is added at 7.5 mM to the first well of a dosing plate and serial 3 fold dilutions are made for the 7 subsequent concentrations in DMSO.
  • RPMI Complete media is then added to the test compound dilutions in order to reach a final compound concentration of 2-fold higher (60 - 0.028 ⁇ M) than the final tested concentration range. Incubation
  • test compound solution is then added to the wells containing the PBMC suspension bringing the test compound concentrations to the desired range (usually 30 - 0.014 ⁇ M) and the DMSO concentration to 0.4 %.
  • the final concentration of PBMC suspension is 2x10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
  • MSD Gaithersburg, MD. The cell-free culture supernatants are removed and transferred to the MSD plates. Fresh samples are typically tested, although they may be maintained at
  • MSD MULTI-SPOT plates contain within each well capture antibodies for human TNF ⁇ and human IFN- ⁇ that have been pre-coated on specific spots.
  • Each well contains four spots: one human TNF- ⁇ capture antibody (MSD) spot, one human IFN- ⁇ capture antibody (PBL Biomedical Laboratories, Piscataway, NJ) spot, and two inactive bovine serum albumin spots.
  • the human TNF- ⁇ capture and detection antibody pair is from MesoScale Discovery.
  • the human IFN- ⁇ multi-subtype antibody (PBL Biomedical Laboratories) captures all IFN- ⁇ subtypes except IFN- ⁇ F (IFNA21).
  • Standards consist of recombinant human TNF- ⁇ (R&D Systems, Minneapolis, MN) and IFN- ⁇ (PBL Biomedical Laboratories). Samples and separate standards are added at the time of analysis to each MSD plate. Two human IFN- ⁇ detection antibodies (Cat. Nos. 21112 & 21100, PBL) are used in a two to one ratio (weightweight) to each other to determine the IFN- ⁇ concentrations.
  • the cytokine-specific detection antibodies are labeled with the SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeled detection antibodies to the wells, each well's electrochemoluminescent levels are read using MSD's SECTOR HTS READER. Results are expressed in pg/rnL upon calculation with known cytokine standards.
  • the data output of the assay consists of concentration values of TNF- ⁇ or
  • IFN- ⁇ (y-axis) as a function of compound concentration (x-axis).
  • a plate-wise scaling is performed within a given experiment aimed at reducing plate-to-plate variability associated within the same experiment.
  • the greater of the median DMSO (DMSO control wells) or the experimental background (usually 20 pg/mL for IFN- ⁇ and 40 pg/mL for TNF- ⁇ ) is subtracted from each reading. Negative values that may result from background subtraction are set to zero.
  • Each plate within a given experiment has a reference compound that serves as a control. This control is used to calculate a median expected area under the curve across all plates in the assay.
  • a plate- wise scaling factor is calculated for each plate as a ratio of the area of the reference compound on the particular plate to the median expected area for the entire experiment.
  • the data from each plate are then multiplied by the plate-wise scaling factor for all plates. Only data from plates bearing a scaling factor of between 0.5 and 2.0 (for both cytokines IFN- ⁇ , TNF- ⁇ ) are reported. Data from plates with scaling factors outside the above mentioned interval are retested until they bear scaling factors inside the above mentioned interval. The above method produces a scaling of the y-values without altering the shape of the curve.
  • the reference compound used is 2-[4-amino-2-ethoxymethyl-6,7,8,9- tetrahydro- ⁇ , ⁇ -dimethyl-lH-imidazo[4,5-c]quinolin-l-yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91).
  • the median expected area is the median area across all plates that are part of a given experiment.
  • a second scaling may also be performed to reduce inter-experiment variability
  • the adjustment ratio is the area of the reference compound in the new experiment divided by the expected area of the reference compound based on an average of previous experiments (unadjusted readings). This results in the scaling of the reading (y-axis) for the new data without changing the shape of the dose-response curve.
  • the reference compound used is 2-[4- amino-2-ethoxymethyl-6,7,8,9-tetrahydro- ⁇ , ⁇ -dimethyl-li ⁇ -imidazo[4 J 5-c]quinolin-l- yl]ethanol hydrate (U.S. Patent No. 5,352,784; Example 91) and the expected area is the sum of the median dose values from an average of previous experiments.
  • the minimum effective concentration is calculated based on the background- subtracted, reference-adjusted results for a given experiment and compound.
  • the minimum effective concentration ( ⁇ molar) is the lowest of the tested compound concentrations that induces a response over a fixed cytokine concentration for the tested cytokine (usually 20 pg/mL for IFN- ⁇ and 40 pg/mL for TNF- ⁇ ).
  • the maximal response is the maximal amount of cytokine (pg/ml) produced in the dose-response.

Abstract

La présente invention a pour objet des composés imidazo cycliques (par exemple des composés de type imidazo[4,5-c]quinoline, 6,7,8,9-tétrahydro-imidazo[4,5-c]quinoléine, imidazo[4,5-c]naphtyridine, 6,7,8,9-tétrahydro-imidazo[4,5-c]naphtyridine et imidazo[4,5-c]pyridine) portant un substituant pyrazoloalkyle en position 1, des préparations pharmaceutiques contenant lesdits composés, des intermédiaires et des méthodes de fabrication et d'utilisation de ces composés en tant qu'immunomodulateurs, pour la modulation de la biosynthèse des cytokines chez l'animal et pour le traitement de maladies incluant des maladies virales et néoplasiques.
PCT/US2006/049307 2005-12-28 2006-12-27 Composés imidazo cycliques substitués par des groupements pyrazoloalkyle et méthodes WO2007079086A1 (fr)

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US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US9789117B2 (en) 2011-05-18 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in diabetes type-2 associated pain
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
WO2017184735A1 (fr) * 2016-04-19 2017-10-26 Ifm Therapeutics, Inc Modulateurs de nlrp3
US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
US10533005B2 (en) 2017-02-17 2020-01-14 Innate Tumor Immunity, Inc. NLRP3 modulators
US10556903B2 (en) 2016-04-19 2020-02-11 Innate Tumor Immunity, Inc. NLRP3 modulators
US10618896B2 (en) 2017-08-22 2020-04-14 Dynavax Technologies Corporation Alkyl chain modified imidazoquinoline TLR7/8 agonist compounds and uses thereof
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