WO2005048945A2 - Hydroxylamine substituted imidazo ring compounds - Google Patents

Hydroxylamine substituted imidazo ring compounds Download PDF

Info

Publication number
WO2005048945A2
WO2005048945A2 PCT/US2004/038033 US2004038033W WO2005048945A2 WO 2005048945 A2 WO2005048945 A2 WO 2005048945A2 US 2004038033 W US2004038033 W US 2004038033W WO 2005048945 A2 WO2005048945 A2 WO 2005048945A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
aryl
alkylene
alkenyl
Prior art date
Application number
PCT/US2004/038033
Other languages
French (fr)
Other versions
WO2005048945A3 (en
Inventor
Tushar A. Kshirsagar
Gregory D. Lundquist, Jr.
David T. Amos
Joseph F. Dellaria, Jr.
Bernhard M. Zimmermann
Philip D. Heppner
Original Assignee
3M Innovative Properties Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 3M Innovative Properties Company filed Critical 3M Innovative Properties Company
Priority to EP04810969A priority Critical patent/EP1682544A4/en
Priority to AU2004291122A priority patent/AU2004291122A1/en
Priority to JP2006539957A priority patent/JP2007511535A/en
Priority to US10/595,790 priority patent/US8598192B2/en
Priority to CA002545825A priority patent/CA2545825A1/en
Publication of WO2005048945A2 publication Critical patent/WO2005048945A2/en
Publication of WO2005048945A3 publication Critical patent/WO2005048945A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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

  • Certain lH-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. Subsequently, certain substituted lH-imidazo[4,5-c]pyridin-4-amine, quinolin-4-amine, tetrahydroquinolin-4-amine, naphthyridin-4-amine, and tetrahydronaphthyridin-4-amine compounds as well as certain analogous thiazolo and oxazolo compounds were synthesized and found to be useful as immune response modifiers (IRMs), rendering them useful in the treatment of a variety of disorders.
  • IRMs immune response modifiers
  • the present invention provides a new class of compounds that are useful in inducing cytokine biosynthesis in animals.
  • Such compounds are of the following Formula
  • R', RA, RB, RAI, RBI, RI, R2, R2a, X, and Y' are as defined below.
  • the compounds of Formulas I and II are useful as immune response modifiers (IRMs) due to their ability to induce cytokine biosynthesis (e.g., induce the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals.
  • IRMs immune response modifiers
  • the present invention provides pharmaceutical compositions containing the immune response modifier compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral disease in an animal, and treating a neoplastic disease in an animal, by administering an effective amount of one or more compounds of Formula I and/or Formula II and/or pharmaceutically acceptable salts thereof to the animal.
  • the invention provides methods of synthesizing compounds of
  • R, R', R' R A , RB, RAI, RBI, RA2, B2, RI, R2, R2a, R3, n, m, p, X, and Y' are as defined below.
  • X is C ⁇ -1 0 alkylene or C 2 . 10 alkenylene
  • R A and R B are each independently selected from the group consisting of: hydrogen, halogen, alkyl, aikenyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or when taken together, R A and R B form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R'" groups; or when taken together, RA and R B form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups; R. is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
  • Y " ' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
  • R 2 and R 2a are 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, halo alkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(O)o-2-alkyl,
  • -S(O)o- 2 -aryl -NH-S(O) 2 -alkyl, -NH-S(O) 2 -aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R 8 ) 2 , -N(R 8 )-C(O)-alkyl, -O-(CO)-alkyl, and
  • R and R 2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R 6 ) -N- S(0) 2
  • R' is hydrogen or a non-interfering substituent
  • R' is a non-interfering substituent
  • R is C 2 - 7 alkylene
  • R 8 is selected from the group consisting of hydrogen, CMQ alkyl, C 2 . 10 alkenyl, C O alkoxy- -io al ylenyl, and aryl-d-io alkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • R 10 is C 3-8 alkylene; or a pharmaceutically acceptable salt thereof.
  • X is C ⁇ -10 alkylene or C 2 - 10 alkenylene
  • R A1 and R B1 are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and
  • R A ⁇ and R ⁇ i form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; or when taken together, R A ⁇ and R B ⁇ form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups;
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
  • R 3 is selected from the group consisting of: -Z-R 4 , -Z-X'-R ⁇
  • Y' is selected from the group consisting of: a bond
  • Ri is selected from the group consisting of:
  • R-2, and R 2a are independently selected from the group consisting of: hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, and alkyl.
  • R la and R ⁇ and/or R 2 and R 2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of:
  • K ⁇ and R ⁇ ' can join together to form a ring system selected from the group consisting of:
  • R e and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
  • X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
  • X" is -CH(R 13 )-alkylene- or -CH(R 13 )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
  • Y is selected from the group consisting of: -S(O)o-2-,
  • Z is a bond or -O-;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of allcyl, alkoxy, hydroxyalkyl, haloalky
  • R 5 is selected from the group consisting of:
  • R 7 is C 2 _ 7 alkylene
  • R 8 is selected from the group consisting of hydrogen, C ⁇ io alkyl, C 2-10 alkenyl, C 1-10 alkoxy-C o alkylenyl, and aryl-Ci.-i.o alkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl;
  • R 10 is C -8 alkylene
  • R ⁇ is C 1-6 alkylene or C 2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R 12 is selected from the group consisting of a bond, C 1-5 alkylene, and C 2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R 13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
  • A is selected from the group consisting of-CH -, -O-, -C(O)-, -S(O) 0-2 -, and -NOE )-;
  • A' is selected from the group consisting of -O-, -S(O)o- 2 -, -N(-Q-R 4 )-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R 6 )-, -S(O) 2 -, -C(R 6 )-N(R 8 )- -, -S(0) 2 -N(R 8 )-, -C(R 6 )-O-, and -C(R 6 )-N(OR 9 )-;
  • V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(R 8 )-C(R 6 )-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; or a pharmaceutically acceptable salt thereof.
  • X is C O alkylene or C 2-10 alkenylene; Y' is selected from the group consisting of: a bond,
  • R 2 and R 2a are 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)o- 2 -alkyl, -S(O)o- 2 -aryl,
  • R 8 is selected from the group consisting of hydrogen, C 1-10 alkyl, C 2 -io alkenyl, C MO alkoxy-Ci-io alkylenyl, and aryl-C 1 . 1 o alkylenyl;
  • R 10 is C 3-8 alkylene;
  • n is an integer from 0 to 4;
  • R'" is a non-interfering substituent;
  • R' is hydrogen or a non-interfering substituent; or a pharmaceutically acceptable salt thereof.
  • X is Ci-io alkylene or C 2-10 alkenylene;
  • Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O) 2 -, -S(O) 2 -N(R 8 )-,
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
  • R ⁇ is selected from the group consisting of:
  • Ria, Rib, Ri', Ri", R_, and R a are 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)o -2 -alkyl, -S(O)o -2 -aryl
  • R la and R lb and/or R 2 and R 2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R 6 ) -N- S(0) 2
  • Ri' and Ri" can join together to form a ring system selected from the group consisting of:
  • the total number of atoms in the ring is 4 to 9
  • R e and R d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and R d can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
  • R 3 is selected from the group consisting of:
  • n is an integer from 0 to 4; m is 0 or 1 ; with the proviso that when m is 1, then n is 0 or 1 ;
  • X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
  • X" is -CH(R 13 )-alkylene- or -CH(R 13 )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
  • Y is selected from the group consisting of:
  • Z is a bond or -O-; 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, hal
  • R 5 is selected from the group consisting of:
  • R 7 is C 2 _ 7 alkylene
  • R 8 is selected from the group consisting of hydrogen, Ci.in alkyl, C 2 - l0 alkenyl, C ⁇ - ⁇ o alkoxy-d- K ) alkylenyl, and aryl-C M o alkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl;
  • R ⁇ is C ⁇ -6 alkylene or C 2 . 6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R 12 is selected from the group consisting of a bond, C 1 . 5 alkylene, and C 2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R 13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
  • A is selected from the group consisting of-CH 2 -, -O-, -C(O)-, -S(O)o -2 -, and
  • A' is selected from the group consisting of -O-, -S(O)o- 2 -, -N ⁇ Q-R ⁇ -, and -CH -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R ⁇ )-, -S(O) 2 -, -C(R 6 )-N(R 8 )-W-, -S(O) 2 -N(R 8 )-, -C(R ⁇ s)-O-, and -C(R 6 )-N(OR 9 )-;
  • V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(R 8 )-C(R 6 )-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; or a pharmaceutically acceptable salt thereof.
  • X is Ci-io alkylene or C 2 - ⁇ o alkenylene; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
  • R 2 and R 2a are 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, -S(O)o- 2 -aryl,
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
  • Ri is selected from the group consisting of: -X'-R 4 , -X-Y-R ⁇ -X'-Y-X'-Y-R ⁇
  • R 3 is selected from the group consisting of: -Z-R 4 ,
  • n is an integer from 0 to 4; m is 0 or 1 ; with the proviso that when m is 1 , then n is 0 or 1 ;
  • X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
  • X" is -CH(R )-alkylene- or -CH(R ⁇ 3 )-alkenylene-;
  • Y is selected from the group consisting of: -S(O) 0 . 2 -, -S(O) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-O-,
  • Z is a bond or -O-
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • Ri' and R ⁇ " axe independently the same as R , or Ri' and R ⁇ " can join together to form a ring system selected from the group consisting of:
  • the total number of atoms in the ring is 4 to 9
  • R e and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and R d can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
  • R 7 is C2- 7 alkylene
  • R 8 is selected from the group consisting of hydrogen, C ⁇ - 10 alkyl, C 2 - 10 alkenyl, C ⁇ -10 alkoxy-Ci-io alkylenyl, and aryl-C 1-10 alkylenyl; R is selected from the group consisting of hydrogen and alkyl;
  • R11 is C ⁇ -6 alkylene or C 2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R 12 is selected from the group consisting of a bond, C ⁇ -5 alkylene, and C -5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R ⁇ 3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
  • A is selected from the group consisting of-CH 2 -, -O-, -C(O)-, -S(O)o- 2 -, and -NOR 4 )-;
  • A' is selected from the group consisting of -O-, -S(O)o -2 -, -N(-Q-R 4 )-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R 6 )-, -S(O) 2 -, -C(R 6 )-N(R 8 )- -, -S(O) 2 -N(R 8 )-, -C(R 6 )-O-, and -C(R 6 )-N(OR 9 )-;
  • V is selected from the group consisting of -C(R($)-, -O-C(R 6 )-, -N(R 8 )-C(R 6 )-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; or a pharmaceutically acceptable salt thereof.
  • X is Ci-io alkylene or C 2 . 1 o alkenylene; Y' is selected from the group consisting of: a bond,
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
  • n is an integer from 0 to 4.
  • R 2 and R 2a are 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 8 is selected from the group consisting of hydrogen, Ci-io alkyl, C - ⁇ 0 alkenyl, C ⁇ - ⁇ 0 alkoxy-Ci-io alkylenyl, and aryl-Q-io alkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl;
  • Rio is C 3 . 8 alkylene; and R' is hydrogen or a non-interfering substituent; or a pharmaceutically acceptable salt thereof.
  • Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O) 2 -,
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
  • Ri is selected from the group consisting of:
  • Ria, Rib, Ri', Ri", R2, and R 2a are 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 la and R ⁇ b and/or R 2 and R 2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R 6 ) -N- S(0) 2 V and ; or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
  • Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R ⁇ and
  • R d can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
  • n is an integer from 0 to 4;
  • X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
  • X" is -CH(R 13 )-alkylene- or -CH(R ⁇ 3 )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
  • Y is selected from the group consisting of: -S(O) 0 -2-, -S(O) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-O-, -O-C(R 6 )-,
  • R ⁇ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 7 is C - 7 alkylene
  • R 8 is selected from the group consisting of hydrogen, C ⁇ - 10 alkyl, C - ⁇ 0 alkenyl,
  • R 9 is selected from the group consisting of hydrogen and alkyl; Rw is C 3 . 8 alkylene;
  • R ⁇ is C ⁇ -6 alkylene or C 2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R ⁇ 2 is selected from the group consisting of a bond, C ⁇ -5 alkylene, and
  • R ⁇ 3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
  • A is selected from the group consisting of-CH 2 -, -O-, -C(O)-, -S(O)o- -, and
  • A' is selected from the group consisting of -O-, -S(O)o- 2 -, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R 6 )-,
  • V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(R 8 )-C(R 6 )-, and
  • X is Ci-io alkylene or C 2- ⁇ o alkenylene
  • Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
  • R 2 and R a are 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)o -2 -alkyl, -S(O)o- 2 -aryl,
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; n is an integer from 0 to 4;
  • R ⁇ is selected from the group consisting of:
  • X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
  • X" is -CH(R 13 )-alkylene- or -CH(R 13 )-alkenylene-;
  • Y is selected from the group consisting of: -S(O)o_2-,
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • Ri' and Ri are independently R 2 , or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
  • R e and Ra are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and R d can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
  • R 7 is C 2 - 7 alkylene;
  • R 8 is selected from the group consisting of hydrogen, C ⁇ - 10 alkyl, C 2 . 1 o alkenyl, Ci-io alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl; R is selected from the group consisting of hydrogen and alkyl;
  • Rn is Ci. 6 alkylene or C 2 . 6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R ⁇ 2 is selected from the group consisting of a bond, C ⁇ _ 5 alkylene, and C _ 5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R 13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
  • A is selected from the group consisting of-CH 2 -, -O-, -C(O)-, -S(O) 0 - 2 -, and -N(R4)-;
  • A' is selected from the group consisting of -O-, -S(O)o-2-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R 6 )-, -S(O) 2 -, -C(R 6 )-N(R 8 )-W-, -S(O) 2 -N(R 8 )-, -C(R 6 )-O-, and -C(R 6 )-N(OR 9 )-;
  • V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(R 8 )-C(R 6 )-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; or a pharmaceutically acceptable salt thereof.
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, aikylthio, and -N(R 9 ) 2 ;
  • Ri is selected from the group consisting of:
  • R ⁇ b , Ri', Ri", R 2 , and R 2a are 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)o -2 -alkyl, -S(O)o -2 -aryl,
  • R la and R Jb and/or R 2 and R 2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of:
  • Ri' and R n together to form a ring system selected from the group consisting of:
  • the total number of atoms in the ring is 4 to 9
  • R e and d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and R d can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
  • R 3 is selected from the group consisting of:
  • X" is -CH(R ⁇ 3 )-alkylene- or -CH(R ⁇ 3 )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
  • Y is selected from the group consisting of: -S(O)o-2",
  • Z is a bond or -O-
  • R A is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 8 is selected from the group consisting of hydrogen, Ci-io alkyl, C 2 - ⁇ o alkenyl, Ci-io alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
  • R 9 is selected from the group consisting of hydrogen and alkyl;
  • Rii is C ⁇ - 6 alkylene or C 2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R ⁇ is selected from the group consisting of a bond, C 1-5 alkylene, and C -5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R 13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
  • A is selected from the group consisting of-CH 2 -, -O-, -C(O)-, -S(O)o -2 -, and
  • A' is selected from the group consisting of -O-, -S(O)o -2 -, -N ⁇ Q-R*)-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(Re)-, -C(R 6 )-C(R 6 )-, -S(O) 2 -, -C(R 6 )-N(R 8 )-W-, -S(O) 2 -N(R 8 )-, -C(R 6 )-O-, and -C(R 6 )-N(OR 9 )-;
  • V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(R 8 )-C(R 6 )-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; or a pharmaceutically acceptable salt thereof.
  • compounds are provided that are of the following Formula VI:
  • X is C i-io alkylene or C 2- ⁇ o alkenylene
  • a 2 and R ⁇ 2 are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R 9 ) 2
  • Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O) 2 -, -S(O) 2 -N(R 8 )-,
  • Ri is selected from the group consisting of:
  • Ri a , R ⁇ , Ri', Ri", R 2 , and R 2a are 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 la and R lb and/or R 2 and R 2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R 6 ) -N- S(O) 2
  • Ri' and Ri" can join together to form a ring system selected from the group consisting of: R 11 ⁇
  • R e and R d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or e and R d can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
  • X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
  • X" is -CH(R ⁇ 3 )-alkylene- or -CH(R ⁇ 3 )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
  • Y is selected from the group consisting of:
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen,
  • R 5 is selected from the group consisting of:
  • R 7 is C _ 7 alkylene;
  • R 8 is selected from the group consisting of hydrogen, C ⁇ - 10 alkyl, C _ ⁇ o alkenyl,
  • R is selected from the group consisting of hydrogen and alkyl; Rio is C 3 - 8 alkylene; Rii is C ⁇ - 6 alkylene or C 2 . 6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R ⁇ 2 is selected from the group consisting of a bond, C ⁇ -5 alkylene, and C 2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
  • R ⁇ is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
  • A is selected from the group consisting of-CH 2 -, -O-, -C(O)-, -S(O)o- -, and
  • A' is selected from the group consisting of -O-, -S(O)o -2 -, -N(-Q-R 4 )-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R ⁇ )-, -C(R 6 )-C(R 6 )-, -S(O) 2 -, -C(R 6 )-N(R 8 )-W-, -S(O) 2 -N(R 8 )-, -C(R 6 )-O-, and -C(R 6 )-N(OR 9 )-;
  • V is selected from the group consisting of -C(R 6 )-, -O-C(R 6 )-, -N(R 8 )-C(R 6 )-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; or a pharmaceutically acceptable salt thereof.
  • R' is hydrogen or a non-interfering substitutent
  • R'" is a non-interfering substituent
  • non-interfering means that the ability of the compound or salt, which includes a non-interfering substituent, to modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not destroyed by the non-interfering substitutent.
  • Illustrative non-interfering R' groups include those described herein for Ri.
  • Illustrative non- interfering R'" groups include those described herein for R and R .
  • alkyl As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms, hi 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.
  • alkylenyl alkenylenyl
  • alkynylenyl use when “alkylene”, “alkenylene”, and “alkynylene”, respectively, are substituted.
  • an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached.
  • haloalkyl is inclusive of 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, fiuorenyl and indenyl.
  • heteroatom refers to the atoms O, S, or N.
  • heteroaryl includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N).
  • Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidiiiyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
  • heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
  • heterocyclic groups include pyrrolidinyl, tefrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, dihydroisoquinolin-(lH)-yl, octahydroisoquinolin-(lH)-yl, dihydroquinolin- (2H)-yl, octahydroquinolin-(2H)-yl, dihydro-lH-imidazolyl, and the like.
  • heterocyclyl contains a nitrogen atom, the point of attachment of the heterocyclyl
  • arylene "heteroarylene,” and “heterocyclylene” are the divalent forms of the "aryl,” “heteroaryl,” and “heterocyclyl” groups defined above.
  • arylenyl “heteroarylenyl”, and “heterocyclylenyl” are used when “arylene,” “heteroarylene,” and “heterocyclylene”, respectively, are substituted.
  • an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
  • each group is independently selected, whether explicitly stated or not.
  • each R 8 group is independently selected, hi another example, when an Ri and an R 3 group both contain an R 4 group, each R group is independently selected.
  • more than one Y group is present (i.e., Ri and R both contain a Y group) and each Y group contains one or more R 7 groups, then each Y group is independently selected, and each R 7 group is independently selected.
  • the invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, and the like.
  • isomers e.g., diastereomers and enantiomers
  • salts e.g., sodium tartrate
  • solvates e.g., sodium metabisulfite
  • polymorphs e.g., sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium metabisulfite, sodium
  • each one of the following variables e.g., R, R', R'", R A , R B , R A ⁇ , R B I, RI, R2, R 2a , R3, n, X, Y, Y', Z and so on
  • each one of the following variables e.g., R, R', R'", R A , R B , R A ⁇ , R B I, RI, R2, R 2a , R3, n, X, Y, Y', Z and so on
  • each of the resulting combinations of variables is an embodiment of the present invention.
  • R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 .
  • R is selected from the group consisting of halogen and hydroxy.
  • RA and R B are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R 9 ) 2 .
  • R A and R B when taken together, form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R'" groups.
  • R A and R B when taken together, form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups.
  • R A and R B are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R 9 ) 2 .
  • R A and R B form a fused aryl or heteroaryl ring.
  • h some embodiments, particularly embodiments of Formula I, RA and R B form a fused 5 to 7 membered saturated ring.
  • R A ⁇ and R BI are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R 9 ) 2 .
  • R AI. and R B1 form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group.
  • R AI and R BI form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups.
  • R AI and R B ⁇ form a fused benzene ring which is unsubstituted.
  • R AI and R B ⁇ fonn a fused pyridine ring which is unsubstituted.
  • R AI and R BI form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, wherein the ring is unsubstituted.
  • R 2 and B2 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R 9 )2. hi certain of these embodiments, R A2 and R ⁇ 2 are each independently alkyl. In some embodiments, R A2 and R B2 are each methyl.
  • R e and R d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and R d can j oin to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms. In certain embodiments, at least one of R e or R d is aryl.
  • Ri is selected from the group consisting of -R , -X'-R4, -X'-Y-Ri,
  • Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, -X'-Y-Ri, and -X'-R 5 .
  • Ri is 2-methylpropyl, 2-hydroxy-2-methylpropyl, or -X'-Y-R
  • Ri is 2-methylpropyl or -X'-Y-R ⁇
  • Ri is 2-methylpropyl or 2-hydroxy-2-methylpropyl.
  • Ri is 2-methyl-2-[(methylsulfonyl)amino]propyl or 4-[(methylsulfonyl)amino]butyl.
  • R' is hydrogen or a non-interfering substituent.
  • Ri' and Ri" are independently the same as R 2 .
  • R ⁇ and Ri" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, as well as 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, -S(O) 0-2 -aryl, -NH-S(O) 2 -alkyl, -NH-S(O) 2 -aryl, haloalkoxy, halogen, cyano, nitro,
  • Ri' and Ri" can join together to form a ring system selected from the group consisting of:
  • Ri' and Ri" can join together to form a ring system selected from the group consisting of:
  • R ⁇ a and R ⁇ b are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, as well as 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, -S(O) 0 - 2 -aryl, -NH-S(O) 2 -alkyl, -NH-S(O) 2 -aryl, haloalkoxy, halogen, cyano
  • R ⁇ a and R ⁇ b together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of -N- C(R 6 ) -N- S(0) 2 R R /
  • R ⁇ a is hydrogen.
  • R 2 and R 2a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, as well as alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of hydroxy (i.e., hydroxyl), alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(O) 0 - 2 -alkyl, -S(O)o- 2 -aryl,
  • R and R a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of
  • R 2a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, wherein the alkyl, alkenyl, aryl, and heteroaryl are each optionally substituted with one or more substitutents selected from the group consisting of Ci-io alkyl, aryl, heteroaryl, Ci-io alkoxy, -O-C(O)-Ci-io alkyl, -C(O)-O-Ci-io alkyl, halogen, and cyano (i.e., nitrile).
  • R 2 is alkyl or substituted alkyl. In some embodiments, R 2 is methyl or cyclopropyl.
  • R 2 is alkenyl or substituted alkenyl. In some embodiments, R 2 is aryl, arylalkylenyl, substituted aryl, or substituted arylalkylenyl. hi some embodiments, R 2 is heteroaryl , heteroarylalkylenyl, substituted heteroaryl, or substituted heteroarylalkylenyl. In some embodiments, R is heterocyclyl, heterocyclylalkylenyl, substituted heterocyclyl, or substituted heterocyclylalkylenyl.
  • R 2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2- (ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3- methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3-ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tetrahydrofuranyl, tetrahydrofuran-3 -ylmethyl, 2- (methylthio)ethyl, 3-(methylthio)propyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6- dimethoxyphenyl, 2-
  • R 2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2- (ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3- methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3-ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tefrahydrofuranyl, tetrahydrofuran-3-ylmethyl, 2- (methylthio)ethyl, 3-(methylthio)propyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6- dimethoxyphenyl,
  • R'" is a non-interfering substituent. In some embodiments, R'" is R 3 . In some embodiments, particularly embodiments of Formula , R'" is R or R 3 when n is 1 , R or one R and one R 3 when n is 2, or R when n is 3 to 4.
  • R 3 is selected from the group consisting of -Z-R 4 , -Z-X'-R 4 , -Z-X'-Y-Ri, -Z-X'-Y-X'-Y-R ⁇ and -Z-X'-R 5 .
  • R 3 is selected from the group consisting of -Z-R 4 and -Z-X'-Y-R
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,
  • R 4 is hydrogen, alkyl, alkenyl, aryl, or heteroaryl.
  • R 4 is hydrogen, alkyl, alkenyl, aryl, or heteroaryl, wherein alkyl and alkenyl are optionally substituted by aryl or aryloxy and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen.
  • * is selected from the group consisting of aryl or heteroaryl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, cyano, hydroxyalkyl, dialkylamino, and alkoxy.
  • R 5 is selected from the group consisting of
  • R 5 is
  • R 7 is C 2-7 alkylene. In some embodiments, R 7 is ethylene. i some embodiments, R 7 is propylene. In some embodiments, R 8 is selected from the group consisting of hydrogen,
  • R 8 is hydrogen or methyl. In some embodiments, R 8 is hydrogen.
  • R is selected from the group consisting of hydrogen and alkyl.
  • Rio is C 3 . 8 alkylene.
  • Rio is pentylene.
  • Rn is C 3 . 9 alkylene or C 3 . 9 alkenylene, optionally interrupted by one hetero atom.
  • Rn is d- ⁇ alkylene or C 2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom.
  • R ⁇ is methylene; in some embodiments, R ⁇ is ethylene.
  • R 12 is C 2-7 alkylene or C2- 7 alkenylene, optionally interrupted by one hetero atom.
  • R ⁇ 2 is selected from the group consisting of a bond, C ⁇ -5 alkylene, and C 2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom.
  • R 12 is ethylene.
  • R ⁇ 3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- -groups, h some embodiments, R ⁇ 3 is hydrogen.
  • A is selected from the group consisting of -CH 2 -, -O-, -C(O)-, -S(O)o -2 -, and -NCR4)-. In some embodiments, A is selected from the group consisting of-CH 2 - and -O-. hi some embodiments, A' is selected from the group consisting of -O-, -S(O)o- 2 -, -N(-Q-R 4 )-, and -CH 2 -. hi some embodiments, A' is -CH 2 -, -O-, or -N(-Q-R 4 )-.
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R 6 )-C(R 6 )-, -S(O) 2 -, -C(R 6 )-N(R 8 )-W-, -S(O) 2 -N(R 8 )-, -C(R 6 )-O-, and -C(R 6 )-N(OR 9 )-.
  • Q is selected from the group consisting of -C(O)-, -S(O) 2 -, and -C(O)-N(R 8 )-W-.
  • V is selected from the group consisting of -C(R 6 )-,
  • V is -N(R 8 )-C(O)-.
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O) 2 -.
  • W is selected from the group consisting of a bond and -C(O)-.
  • X is C 1 - 10 alkylene or C 2- ⁇ o alkenylene.
  • X is
  • Ci-io alkylene or C 3-1 o alkenylene In some embodiments, particularly embodiments of Formulas a and IVa, X is C ⁇ -4 alkylene. In some embodiments, X is methylene.
  • X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups, hi some embodiments, X' is alkylene. i some embodiments, X' is ethylene, propylene, or butylene (including isobutylene).
  • X" is -CH(R ⁇ 3 )-alkylene- or -CH(R ⁇ 3 )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups.
  • X" is -CH(R ⁇ 3 )-alkylene- or -CH(R ⁇ 3 )-alkenylene-.
  • Y is selected from the group consisting of -S(O)o -2 -, -S(O) 2 -N(R 8 )-, -C(R 6 )-, -C(R 6 )-O-, -O-C(R 6 )-, -O-C(O)-O-, -N(R 8 )-Q-, -C(R 6 )-N(R 8 )-, -O-C(R 6 )-N(R 8 )-, -C(R 6 )-N(OR 9 )-,
  • Y is selected from the group consisting of -S(O)o -2 -, -S(O) 2 -N(R 8 >, -C(R 6 )-, -C(R 6 )-O-, -O-C(R 6 )-, -O-C(O)-O-, -N(R 8 )-Q-, -C(R 6 )-N(R 8 )-, -O-C(R 6 )-N(R 8 )-, -C(R 6 )-N(OR 9 )-,
  • Y is -N(R 8 )-C(O)-, -N(R 8 )-S(O) 2 -, -N(R 8 )-S(O) 2 -N(R 8 )-, -N(R 8 )-C(O)-N(R 8 )-, -N(R 8 )-C(O)-N(R 8 )-C(O)-,
  • Y is -NH-C(O)-, -NH-S(O) 2 -, -NH-S(O) 2 -N(R 8 )-, -NH-C(O)-N(R 8 )-, -NH-C(O)-NH-C(O)-, or — H- C(O)-N
  • Y' is selected from the group consisting of a bond, -C(O)-, -C(S)-, -S(O) 2 -, -S(O) 2 -N(R 8 )-,
  • Y' is selected from the group consisting of a bond, -C(O)-, -C(O)-O-, -S(O) 2 -, -S(O) 2 -N(R 8 )-, -C(O)-N(R 8 )-, -C(S)-N(R 8 )-, -C(O)-N(R 8 )-C(O)-, and
  • Y' is selected from the group consisting of a bond, -C(O)-, -C(O)-O-, -S(O) 2 -, -S(O) 2 -N(R 8 )-, -C(O)-N(R 8 )-, -C(O)-N(R 8 )-C(O)-, and
  • Y' is selected from the group consisting of -C(O)-, -S(O) 2 -, and -C(O)-N(R 8 )-.
  • Z is a bond or -O-.
  • Z is a bond.
  • Z is -O-.
  • a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7.
  • a and b are each 2.
  • n is an integer from 0 to 4.
  • n is 0 or 1.
  • n is 0.
  • m is 0 or 1.
  • m is 1.
  • m is 0.
  • h some embodiments, m is 0 or 1 ; with the proviso that when m is 1, then n is 0 or 1.
  • particularly embodiments of Formula ma m and n are 0. hi some embodiments, n is 0 or m is 0.
  • p is an integer from 0 to 3. In some embodiments, p is 0 or 1. In some embodiments, p is 0.
  • m is 0 or 1, with the proviso that when m is 1, p is 0 or 1. In some embodiments, p and m are 0.
  • R' is selected from the group consisting of:
  • R'" is R or R 3 when n is 1 , R or one R and one R 3 when n is 2, or R when n is 3 to 4; wherein:
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ;
  • R 3 is selected from the group consisting of: -Z-R4, -Z-X'-R 4 , -Z-X'-Y-R4,
  • n is an integer from 0 to 4;
  • Z is a bond or -O-; and
  • X', Y, R 4 , R 5 , and R 9 are as defined above.
  • R 2 is alkyl or substituted alkyl, and R 2a is hydrogen.
  • R 2 is methyl or cyclopropyl, and R 2a is hydrogen.
  • R 2 is alkenyl or substituted alkenyl, and R2a is hydrogen.
  • R 2 is aryl, arylalkylenyl, substituted aryl, or substituted arylalkylenyl, and R 2a is hydrogen.
  • R 2 is heteroaryl, heteroarylalkylenyl, substituted heteroaryl, or substituted heteroarylalkylenyl, and R 2a is hydrogen.
  • R 2 is heterocyclyl, heterocyclylalkylenyl, substituted heterocyclyl, or substituted heterocyclylalkylenyl
  • R 2a is hydrogen.
  • R 2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-
  • R 2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-(ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3 -methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3- ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tetrahydrofuranyl, tetrahydrofuran-3- ylmethyl, 2-(methylthio)ethyl, 2-(methylthio)propyl, phenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-methoxyphenyl, 4-methoxypheny
  • Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, -X'-Y-R ⁇ and -X*-R 5 ; wherein X' is alkylene; Y is -N(R 8 )-C(O)-, -N(R 8 )-S(O) 2 -, -N(R 8 )-S(O) 2 -N(R 8 )-, -N(R 8 )-C(O)-N(R 8 )-, -N(R 8 )-C(O)-N(R 8 )-C(O)-N(R 8 )-, -N(R 8 )-C(O)-N(R 8 )-C(O)-,
  • R 4 is hydrogen, alkyl, alkenyl, aryl, or heteroaryl; and R 5 is
  • Ri is 2-methylpropyl or -X'-Y-Ri;
  • X' is ethylene, propylene, or butylene;
  • Y is -NH-C(O)-, -NH-S(O) 2 -, -NH-S(O) 2 -N(R 8 )-, -NH-C(O)-N(R 8 )-, -NH-C(O)-NH-C(O)-, or
  • R 8 is hydrogen or methyl.
  • R ⁇ is 2-methylpropyl, 2-hydroxy-2-methylpropyl, or
  • X' is ethylene, propylene, or butylene (including isobutylene);
  • Y is -NH-C(O)-,
  • Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, -X'-Y-R-t, and -X'-R 5 ; wherein X' is alkylene; Y is -N(R 8 )-C(O)-, -N(R 8 )-S(O) 2 -, -N(R 8 )-S(O) 2 -N(R 8 )- -N(R 8 )-C(O)-N(R 8 )-, -N(R 8 )-C(O)-N(R 8 )-C(O)-N(R 8 )-, -N(R 8 )-C(O)-N(R 8 )-C(O)-,
  • R 4 is hydrogen, alkyl, alkenyl, aryl, or heteroaryl, wherein alkyl and alkenyl are optionally substituted by aryl or aryloxy and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen; and R 5 is
  • Ri' and Ri" can join together to form a ring system selected from the group consisting of:
  • A' is selected from the group consisting of
  • R ⁇ is C 3-9 alkylene or C 3-9 alkenylene, optionally interrupted by one hetero atom
  • R 1 2 is C2- 7 alkylene or C2- 7 alkenylene, optionally interrupted by one heteroatom
  • R e and R d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and R d can join to fonn a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms.
  • Ri' and Ri" can join together to form a ring system selected from the group consisting of:
  • R e and R d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R 9 ) 2 ; or R e and R d can join to form a fused aryl ring or fused 5-10 membered hetero
  • Step (1) of Reaction Scheme I a quinoline-3,4-diamine of Formula X is reacted with a carboxylic acid or an equivalent thereof to provide a lH-imidazo[4,5-c]quinoline of Formula XI.
  • Suitable equivalents to a carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates.
  • the carboxylic acid or equivalent is selected such that it will provide the desired -X-Hal substituent in a compound of Formula XI.
  • Hal-X-CO 2 H or Hal-X-C(O-alkyl) will provide a compound with the desired -X-Hal substitutent at the 2-position.
  • the reaction can be run in the absence of solvent or in an inert solvent such as toluene.
  • the reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
  • a catalyst such as pyridine hydrochloride can be included.
  • step (1) can be carried out by (i) reacting a compound of Formula X with an acyl halide of formula Hal-X-C(O)Cl or Hal-X-C(O)Br and then (ii) cyclizing.
  • the acyl halide is added to a solution of a compound of Formula X in an inert solvent such as acetonitrile, pyridine or dichloromethane.
  • the reaction can be carried out at ambient temperature.
  • a catalyst such as pyridine hydrochloride can be included.
  • the reaction can be carried out in the presence of triethylamine.
  • the product of part (i) is heated in pyridine.
  • step (2) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline of Formula XI is oxidized to provide an N-oxide of Formula XII using a conventional oxidizing agent that is capable of forming N-oxides.
  • the reaction can be carried out by treating a solution of a compound of Formula XI in a suitable solvent such as chloroform or dichloromethane with
  • step (3) of Reaction Scheme I an N-oxide of Formula XII is animated to provide a lH-imidazo[4,5-c]quinoline-4-amine of Formula Xm.
  • the reaction is carried out in two parts.
  • a compound of Formula XII is reacted with an acylating agent.
  • Suitable acylating agents include alkyl- or arylsulfonyl chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride, or/?-toluenesulfonyl chloride).
  • the product of part (i) is reacted with an excess of an aminating agent.
  • Suitable aminating agents include ammonia (e.g. in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate).
  • ammonia e.g. in the form of ammonium hydroxide
  • ammonium salts e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate.
  • the reaction can be carried out by dissolving a compound of Formula XE in a suitable solvent such as dichloromethane or chloroform, adding ammonium hydroxide to the solution, and then adding >-toluenesulfonyl chloride.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a lH-imidazo[4,5-c]quinoline-4-amine of Formula Xm is treated with N-hydroxyphthalimide to provide an N-phthalimide-protected lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIV.
  • the reaction is conveniently carried out by adding a base, such as triethylamine, to a solution of N- hydroxyphthalimide in a suitable solvent such as N,N-dimethylformamide (DMF); and then adding the lH-imidazo[4,5-c]quinoline-4-amine of Formula XUI in a suitable solvent (for example, DMF) to the resulting mixture.
  • a suitable solvent for example, DMF
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (5) of Reaction Scheme I an N-phthalimide-protected lH-imidazo[4,5- c]quinolin-2-yl hydroxylamine of Formula XIV is converted to a lH-imidazo[4,5- c]quinolin-2-yl hydroxylamine of Formula XV.
  • Removal of the N-phthalimide protecting group is conveniently carried out by adding hydrazine to a suspension of anN- phthalimide-protected lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIV in a suitable solvent such as ethanol.
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods .
  • step (6) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XV is reacted with an aldehyde or ketone of formula R 2 'C(O)R 2 " to provide a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XVI.
  • aldehydes and ketones of formula R 2 'C(O)R 2 " are commercially available; others can be readily prepared using known synthetic methods.
  • reaction can be conveniently carried out by adding the aldehyde or ketone of formula R 2 'C(O)R 2 " to a lH-imidazo[4,5-c]quinolin-4-amine of Formula XV in a suitable solvent such as methanol.
  • a suitable solvent such as methanol.
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (7) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-2-yl oxime of
  • Formula XVI is reduced to provide a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XVII, which is a subgenus of Formulas I, II, m, and ma.
  • the reduction is conveniently carried out by treating a lH-imidazo[4,5-c]quinolin-2-yl oxime of Fonnula XVI with excess sodium cyanoborohydride in a suitable solvent or solvent mixture such as methanol/acetic acid.
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-l-yl tert-butylcarbamate of Formula XVm is treated with N-hydroxyphthalimide to provide an N-phthalimide-protected 1H- imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIX.
  • the reaction is conveniently carried out by adding a base, such as triethylamine, to N-hydroxyphthalimide dissolved in a suitable solvent such as DMF; and then adding the lH-imidazo[4,5-c]quinolin-l-yl tgrt- butylcarbamate of Formula XV in a suitable solvent (for example, DMF) to the resulting mixture.
  • a suitable solvent for example, DMF
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Compounds of Formula XVLU can be readily prepared using known synthetic routes; see for example, U.S. Patent No.
  • Removal of the N-phthalimide protecting group is conveniently carried out by adding hydrazine to a suspension of an N- phthalimide-protected lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIX in a suitable solvent such as ethanol.
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (3) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XX is reacted with an aldehyde or ketone of formula R 2 'C(O)R 2 " to provide a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXI.
  • aldehydes and ketones of formula R 2 'C(O)R 2 " are commercially available; others can be readily prepared using known synthetic methods.
  • the reaction can be conveniently carried out by adding the aldehyde or ketone of formula R 2 'C(O)R 2 " to a solution of the lH-imidazp[4,5-c]quinolin- 4-amine of Formula XX in a suitable solvent such as methanol.
  • a suitable solvent such as methanol.
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (4) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXI is deprotected to provide an amino group at the 1 -position of a 1H- imidazo[4,5-c]quinolin-2-yl oxime of Formula XXII.
  • the reaction can be conveniently carried out by dissolving a compound of Formula XXI in a mixture of trifluoroacetic acid and a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof, including the trifluoro acetate salt can be isolated using conventional methods.
  • a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXLI is converted to a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXm or XXIV, using conventional methods.
  • Formula XXTH (Q is -S(O) 2 -) can be prepared by reacting a compound of Formula XXII with a sulfonyl chloride of formula R 4 S(O) 2 Cl.
  • the reaction can be carried out at ambient temperature in an inert solvent such as chloroform or dichloromethane by adding the sulfonyl chloride to a compound of Formula XXLI in the presence of a base such as N,N- diisopropylethylamine, triethylamine, or pyridine.
  • Sulfamides of Fonnula XXTfl (Q is, for example, -S(O) 2 - ⁇ (R 8 )-) can be prepared by reacting a compound of Formula XXJT with a sulfamoyl chloride of formula R 4 (R 8 )NS(O) 2 Cl or by reacting a compound of Formula XX ⁇ with sulfuryl chloride to generate a sulfamoyl chloride in situ, and then reacting the resulting sulfamoyl chloride with an amine of formula ⁇ N(R 8 )R 4 .
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Some sulfamoyl chlorides of formula R 4 (R 8 )NS(O) 2 ⁇ and many sulfonyl chlorides of formula 4 S(O) 2 Cl and amines of formula HN(R 8 )R 4 are commercially available; others can be prepared using known synthetic methods.
  • step (5a) of Reaction Scheme II a lH-imidazo[4,5- c]quinolin-2-yl oxime of Formula XXII is reacted with a chloroalkanesulfonyl chloride of formula Cl-R 7 -S(O) 2 Cl to provide a compound of Formula XXIV, wherein R 5a is a ring having the structure
  • the reaction is preferably carried out by adding the chloroalkanesulfonyl chloride to a solution of a compound of Formula XXII in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine.
  • a suitable solvent such as dichloromethane
  • the intermediate chloroalkanesulfonamide may optionally be isolated before treatment with a stronger base such as 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) at ambient temperature. If the intermediate chloroalkanesulfonamide is isolated, the reaction with DBU can be carried out in a suitable solvent such as DMF.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Amides of Formulas XXm (Q is, for example, -C(O)-) and XXIV can be prepared from lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXII using conventional methods.
  • a compound of Formula XXLI can be reacted with an acid chloride of formula 4 C(O)Cl to provide a compound of Formula XXHI.
  • the reaction can be carried out by adding the acid chloride to a solution of a compound of Formula XXLI in a suitable solvent such as chloroform, optionally in the presence of a base such as N,N- diisopropylethylamine, triethylamine, or pyridine, at ambient temperature.
  • a base such as N,N- diisopropylethylamine, triethylamine, or pyridine
  • step (5a) a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXII is reacted with a chloroalkanoyl chloride compound of formula Cl-R 7 -C(O)Cl to provide a compound of Formula XXIV, wherein R 5a is a ring having the structure
  • the reaction is preferably carried out by adding the chloroalkanoyl chloride compound to a compound of Formula XXII in a suitable solvent such as dichloromethane in the presence of a base such as N,N-diisopropylethylamine.
  • a suitable solvent such as dichloromethane
  • the intermediate chloroalkanamide may optionally be isolated before treatment with a stronger base such as DBU at ambient temperature. If the intermediate chloroalkanamide is isolated, the reaction with DBU can be carried out in a suitable solvent such as DMF.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Ureas and thioureas of Formula XXHI (Q is, for example, -C(O)- ⁇ (R 8 )- or -C(S)-N(R 8 )-) and XXIV can be prepared from lH-imidazo[4,5-c]quinolin-2-yl oximes of Formula XXII using conventional methods.
  • the reaction can be carried out by adding the isocyanate to a solution of a compound of Formula XXII in a suitable solvent such as chloroform, optionally in the presence of a base such as N,N- diisopropylethylamine, or triethylamine, at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXTH or Formula XXIV is reduced to provide a lH-imidazo[4,5- c]quinolin-2-yl hydroxylamine of Formula XXV or Formula XXVI, each of which is a subgenus of Formulas I, ⁇ , HI, and ma.
  • the reduction is conveniently carried out by treating a li ⁇ -imidazo[4,5-c]quinolin-2-yl oxime of Fonnula XXHI or Formula XXIV with excess sodium cyanoborohydride in a suitable solvent or solvent mixture such as methanol/acetic acid.
  • the reaction can be carried out at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • each R B is independently selected from the group consisting of hydroxy, alkyl, alkoxy, -N(R 9 ) 2 ;
  • X c is C O alkylene;
  • P is a removable protecting group, such as an alkanoyloxy group (e.g., acetoxy) or an aroyloxy group (e.g., benzoyloxy);
  • R 2 ' and R 2 " are the same as Ri' and Ri" as defined above; and
  • R lc is a subset of Ri as defined above, which does not include those groups that one skilled in the art would recognize as being susceptible to reduction in step (5).
  • These groups include, for example, alkenyl, alkynyl, and aryl groups, and groups bearing nitro and -S- substitutents.
  • Reaction Scheme HI a quinoline-3,4-diamine of Formula Xa is reacted with a carboxylic acid of the formula, HO-X-CO 2 H, with a trialkyl orthoester of the formula HO-X-C(O-Ci_ alkyl) 3 , or with a combination thereof (wherein "alkyl” is a straight or branched chain) to provide a lH-imidazo[4,5-c]quinolin-2-yl alcohol of Formula XXVII.
  • the reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
  • a catalyst such as pyridine hydrochloride can be included.
  • Compounds of Formula Xa are a subset of compounds of Formula X, which are shown in Reaction Scheme I.
  • step (2) of Reaction Scheme HI the hydroxyl group of a lH-imidazo[4,5- c] quinoline of Formula XXVII is protected with a removable protecting group such as an alkanoyloxy group (e.g., acetoxy) or aroyloxy group (e.g., benzoyloxy) to provide a 1H- imidazo[4,5-c]quinoline of Formula XXVHI.
  • Suitable protecting groups and reactions for their placement and removal are well known to those skilled in the art. See, for example, U.S. Patent No. 4,689,338 (Gerster), Examples 115 and 120 and 5,389,640 (Gerster et al), Examples 2 and 3.
  • step (1) it is possible to combine steps (1) and (2) when an acid chloride of the Formula PO-X-CO 2 Cl is used under the conditions of step (1).
  • Some acid chlorides of this type for example, acetoxyacetyl chloride, are commercially available
  • hi step (3) of Reaction Scheme HI a lH-imidazo[4,5-c]quinoline of Formula XXVi ⁇ is oxidized to provide an N-oxide of Formula XXIX using a conventional oxidizing agent that is capable of forming N-oxides.
  • the reaction can be carried out by treating a solution of a compound of Formula XXVLTI in a suitable solvent such as chloroform or dichloromethane with 3-chloroperoxybenzoic acid at ambient temperature.
  • step (4) of Reaction Scheme HI an N-oxide of Formula XXIX is aminated and the protecting group removed to provide a lH-imidazo[4,5-c]quinoline-4-amine of
  • Formula XXX The animation reaction is carried out in two parts, hi part (i) a compound of Formula XXTX is reacted with an acylating agent.
  • Suitable acylating agents include alkyl- or arylsulfonyl chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride, or j9-toluenesulfonyl chloride).
  • Suitable aminating agents include ammonia (e.g.
  • ammonium hydroxide in the form of ammonium hydroxide
  • ammonium salts e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate
  • the reaction can be carried out by dissolving a compound of Formula XXIX in a suitable solvent such as dichloromethane or chloroform, adding ammonium hydroxide to the solution, and then adding -toluenesulfonyl chloride.
  • the protecting group is removed using well-known methods.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (5) of Reaction Scheme HI a lH-imidazo[4,5-c]quinoline-4-amine of Formula XXX is reduced to provide a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinoline-4- amine of Formula XXXI.
  • the reaction can be conveniently carried out by suspending or dissolving a compound of Formula XXX in ethanol, adding a catalytic amount of rhodium on carbon, and hydrogenating.
  • the reaction can be carried out by suspending or dissolving a compound of Formula XXXX in trifluoroacetic acid, and adding platinum(lV) oxide, and hydrogenating.
  • the reaction can be carried out in a Pan apparatus.
  • a 6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinoline-4-amine of Formula XXXI is treated with N-hydroxyphthalimide under Mitsunobu reaction conditions to provide an N-phthalimide-protected 6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXII.
  • step (6) may be carried out in two parts by (i) converting the hydroxy group in a compound of Formula XXXI to a leaving group and (ii) displacing the leaving group with N-hydroxyphthalimide in the presence of a base.
  • Part (i) of step (6) is conveniently carried out by treating the hydroxy-substituted 6,7,8,9-tetrahydiO-lH- imidazo[4,5-c]quinoline-4-amine of Formula XXXI with thionyl chloride in a suitable solvent such as 1,2-dichloroethane.
  • the reaction may be carried out at ambient temperature, and the product can be isolated by conventional methods.
  • Part (ii) of step (6) may be carried out under the conditions described in step (4) of Reaction Scheme I, and the product of Formula XXXII or phannaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (7) of Reaction Scheme m an N-phthalimide-protected 6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXX ⁇ is converted to a
  • step (8) of Reaction Scheme m a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin- 2-yl hydroxylamine of Formula XXXL ⁇ is reacted with an aldehyde or ketone of formula R 2 'C(O)R 2 " to provide a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXXIV as in step (3) of Reaction Scheme ⁇ .
  • the product or phannaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (9) of Reaction Scheme HI a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXXIV is reduced to provide a lH-imidazo[4,5-e]quinolin-2-yl hydroxylamine of Formula XXXV, which is a subgenus of Formulas I, H, IV and IVa.
  • the reduction is carried out as described in step (7) of Reaction Scheme I.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a compound of Formula XXXVI is combined with a boronic acid of the fomiula R 3a -B(O ⁇ ) 2 in the presence of palladium (LT) acetate, triphenylphosphine and a base such as aqueous sodium carbonate in a suitable solvent such as n-propanol or «-propanol and water.
  • the reaction can be canied out at an elevated temperature (e.g., 80 °C-100 °C).
  • Halogen substituted lH-imidazo[4,5-c]quinolin-2-yl oximes of Formula XXXVI can be prepared as described above in steps (l)-(6) of Reaction Scheme I or steps (1) - (5) or (5a) or Reaction Scheme ⁇ , wherein one of the R groups is Hal.
  • Numerous boronic acids of Formula R 3a -B(OH)2, anhydrides thereof, and boronic acid esters of Formula R 3a -B(O-alkyl) are commercially available; others can be readily prepared using known synthetic methods.
  • a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXXV ⁇ is reduced to provide a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXVm, which is a subgenus of Formulas I, ⁇ , , and ma.
  • the reduction is carried out as described in step (7) of Reaction Scheme I.
  • the product or a phannaceutically acceptable salt thereof can be isolated using conventional methods.
  • Step (1) of Reaction Scheme V a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XV is converted to a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXLX, a subgenus of Formulas I, ⁇ , m, and a, using conventional methods.
  • sulfonamides of Formula XXXLX (Y a ' is -S(O) 2 -) can be prepared by reacting a compound of Formula XV with a sulfonyl chloride of formula R 2 S(O) 2 ⁇ .
  • the reaction can be carried out at ambient temperature in an inert solvent such as chloroform or dichloromethane by adding the sulfonyl chloride to a compound of Formula XV in the presence of a base such as iV,N-diisopropylethylamine, triethylamine, or pyridine.
  • Sulfamides of Formula XXXLX (Y a ' is -S(O) 2 - ⁇ (R 8 )- or ⁇ • R 1 i 0 , ) can be prepared by reacting a compound of Formula XV with sulfuryl chloride to generate a sulfamoyl chloride in situ, and then reacting the sulfamoyl chloride with an amine of
  • R sulfamoyl chloride of formula R 2 (R 8 )NS(O) 2 ⁇ or 10 The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Many sulfonyl chlorides of formula R 2 S(O) 2 Cl, amines of formulas HN(R 8 )R 2 , and
  • Amides of Formula XXXIX (Y a ' is -C(O)-) can be prepared from lH-imidazo[4,5- c]quinolin-2-yl hydroxylamines of Formula XV using conventional methods.
  • a compound of Formula XV can be reacted with an acid chloride of formula
  • R 2 C(O)Cl to provide a compound of Formula XXXLX.
  • the reaction can be carried out by adding the acid chloride to a solution of a compound of Formula XV in a suitable solvent such as chloroform, optionally in the presence of a base such as NJV- diisopropylethylamine, triethylamine, or pyridine, at ambient temperature.
  • a base such as NJV- diisopropylethylamine, triethylamine, or pyridine, at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • the reaction can be carried out by adding the isocyanate to a solution of a compound of Formula XV in a suitable solvent such as chloroform, optionally in the presence of a base such as N,N- diisopropylethylamine, or triethylamine, at ambient temperature.
  • R 2a is other than hydrogen
  • Reaction Scheme VI where R, R ls R 2 , X, Y', and n are as defined above, hi step (1) of Reaction Scheme VI, a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XL, a subgenus of Formulas I, II, HI, and a, is prepared by reductive alkylation of a lH-imidazo[4,5-cjquinolin-2-yl hydroxylamine of Formula XV.
  • reaction is carried out in two steps, (i) reacting a compound of Formula XV with the appropriate aldehyde to provide an oxime and (ii) reducing the oxime, using the methods of steps (6) and (7), respectively, of Reaction Scheme I.
  • step (2) of Reaction Scheme VI a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XL is converted to a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XLI, a subgenus of Formulas I, ⁇ , and Id.
  • Compounds of Formula XLI wherein Y' is a bond are prepared by subjecting the compound of Formula
  • tetrahydroquinolines of the invention can be prepared according to Reaction Scheme VII, wherein RB, RI C , XC, Y a ', R2, and n are as defined above.
  • the reaction in Reaction Scheme VH can be carried out according to one of the methods described in Reaction Scheme V to provide a tetrahydroquinoline of Formula XLE, a subgenus of Formulas I, U, TV, and IVa.
  • the product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • Tetrahydroquinolines of Formula XXXm can also be treated according to the methods described in Reaction Scheme V to provide compounds of the invention.
  • R, R 1? R 2 , R2', R2", R2a, X, Y', and Hal are as defined above;
  • E is carbon (imidazoquinoline ring) or nitrogen (imidazonaphthyridine ring); n is an integer from 0 to 4 (imidazoquinoline ring) or 0 to 3 (imidazonaphthyridine ring) with the proviso that when m is 1, then n is 0 or 1; and D is -Br, -I, or -OCH2PI1; wherein Ph is phenyl.
  • an aniline or aminopyridine of Formula XLILL is treated with the condensation product generated from 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid) and triethyl orthoformate to provide an imine of Formula XLTV.
  • the reaction is conveniently carried out by adding a solution of an aniline or aminopyridine of Formula XLi ⁇ to a heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an elevated temperature.
  • the product can be isolated using conventional methods.
  • Many anilines and aminopyridines of Formula XLIH are commercially available; others can be prepared by known synthetic methods.
  • benzyloxypyridines of Formula XLIH can be prepared using the method of Holladay et al., Biorg. Med. Chem. Lett, 8, pp. 2797-2802, (1998).
  • step (2) of Reaction Scheme Vm an imine of Formula XLTV undergoes thermolysis and cyclization to provide a compound of Formula XLV.
  • the reaction is conveniently carried out in a medium such as DOWTHERM A heat transfer fluid at a temperature of 200 °C to 250 °C.
  • the product can be isolated using conventional methods. Isomers of the compound of Formula XLIH or Formula XLV, wherein E is nitrogen, can also be synthesized and can be used to prepare compounds of the invention.
  • step (3) of Reaction Scheme Vm a compound of Formula XLV is nitrated under conventional nitration conditions to provide a compound of Formula XLVI.
  • the reaction is conveniently carried out by adding nitric acid to the compound of Formula XLV in a suitable solvent such as propionic acid and heating the mixture at an elevated temperature.
  • the product can be isolated using conventional methods.
  • step (4) of Reaction Scheme VHL a 3-nitro[l,5]naphthyridin-4-ol or 3- nitroquinolin-4-ol of Formula XLVI is chlorinated using conventional chlorination chemistry to provide a 4-chloro-3-nitro[l,5]naphthyridine or 4-chloro-3-mtroquinoline of Formula XLVH
  • the reaction is conveniently carried out by treating the compound of Formula XLVI with phosphorous oxychloride in a suitable solvent such as DMF.
  • the reaction can be carried out at ambient temperature or at an elevated temperature such as
  • step (5) of Reaction Scheme VILL a 4-chloro-3 -nitro [l,5]naphthyridine or 4- chloro-3-nitroquinoline of Formula XLVH is treated with an amine of Formula R 1 -NH 2 to provide a compound of Formula XX Vm.
  • amines of Formula R ⁇ -NH 2 are commercially available; others can be prepared by known synthetic methods.
  • the reaction is conveniently carried out by adding the amine of Formula R ⁇ -NH 2 to a solution of the 4- chloro-3-nitro[l,5]naphthyridine or 4-chloro-3-nitroquinoline of Formula XLVII in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine.
  • a suitable solvent such as dichloromethane
  • the reaction can be carried out at ambient temperature or at a sub-ambient temperature such as, for example, 0 °C.
  • the reaction product can be isolated using conventional methods.
  • a compound of Formula XLVm is reduced to provide a diamine of Formula XLEX.
  • the reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as palladium on carbon or platinum on carbon.
  • the hydrogenation is conveniently carried out in a Parr apparatus in a suitable solvent such as toluene, methanol, acetonitrile, or ethyl acetate.
  • the prefened catalyst is platinum on carbon.
  • the reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
  • the reduction in step (6) can be carried out using nickel boride, prepared in situ from sodium borohydride and nickel(II) chloride.
  • the reduction is conveniently carried out by adding a solution of a compound of Formula XLVm in a suitable solvent or solvent mixture such as dichloromethane/methanol to a mixture of excess sodium borohydride and catalytic nickel(H) chloride in methanol.
  • the reaction can be carried out at ambient temperature.
  • the product can be isolated using conventional methods.
  • step (7) of Reaction Scheme VflT a diamine of Formula XLLX, is reacted with a carboxylic acid equivalent to provide a lH-imidazo[4,5-c][l,5]naphthyridine or 1H- imidazo[4,5-c]quinoline of Formula L.
  • the carboxylic acid or equivalent is selected such that it will provide the desired -X-Hal substituent in a compound of Formula L and the reaction can be carried out as described in step (1) of Reaction Scheme I.
  • an acid chloride for example chloroacetyl chloride
  • the reaction can be carried out in two steps.
  • Part (i) of step (7) is conveniently carried out by adding the acid chloride to a solution of a diamine of Formula XLIX in a suitable solvent such as dichloromethane, chloroform, or acetonitrile.
  • a tertiary amine such as triethylamine, pyridine, or 4-dimethylaminopyridine can be added.
  • the reaction can be carried out at ambient temperature.
  • the amide product or the salt thereof can be isolated and optionally purified using conventional techniques.
  • Part (ii) of step (7) involves heating the amide prepared in part (i) in the presence of base to provide a lH-imidazo[4,5- c][l,5]naphthyridine or lH-imidazo[4,5-c]quinoline of Formula L.
  • the reaction is conveniently carried out in a suitable solvent such as ethanol in the presence of a base such aqueous sodium hydroxide, aqueous potassium carbonate, or triethylamine at elevated temperature, hi some instances, the product of Formula L may be obtained directly from Part (i).
  • a diamine of Formula XLIX can be treated with ethyl chloroacetimidate hydrochloride as the carboxylic acid equivalent to provide a compound wherein X is methylene.
  • the reaction is carried out in a suitable solvent such as chloroform at ambient temperature and the product of Formula L can be isolated using conventional methods.
  • Ethyl chloroacetimidate hydrochloride is a known compound that can be prepared according to the literature procedure: Stillings, M. R. et al., J. Med.
  • a halogen-substituted lH-imidazo[4,5- c][l,5]naphthyridine or lH-imidazo [4, 5 -c] quinoline of Formula L can be converted into phthalimide-substituted lH-imidazo[4,5-c][l,5]naphthyridin-4-amine or lH-imidazo[4,5- c]quinolin-4-amine of Formula Lm using the chemistry described in steps (2) - (4) of
  • Steps (8) and (9) can alternatively be combined and carried out as a one-pot procedure by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula L in a solvent such as dichloromethane or chloroform and then adding ammomum hydroxide and j-toluenesulfonyl chloride without isolating the N-oxide of Formula LL
  • a solvent such as dichloromethane or chloroform
  • a phthalimide-substituted ⁇ H- imidazo[4,5-c][l,5]naphthyridin-4-amine or lH-imidazo[4,5-c]quinolin-4-amine of Formula Lm is converted to a hydroxylamine-subsitituted lH-imidazo[4,5- c][l,5]naphthyridin-4-amine or lH-imidazo[4,5-c]quinolm-4-amine of Formula LIV which is condensed with an aldehyde or ketone to form an oxime of Formula LV, sequentially using the chemistry described in steps (5) and (6) of Reaction Scheme I.
  • an oxime of Formula LV is reduced to provide a hydroxylamine of Formula LVI, a subgenus of Formulas I and II.
  • the reduction is conveniently carried out by treating the oxime of Formula LV with excess sodium cyanoborohydride in a suitable solvent or solvent mixture such as methanol/acetic acid.
  • a suitable solvent or solvent mixture such as methanol/acetic acid.
  • hydrochloric acid may be added.
  • the reaction can be carried out at ambient temperature or at elevated temperature.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (14) of Reaction Scheme VAX a hydroxylamine of Formula LVI is converted to a compound of Formula LVH, a subgenus of Formulas I and H
  • the reaction is carried out using one of the methods described in Reaction Scheme V or step (2) of Reaction Scheme VI.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a compound of Formula LIV can be converted to a compound of Formula LVLH, a subgenus of Formulas I and H, as shown in step (12a) of Reaction Scheme VIH.
  • the transformation is conveniently carried out by using the conditions described in Reaction Scheme V and step (2) of Reaction Scheme VI.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a compound of Formula LVm is alkylated to provide a compound of Formula LVH.
  • the reaction can be carried out with an alkylating agent that is generated in situ from an alcohol of Formula R 2a -OH under Mitsunobu reaction conditions (described in step (6) of Reaction Scheme HT) or an alkylating agent of Formula R 2a -Br or ⁇ -I in the presence of a base such as cesium carbonate in a suitable solvent such as DMF.
  • the latter reaction may be carried out at ambient temperature for reactive alkylating agents such as, for example, methyl iodide, benzyl bromide, and substituted benzyl bromides, or at an elevated temperature.
  • catalytic tetrabutylammonium hydrogensulfate can be added.
  • the product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • One skilled in the art would recognize that the reactions described for the alkylation step would probably not be successful for R 2a groups that are difficult to introduce via bimolecular nucleophihc substitution reactions. These groups include, for example, sterically hindered alkyl groups.
  • a reagent of the Formula P-0-R. 7 C(O)Cl, wherein P is a protecting group may react with a compound of Formula LIV to generate an isolable intermediate that can then be deprotected to yield a hydroxyalkanamide.
  • the isolable hydroxyalkanamide is cyclized under Mitsunobu conditions, described in step (6) of Reaction Scheme HI.
  • the product or phannaceutically acceptable salt thereof can be isolated using conventional methods.
  • R 1 -NH2, used in step (5) of Reaction Scheme VIH may contain a protected functional group, such as a tert-butoxycarbonyl-protected amino group.
  • the protecting group maybe removed after step (14) of Reaction Scheme V to reveal an amine on the Ri group.
  • An amino group introduced in this manner may be further functionalized using the chemistry described in steps (5) and (5a) of Reaction Scheme H to provide compounds of the
  • the amine of Formula R 1 -NH2 used in step (5) of Reaction Scheme Vm may contain an appropriately-protected hydroxyl group, for example, a tert- butyldimethylsilyl-protected hydroxyl group.
  • the protecting group may be removed after step (14) in Reaction Scheme VIH to provide an alcohol on the Ri group.
  • An alcohol introduced in this manner into a compound of Formula LVH may be converted into a hydroxylamine upon treatment with N-hydroxyphthalimide using the Mitsunobu reaction conditions described in step (6) of Reaction Scheme HI, followed by deprotection of the resulting phthalimide-protected hydroxylamine with hydrazine in ethanol.
  • a hydroxylamine on the Ri group can undergo reaction with a ketone or aldehyde of Fonnula R ⁇ 'C(O)R ⁇ " to form an oxime using the reaction conditions described in step (6) of
  • a hydroxylamine on the Ri group of a compound of Formula LVH, prepared as described above, can also be further functionalized to a compound of the Formula LVH in which Ri is -X"-O-NR ⁇ a -Y'-R ⁇ b wherein Y' is -C(O)-, -S(O) 2 -, -C(O)-N(R 8 >,
  • R ia is hydrogen
  • R ⁇ b is as defined above using, respectively, an acid chloride, a sulfonyl chloride or a sulfonic anhydride; an isocyanate; an acyl isocyanate, an isothiocyanate, a sulfonyl isocyanate, a carbamoyl chloride, or a sulfamoyl chloride.
  • the reaction can be carried out using the conditions described in step (5) of Reaction Scheme H.
  • a large number of the reagents listed above are commercially available; others can be readily prepared using known synthetic methods.
  • a compound of Formula LVH in which Ri is -X"-O-NR ⁇ a -Y'-R ⁇ b wherein Y' is a bond, -C(O)-, -C(S)-, -S(O) 2 -, or -C(O)-C(O)-; R l is defined above, and R is hydrogen, can be derivatized further upon treatment with an alkylating agent that is generated in situ from an alcohol of Formula R ⁇ a -OH under Mitsunobu reaction conditions or an alkylating agent of Formula R ⁇ a -Br or R ⁇ a -I as described in step (13a) above.
  • R 7 or 7 can be prepared in a two-step procedure from a compound of Formula LVH in which Ri is -X"-0-NH 2 , using one of the methods described in step 5a of Reaction Scheme H or step 13a above.
  • Reaction Scheme LX wherein D, E, R, Ri, R 2 , R 2a , X, and Y'are as defined above, m is 1, n is 0 or 1, and R 3b and R 3c are as defined below.
  • step (1) is used to react a lH-imidazo[4,5-c]quinoline-4-amine or lH-imidazo[4,5-c][l,5]naphthyridine-4- amine of Formula LV ⁇ using known palladium-catalyzed coupling reactions such as the Suzuki coupling and the ⁇ eck reaction.
  • a bromo or iodo-substituted compound of Fonnula LV ⁇ undergoes Suzuki coupling with a boronic acid of Formula
  • R 3a -B(O ⁇ ) 2 an anhydride thereof, or a boronic acid ester of Formula R 3a -B(O-alkyl) 2 , wherein R a is as defined above, according to the method described in Reaction Scheme IV.
  • the product of Formula LIX, a subgenus of Formulas I and H wherein R 3b is the same as R a , or a pharmaceutically acceptable salt thereof, can be isolated by conventional methods.
  • the Heck reaction can also be used in step (1) of Reaction Scheme IX to provide compounds of Formula LLX, wherein R 3 is -X R ⁇ and -XVY-R 4 , wherein X' a , Y, R 4 , and ⁇ are as defined above.
  • the reaction is conveniently carried out by combining the compound of Formula LVH and the vinyl-substituted compound in the presence of palladium (TT) acetate, triphenylphosphine or tri-ortAo-tolylphosphine, and a base such as triethylamine in a suitable solvent such as acetonitrile or toluene.
  • TT palladium
  • triphenylphosphine or tri-ortAo-tolylphosphine a base
  • a base such as triethylamine
  • a suitable solvent such as acetonitrile or toluene
  • the reduction can be carried out by hydrogenation using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon.
  • a conventional heterogeneous hydrogenation catalyst such as palladium on carbon.
  • the reaction can conveniently be carried out on a Pan apparatus in a suitable solvent such as ethanol, methanol, or mixtures thereof.
  • the product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Compounds of Formula LVH wherein D is -OCH 2 Ph can be converted in Reaction
  • step (la) of Reaction Scheme DC the benzyl group in a lH-imidazo[4,5-c]quinoline-4-amine or 1H- imidazo[4,5-c][l,5]naphthyridine-4-amine of Formula LV ⁇ , wherein D is -OC ⁇ 2 Ph, is cleaved to provide a hydroxy group.
  • the cleavage is conveniently carried out on a Pan apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as palladium or platinum on carbon in a solvent such as ethanol.
  • the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst.
  • the transfer hydrogenation is conveniently carried out by adding ammomum formate to a solution of a compound of Formula LVH in a suitable solvent such as ethanol in the presence of a catalyst such as palladium on carbon.
  • the reaction is carried out at an elevated temperature, for example, the refluxing temperature of the solvent.
  • the product of Formula LX, a subgenus of Formulas I and H, or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (2) of Reaction Scheme IX a hydroxy-substituted lH-imidazo[4,5- c]quinoline-4-amine or lH-imidazo[4,5-c][l,5]naphthyridine-4-amine of Formula LX is converted to a compound of Formula LXI, a subgenus of Formula I and ⁇ wherein R 3c is -O-Rft, -O-X'-R/j, -O-X'-Y-Ri, or -O-X'-R 5 , using a Williamson-type ether synthesis.
  • the reaction is effected by treating a hydroxy-substituted lH-imidazo[4,5-c]quinoline-4-amine or lH-imidazo[4,5-c][l,5]naphthyridine-4-amine of Formula LX with an aryl, alkyl, or arylalkylenyl halide of Formula Halide-Rn,, Halide-alkylene-R ⁇ , Halide-alkylene-Y-R 4 , or Halide-alkylene-R 5 in the presence of a base.
  • alkyl, arylalkylenyl, and aryl halides of these formulas are commercially available, including substituted benzyl bromides and chlorides, substituted or unsubstituted alkyl or arylalkylenyl bromides and chlorides, and substituted fluorobenzenes.
  • Other halides of these formulas can be prepared using conventional synthetic methods. The reaction is conveniently carried out by combining an alkyl, arylalkylenyl, or aryl halide with the hydroxy-substituted compound of Fonnula LX in a solvent such as DMF in the presence of a suitable base such as cesium carbonate.
  • step (2) may be carried out using the Ullmann ether synthesis, in which an alkali metal aryloxide prepared from the hydroxy-substituted compound of Formula LX reacts with an aryl halide in the presence of copper salts, to provide a compound of Formula LXI, where R 3c is -O-R ⁇ , -O-XVR 4 , or -O-X Y-R4 5 wherein X' f is an arylene or heteroarylene.
  • Numerous substituted and unsubstituted aryl halides are commercially available; others can be prepared using conventional methods.
  • the product of Formula LXI, prepared by either of these methods, or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • compounds of the invention are prepared according to Reaction Scheme X, where R ls R 2 , R 2 ', R 2 ", R 2a , X, Y' , R A2 , R B2 , and Hal are as defined above, and Ph is phenyl.
  • step (1) of Reaction Scheme X a 2,4-dichloro-3-nitropyridine of Formula LXH is reacted with an amine of the Formula to form a 2-chloro-3- nitropyridine of Formula LXH
  • the reaction is conveniently carried out by combining an amine of Fonnula ⁇ N-Ri and a 2,4-dichloro-3-nitropyridine of Formula LXH in the presence of a base such as triethylamine in an inert solvent such as DMF.
  • the reaction can be carried out at ambient temperature, and the product can be isolated from the reaction mixture using conventional methods.
  • Many amines of Formula are commercially available; others can be prepared by known synthetic methods.
  • a 2-chloro-3-nitropyridine of Formula LXTH is reacted with an alkali metal azide to provide an 8-nitrotetrazolo[l,5- ⁇ ]pyridin-7-amine of Formula LXTV.
  • the reaction can be carried out by combining the compound of Formula LXTH with an alkali metal azide, for example, sodium azide, in a suitable solvent such as acetonixrile/water, preferably 90/10 acetonitrile ⁇ vater, in the presence of cerium(m) chloride, preferably cerium(IH) chloride heptahydrate.
  • the reaction can be carried out with heating, for example, at the reflux temperature.
  • the reaction can be carried out by combining the compound of Formula LXTH with an alkali metal azide, for example, sodium azide, in a suitable solvent such as DMF and heating, for example to about 50 °C -60 °C, optionally in the presence of ammonium chloride.
  • an alkali metal azide for example, sodium azide
  • DMF a suitable solvent
  • heating for example to about 50 °C -60 °C, optionally in the presence of ammonium chloride.
  • the product can be isolated from the reaction mixture using conventional methods.
  • step (3) of Reaction Scheme X an 8-nitrotetrazolo[l,5- ⁇ ]pyridin-7-amine of Fomiula LXTV is reduced to provide a compound of Formula LXV.
  • the reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as palladium on carbon or platinum on carbon.
  • the hydrogenation is conveniently carried out in a Pan apparatus in a suitable solvent such as toluene, methanol, acetonitrile, or ethyl acetate.
  • the reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
  • step (4) of Reaction Scheme X a tetrazolo[l,5-a]pyridine-7,8-diamine of Formula LXV, is reacted with a carboxylic acid or an equivalent thereof to provide a 7H- imidazo[4,5-c]tetrazolo[l,5- ⁇ ]pyridine of Formula LXVI.
  • the carboxylic acid or equivalent is selected such that it will provide the desired -X- ⁇ al substituent in a compound of Formula LXVI.
  • the reaction can be carried out as described in step (7) of
  • Reaction Scheme V ⁇ L The product can be isolated using conventional methods.
  • h step (5) of Reaction Scheme X a 7H-imidazo[4,5-c]tetrazolo[l,5- ⁇ ]pyridine of Formula LXVI is treated with N-hydroxyphthalimide to provide a compound of Formula LXV ⁇ , which contains a N-phthalimide-protected hydroxylamine.
  • the reaction is conveniently carried out as described in step (4) of Reaction Scheme I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (6) of Reaction Scheme X the N-phthalimide-protected hydroxylamine of Formula LXV ⁇ is treated with hydrazine in a suitable solvent such as ethanol to provide a hydroxylamine of Formula LXV ⁇ I.
  • a suitable solvent such as ethanol
  • the reaction can be carried out at ambient temperature and the product can be isolated from the reaction mixture using conventional methods.
  • step (7) Reaction Scheme X the hydroxylamine group in a 7H-imidazo[4,5- c]tetrazolo[l,5-fl]pyridine of Formula LXV ⁇ I reacts with an aldehyde or ketone of Formula R 2 'C(O)R 2 M to provide an oxime of Formula LXIX.
  • the reaction can be carried out using the conditions described above in step (6) of Reaction Scheme I and the product can be isolated from the reaction mixture using conventional methods.
  • step (8) of Reaction Scheme X the tetrazolo ring is removed from a 7H- imidazo[4,5-c]tetrazolo[l,5- ⁇ ]pyridine of Formula LXIX by reaction with triphenylphosphine to form an N-triphenylphosphinyl intermediate of Formula LXX.
  • the reaction with triphenylphosphine can be run in a suitable solvent such as toluene or 1,2- dichlorobenzene under an atmosphere of nitrogen with heating, for example at the reflux temperature.
  • an N-triphenylphosphinyl intermediate of Formula LXX is hydrolyzed to provide an oxime-substituted lH-imidazo[4,5-c]pyridin-4- amine of Formula LXXI.
  • the hydrolysis can be carried out by general methods well known to those skilled in the art, for example, by heating in a lower alkanol or an alkanol/water solution in the presence of an acid such as trifluoroacetic acid, acetic acid, or hydrochloric acid.
  • the product can be isolated from the reaction mixture using conventional methods as the compound of Formula LXXI or as a pharmaceutically acceptable salt thereof.
  • a compound of the Formula LXXI may also be obtained through an alternative two-step route from a compound of Formula LXV ⁇ .
  • step (6a) of Reaction Scheme X a compound of Formula LXV ⁇ is treated sequentially according to the reaction conditions described in steps (8) and (9) of Reaction Scheme X using hydrochloric acid as the acid in step (9). Under these reaction conditions, the N-phthalimide is removed to provide the hydroxylamine-substituted lH-imidazo[4,5-c]pyridin-4-amine of Formula LXX ⁇ .
  • the product can be isolated and purified using conventional methods.
  • step (7a) of Reaction Scheme X a hydroxylamine-substituted lH-imidazo[4,5- c]pyridin-4-amine of Formula LXX ⁇ reacts with an aldehyde or ketone of Formula R 2 'C(O)R 2 " to provide an oxime of Formula LXXI.
  • the reaction can be earned out using the conditions described above in step (6) of Reaction Scheme I, and the product or the pharmaceutically acceptable salt thereof can be isolated from the reaction mixture using conventional methods.
  • step (10) of Reaction Scheme X the oxime of Formula LXXI is reduced using the conditions described in step (7) of Reaction Scheme I to afford a compound of Formula LXXIH, a subgenus of Formulas I, H, and VI.
  • the product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • step (11) of Reaction Scheme X a hydroxylamine of Formula LXXIH is converted into a compound of Formula LXXIV, a subgenus of Formulas I, H, and VI, using the reagents and conditions described in Reaction Scheme V or step (2) of Reaction Scheme VI.
  • the product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • steps (10a) and (Ila) of Reaction Scheme X a hydroxylamine of Formula LXXH is converted into a compound of Formula LXXIV using the reagents and methods described in steps (12a) and (13a), respectively, of Reaction Scheme VHL
  • the product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
  • amines of Formula R ⁇ -NH 2 used in step (1) of Reaction Scheme X, may contain a protected functional group, such as a tert-butoxycarbonyl-protected amino group.
  • the protecting group may be removed later in Reaction Scheme X after step (4) to reveal, for example, an amine on the Ri group of a compound of Formula LXVI.
  • compositions of the invention contain a therapeutically effective amount of a compound or salt of the invention as described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount and “effective amount” mean an amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral activity.
  • a therapeutic or prophylactic effect such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral activity.
  • the exact amount of active 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, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably about 10 micrograms per kilogram ( ⁇ g/kg) to about 5 mg/kg, of the compound or salt to the subject.
  • a variety of dosage forms maybe used, such as tablets, lozenges, capsules
  • the compounds or salts of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.
  • Cytokines whose production may be induced by the administration of compounds or salts of the invention generally include interferon- ⁇ (IFN- ⁇ ) and/or tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (TL). Cytokines whose biosynthesis may be induced by compounds or salts of the invention include IFN- ⁇ , TNF- ⁇ , IL-1, TL-6, EL- 10 and H-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds or salts useful in the treatment of viral diseases and neoplastic diseases.
  • IFN- ⁇ interferon- ⁇
  • TNF- ⁇ tumor necrosis factor- ⁇
  • TL-6 interleukins
  • the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal.
  • the animal to which the compound or salt or composition is administered for induction of cytokine biosynthesis may have a disease as described infra, for example a viral disease or a neoplastic disease, and administration of the compound or salt may provide therapeutic treatment.
  • the compound or salt may be administered to the animal prior to the animal acquiring the disease so that administration of the compound or salt may provide a prophylactic treatment.
  • compounds or salts of the invention can affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
  • the compounds or salts may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, the compounds or salts may cause proliferation and differentiation of B-lymphocytes.
  • T helper type 1 T R T
  • T helper type 2 T H 2
  • H-5 and H-13 maybe inhibited upon administration of the compounds or salts.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • the invention provides a method of inhibiting TNF- ⁇ biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal.
  • the animal to which the compound or salt or composition is administered for inhibition of TNF- ⁇ biosynthesis may have a disease as described infra, for example an autoimmune disease, and administration of the compound or salt may provide therapeutic treatment.
  • the compound or salt may be administered to the animal prior to the animal acquiring the disease so that administration of the compound or salt may provide a prophylactic treatment.
  • the compound or salt or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant.
  • the compound or salt and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.
  • Conditions for which IRMs identified herein may be used as treatments include, but are not limited to:
  • viral diseases such as, for example, diseases resulting from infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-H, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
  • a herpesvirus e.g., HSV-I, HSV-H, CMV, or VZV
  • a poxvirus e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum
  • a picornavirus e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum
  • a coronavims e.g., SARS
  • a papovaviras 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, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus,
  • 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 myelogeous leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers; (e) T ⁇ 2-mediated, atopic diseases, such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
  • atopic diseases such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen
  • autoimmune diseases such as systemic lupus erythernatosus, essential thrombocythaemia, multiple sclerosis, discoid lupus, alopecia areata; and (g) 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).
  • an IRM compound or salt of the present invention maybe 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, mening
  • Certain IRM compounds or salts of the present invention maybe particularly helpful in individuals having compromised immune function.
  • certain compounds or salts may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HTV patients.
  • one or more of the above diseases or types of diseases may be treated in an animal in need thereof (having the disease) by administering a therapeutically effective amount of a compound or salt of the invention to the animal.
  • An amount of a compound or salt effective to induce or inhibit cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-1, T -6, TL-10 and H-12 that is increased (induced) or decreased (inhibited) over a background level of such cytokines.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
  • 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.
  • 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.
  • N 4 -(2-Methylpropyl)quinoline-3,4-diamine 41 g
  • dichloromethane 550 mL
  • triethylamine 40 mL, 1.5 eq
  • chloroacetyl chloride 16.7 mL, 1.1 eq.
  • the reaction mixture was diluted with 1,2-dichloroethane (75 mL) and then washed with saturated aqueous sodium bicarbonate (3 x 400 mL).
  • the reaction mixture was stirred at ambient temperature for 1 hour and then filtered to remove a precipitate.
  • the filtrate was transfened to a separatory funnel and the layers were separated.
  • the aqueous layer was extracted with dichloromethane (2 x 100 mL).
  • the combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 16 g of crade product as a yellow foam.
  • the foam was dissolved in 10% methanol in dichloromethane (20 mL).
  • the solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g), (available from Biotage, Inc, Charlottesville, Virginia, USA).
  • the cartridges were eluted sequentially with IL 1 :1 ethyl acetate:hexanes, 2% methanol in 1:1 ethyl acetate :hexanes, and 5% methanol in 1:1 ethyl acetate:hexanes.
  • the fractions containing product were combined and then concentrated under reduced pressure to provide 6.4 g of 2-chloromethyl-l -(2-methylpropyl)- 1H- imidazo[4,5-c]quinolin-4-amine as an orange foam.
  • Triethylamine (536 mg, 5.19 mmol) was added to a solution of N- hydroxyphthalimide (678 mg, 4.16 mmol) in N,N-dimethylformamide (DMF); after 5 minutes a solution of 2-chloromethyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-4- amine (1 g) in DMF (10 mL) was added. The reaction mixture was stined at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL) and then washed with water (1 x 100 mL).
  • aqueous layer was extracted with dichloromethane (2 x 50 mL) and ethyl acetate (1 x 50 mL).
  • the combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 1.8 g of crade product as a yellow solid.
  • the solid was dissolved in 5% methanol in chloroform (10 mL) and loaded onto a FLASH 40+M silica cartridge (90 g).
  • the cartridge was eluted sequentially with IL 1% methanol in chloroform and 3% methanol in chloroform.
  • the fractions containing the desired product were combined and then concentrated under reduced pressure to provide 950 mg of a yellow solid.
  • the filter cake was washed with several portions of dichloromethane.
  • the filtrate was concentrated under reduced pressure to provide 40 g of crude product as a brown semi- solid.
  • the solid was partitioned between IM aqueous hydrochloric acid (300 mL) and dichloromethane (100 mL). The layers were separated.
  • the aqueous layer was extracted with dichloromethane (2 x 100 mL). Analysis by liquid chromatography/mass spectroscopy (LCMS) showed that the organics did not contain product.
  • the aqueous layer was made basic (pH -10) with solid sodium carbonate and then extracted with dichloromethane (3 x 100 mL).
  • the resulting precipitate was isolated by filtration and then partitioned between dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organics were concentrated under reduced pressure to provide 500 mg of a foam. This material was dissolved in dichloromethane (50 mL) and then combined with 4M hydrochloric acid in dioxane (30 mL). A precipitate formed. The mixture was concentrated and then dissolved in hot ethanol. The solution was allowed to cool to ambient temperature, chilled (-10 °C) in a freezer overnight, and then allowed to warm to ambient temperature.
  • Triethylamine (1.47 mL, 10.5 mmol) was added to a solution of O- ⁇ [4-amino-l-(2- methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methyl ⁇ hydroxylamine (1.5 g, 5.3 mmol) in dichloromethane (50 mL). Methanesulfonyl chloride (0.448 mL, 5.78 mmol) was added and the reaction mixture was stined at ambient temperature for 2 hours.
  • the reaction mixture was washed with saturated aqueous sodium bicarbonate (1 x 30 mL) and brine (1 x 30 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 2.16 g of crade product as a brown foam.
  • This material was dissolved in dichloromethane (10 mL) and then loaded onto a FLASH 40+S silica cartridge (4O g). The cartridge was eluted sequentially with 500 mL ethyl acetate, 2%, 3%, and 5% methanol in ethyl acetate. The fractions containing product were combined and then concentrated under reduced pressure to provide 850 mg of a yellow solid.
  • the cartridge was eluted sequentially with 500 mL 2%, 4%, 6%, and 8% methanol in ethyl acetate. The fractions containing product were combined and then concentrated under reduced pressure to provide 880 mg of a yellow solid. This solid was recrystallized from acetonitrile, isolated by filtration, washed with acetonitrile and diethyl ether, and then dried under high vacuum to provide 365 mg of N- ⁇ [4-amino-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2- yl]methoxy ⁇ -N '-isopropylurea as a light yellow crystalline solid, mp 218-219 °C.
  • the cartridges were eluted sequentially with 1 L 1:1 ethyl acetate :hexanes, 5% methanol in 1:1 ethyl acetate :hexanes, and 10% methanol in 1:1 ethyl acetate :hexanes.
  • the fractions containing product were combined and concentrated under reduced pressure to provide 8.96 g of tert-butyl [3-(2-chloromethyl-lH-imidazo[4,5- c] quinolin- 1 -yl)propyl] carbamate as a light brown foam.
  • the reaction mixture was stined at ambient temperature for 2 hours; an additional 1 g of para- toluensulfonyl chloride was added and the reaction mixture was stined for another hour.
  • the reaction mixture was filtered to remove solids. The filtrate was transfened to a separatory funnel and the layers were separated.
  • the organic layer was washed with 1:1 water: saturated aqueous sodium bicarbonate (2 x 150 mL).
  • the combined aqueous was extracted with dichloromethane (2 x 150 mL) and ethyl acetate (1 x 100 mL).
  • the combined organic extracts were concentrated under reduced pressure to provide 13.6 g of crade product as a brown foam.
  • the foam was dissolved in dichloromethane (20 mL).
  • the solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g).
  • the first cartridge was eluted sequentially with IL 1 :1 ethyl acetate :hexanes, 5% methanol in 1:1 ethyl acetate :hexanes, and 10% methanol in 1:1 ethyl acetate:hexanes.
  • the second cartridge was eluted sequentially with IL 1:1 ethyl acetate :hexanes, 7% methanol in 1:1 ethyl acetate :hexanes, and 7% methanol in 1:1 ethyl acetate:hexanes.
  • Trifluoroacetic acid (7 mL) was added to a suspension of tert-butyl [3-(4-amino-2- isopropylideneaminoxymethyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]carbamate (4.12 g) in dichloromethane (70 mL). The reaction became homogeneous and was stined at ambient temperature for 2.5 hours. More trifluoroacetic acid (10 mL) was added and the reaction was stined for another hour.
  • the table below shows the acid chloride, sulfonyl chloride, sulfamoyl chloride, carbamoyl chloride or isocyanate used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
  • Acetone 25 mL was added to a suspension of the crude material from Part D in methanol (100 mL). The resulting solution was stined at ambient temperature for 3 hours and then concentrated under reduced pressure. The residue was azeotroped once with toluene, slurried with ethanol (100 mL) and then filtered. The filter cake was washed with additional ethanol. The filtrate was concentrated under reduced pressure to provide 3.9 g of product as a yellow solid. Additional product (0.9 g) was obtained by extracting the filter cake with dichloromethane.
  • Trifluoroacetic acid (10 mL) was added to a suspension of tert-butyl [2-(4-amino- 2-isopropylideneaminooxymethyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]carbamate (4.8 g) in dichloromethane (100 mL). The reaction became homogeneous and was stined at ambient temperature. At 2.5 hours and 3.5 hours more trifluoroacetic acid (10 mL and 5 mL respectively) was added. After a total reaction time of 4 hours the reaction mixture was concentrated under reduced pressure.
  • Part ⁇ A portion (1 mL) of the solution from Part G was transfened to a fresh test tube and then the solvent was removed by vacuum centrifugation. Methanol (1 mL), glacial acetic acid (1 mL), and 300 ⁇ L of a 1.0 M solution of sodium cyanoborohydride in tetrahydrofuran were added to the test tube. The test tube was capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). The solvent was removed by vacuum centrifugation. The compounds were purified by preparative high performance liquid chromatography (prep ⁇ PLC) using a Waters Fraction Lynx automated purification system using the method described above for Examples 4 - 42.
  • prep ⁇ PLC preparative high performance liquid chromatography
  • the crade product was purified by flash chromatography (silica gel, elution with 33% ethyl acetate in hexanes followed by 66% ethyl acetate in hexanes) to afford 9.2 g of tert-butyl 4-[(2-chloro-5,6- dimethyl-3-nitropyridin-4-yl)amino]butylcarbamate.
  • Ethyl 2-chloroethanimidoate hydrochloride (ethyl chloroacetimidate hydrochloride) (2.58 g, 16.4 mmol) was added to a solution of tert-butyl 4-[(8-amino-5,6- dimethyltetraazolo[l,5- ]pyridin-7-yl)amino]butylcarbamate (3.80 g, 10.9 mmol) in chloroform (75 mL). The solution was stined for 3 days, then saturated aqueous sodium bicarbonate (40 mL) was added. The aqueous phase was extracted with chloroform (3 x
  • Benzoic anhydride (3.1 g, 13.8 mmol) was added to a flask containing 4-[8- (chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5- ⁇ ]pyridin-7-yl]butan-l- amine hydrochloride (4.30 g, 12.5 mmol), triethylamine (3.70 mL, 26.3 mmol), and dichloromethane (100 mL) at 0 °C. The reaction mixture was stined at room temperature for 1 day and additional triethylamine (0.5 mL) and benzoic anhydride (0.8 g) were added.
  • reaction mixture was stined for 6 hours at room temperature.
  • the volatiles were removed under reduced pressure and water (50 mL) followed by ethyl acetate (50 mL) were added to the solid residue.
  • the mixture was sonicated for 1 minute, then the solid was isolated by filtration, washed with water and ethyl acetate, and dried under vacuum to afford 4.7 g of N- ⁇ 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5- ⁇ ]pyridin-7-yl]butyl ⁇ benzamide.
  • N- ⁇ ydroxyphthalimide (2.60 g, 16.0 mmol) and triethylamine (2.20 mL, 16.0 mmmol) were added to a suspension of N- ⁇ 4-[8-(chloromethyl)-5,6-dimethyl-7H- imidazo[4,5-c]tetraazolo[l,5- ⁇ ]pyridin-7-yl]butyl ⁇ benzamide (4.70 g, 11.4 mmol) in DMF (285 mL).
  • the reaction mixture was allowed to stir for 3 days, then was concentrated under reduced pressure to a white slurry. Methanol was added and a white solid was isolated by filtration, washed with methanol, and dried under vacuum to afford 5.70 g of
  • the solid was purified by chromatography using a HORIZON HPFC system (an automated, modular high- performance flash purification product available from Biotage, ie, Charlottesville, Virginia, USA) (silica gel, gradient elution with 10-35% CM A in chloroform, where CM A is 80:18:2 chloroform/methanol/concentrated ammonium hydroxide). The appropriate fractions were combined and concentrated under reduced pressure.
  • HORIZON HPFC system an automated, modular high- performance flash purification product available from Biotage, ie, Charlottesville, Virginia, USA
  • CM A is 80:18:2 chloroform/methanol/concentrated ammonium hydroxide
  • the foam was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 3-35%) CM A in chloroform) followed by crystallization from acetonitrile. The crystals were isolated by filtration and dried under vacuum at 70 °C to yield 80 mg of N-
  • the crade material was not purified by chromatography, rather by trituration with acetonitrile.
  • the purified product was isolated by filtration and was dried under vacuum to afford N-[4-(4-amino-2- ⁇ [(isopropylamino)oxy]methyl ⁇ -6,7-dimethyl-lH-imidazo[4,5- cjpyridin- 1 -yl)butyl]-2-methylpropanamide as a white powder, mp 156.0-157.0 °C.
  • Triethylamine (50.0 mL, 360 mmol) was added to a suspension of 4-chloro-3- nitroquinoline (50.0 g, 240 mmol) in DMF (200 mL), followed by dropwise addition of a solution of l-amino-2-methyl-propan-2-ol (23.5 g, 264 mmol) in DMF (50 mL). The reaction mixture was stined overnight at room temperature, then water (500 mL) was added and stirring was continued for 30 minutes.
  • Part B A mixture of 2-methyl-l-[(3-nitroquinolin-4-yl)amino]propan-2-ol (60.9 g, 233 mmol), 5% platinum on carbon (6.1 g), and ethanol (500 mL) was hydrogenated on a Parr apparatus at 30 psi (2.1 x 10 5 Pa) for 3 hours. The mixture was filtered through CELITE filter agent, which was subsequently rinsed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to yield an oil that was concentrated twice from toluene to afford 56.6 g of a brown oil that was used directly in the next step.
  • Triethylamine (49.0 mL, 350 mmol) was added to a stined suspension of the material from Part B in dichloromethane (450 mL).
  • the reaction mixture was stined for approximately 3 days at room temperature.
  • the solution was concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate (500 mL) and 1:1 saturated aqueous sodium bicarbonate/water (500 mL).
  • the aqueous layer was extracted with ethyl acetate (3 x 250 mL) and chloroform (250 mL).
  • the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Part D mCPBA (77% pure, 36.5 g, 163 mmol) was added over 10 minutes to a stined suspension of l-[2-(chloromethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol (23.6 g, 81.4 mmol) in chloroform (500 mL). The resulting solution was stined at room temperature for 1.5 hours. Concentrated ammonium hydroxide (200 mL) was added.
  • the crade product was purified in portions by chromatography on a HORIZON HPFC system (silica gel, elution with 5% methanol in chloroform followed by gradient elution with 5-15%) methanol in chloroform) to yield 9.42 g of l-[4-amino-2-(chloromethyl)-lH- imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol as a pale yellow solid.
  • the flask containing the solution of l-[4-amirio-2-(chloromethyl)-lH- imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol was rinsed with DMF (3.0 mL), wliich was added to the reaction solution.
  • the solution was stined at room temperature for 3 hours and a solid formed.
  • the solid was isolated by filtration, washed with dichloromethane, and dried.
  • the off-white solid was dissolved in hot DMF (20 mL). Acetonitrile (50 mL) was added to the solution, which was then placed in a freezer.
  • Methyl isocyanate (0.148 mL, 2.39 mmol) was added to a stined solution of 1 - ⁇ 4- amino-2- [(aminooxy)methyl] - lH-imidazo [4,5 -c] quinolin- 1 -yl ⁇ -2-methylpropan-2-ol (prepared as described in Example 100, 600 mg, 1.99 mmol) in DMF (5 mL). A solid formed immediately. The mixture was stined for 2 hours at room temperature, then was heated to form a solution to which acetonitrile (10 mL) was added. Crystals formed that were isolated by filtration and purified by chromatography using a HORIZON HPFC
  • the aqueous layer was extracted with dichloromethane (2 x 30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration to provide 40 mg of N- ⁇ [4-amino-l-(2-hydroxy-2- methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methoxy ⁇ methanesulfonamide. Additional crystals were isolated from the mother liquor after a seed crystal was added.
  • Triethylamine (0.634 mL, 4.55 mmol) and cyclopropanecarbonyl chloride (0.248 mL, 2.73 mmol) were added to a solution of l- ⁇ 4-amino-2-[(aminooxy)methyl]-lH- imidazo[4,5-c]quinolin-l-yl ⁇ -2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL).
  • the cloudy mixture was stined for 2 hours at room temperature, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2 x 30 mL).
  • Examples 105-122 A reagent from the table below (1.1 equivalents, 0.10 mmol) was added to a test tube containing a solution of 1- ⁇ 4-amino-2-[(aminooxy)methyl]-lH-imidazo[4,5- c]quinolin-l-yl ⁇ -2-methylpropan-2-ol (prepared as described in Example 100, 29 mg, 0.09 mmol) and triethylamine (26 ⁇ L, 0.20 mmol) in DMF (1 mL). The test tubes were capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). The solvent was removed from the test tubes by vacuum centrifugation.
  • the compounds were purified by preparative high perfonnance liquid chromatography (prep HPLC) using a Waters FractionLynx automated purification system.
  • the prep HPLC fractions were analyzed using a Waters LC/TOF-MS, and the appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the desired compound.
  • Reversed phase preparative liquid cliromatography was performed with non-linear gradient elution from 5- 95%) B where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic acid/acetonitrile.
  • Fractions were collected by mass-selective triggering.
  • the table below shows the reagent used for each example, the stracture of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
  • a reagent from the table below (1.1 equivalents, 0.11 mmol) was added to a test tube containing a solution of 2-[(aminooxy)methyl]-l-(2-methylpropyl)-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 123, 29 mg, 0.10 mmol) and NN-diisopropylethylamine (36 ⁇ L, 0.20 mmol) in chloroform (1 mL).
  • the test tubes were capped and placed on a shaker at ambient temperature for 4 hours. Water (two drops) was added to each test tube and the volatiles were removed from the test tubes by vacuum centrifugation.
  • the compounds were purified as described in Examples 105-122.
  • the table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
  • Part C The general method described in Part C of Example 92 was used to convert N 4 - ⁇ - methyl ⁇ ropyl)[l,5]naphthyridine-3,4-diamine (from Part B) into 2-chloro-N- ⁇ 4-[(2- methylpropyl)amino][l,5]naphthyridin-3-yl ⁇ acetamide hydrochloride, which was isolated as a pale yellow solid that was used directly in the next step without purification.
  • Part F The material from Part E was dissolved in methanol (70 mL) and the solution was cooled to 0 °C. Concentrated ammonium hydroxide (6.7 mL) was added, followed by dropwise addition of benzenesulfonyl chloride (5.25 mL, 42.0 mmol). The reaction mixture was stined at 0 °C for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated.
  • dichloromethane 150 mL
  • saturated aqueous sodium bicarbonate 75 mL
  • the aqueous layer was extracted with dichloromethane (50 mL).
  • the crade product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 0-25 % CMA in chloroform) to afford 4.14 g of approximately 85% pure 2-(chloromethyl)-l-(2-methylpropyl)-lH-imidazo[4,5- c] [ 1 ,5]naphthyridin-4-amine, wliich was used in the next step without further purification.
  • HORIZON HPFC system sica gel, gradient elution with 0-25 % CMA in chloroform
  • a reagent from the table below (1.1 equivalents, 0.11 mmol) was added to a test tube containing a solution of 2-[(aminooxy)methyl]-l-(2-methylpropyl)-lH-imidazo[4,5- c][l,5]naphthyridin-4-amine (prepared as described in Example 136, 29 mg, 0.10 mmol) and N,N-diisopropylethylamine (35 ⁇ L, 0.20 mmol) in chloroform (1 mL).
  • the test tubes were capped and placed on a shaker at ambient temperature for 4 hours. The solvent was removed from the test tubes by vacuum centrifugation.
  • the compounds were purified as described in Examples 105-122.
  • the table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
  • Part D 7-Bromo-3-nitroquinolin-4-ol (42 g, 156 mmol) was suspended in POCl 3 (130 mL) and brought to 102 °C under an atmosphere of N 2 . After 45 min, all of the solids had dissolved, so the reaction was cooled to room temperature. The resulting solids were collected by filtration, washed with H 2 O, and then partitioned with CH C1 2 (3 L) and 2M

Abstract

Imidazo ring compounds (e.g., imidazoquinolines, 6, 7, 8, 9-tetrahydroimidazoquinolines, imidazonaphthyridines, and imidazopyridines) with a hydroxylamine substituent at the 2-position, pharmaceutical compositions containing the compounds, intermediates, and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.

Description

HYDROXYLAMLNE SUBSTITUTED IMTDAZO RING COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Application Serial No. 60/520,215, filed on November 14, 2003, which is incorporated herein in its entirety.
BACKGROUND
In the 1950's the lH-imidazo[4,5-c]quinoline ring system was developed, and l-(6- methoxy-8-quinolinyl)-2-methyl-lH-imidazo[4,5-c]quinoline was synthesized for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H- imidazo[4,5-c]quinolines were reported. For example, l-[2-(4-piperidyl)ethyl]-lH- imidazo[4,5-c]quinoline was synthesized as a possible anticonvulsant and cardiovascular agent. Also, several 2-oxoimidazo[4,5-c]quinolines have been reported.
Certain lH-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. Subsequently, certain substituted lH-imidazo[4,5-c]pyridin-4-amine, quinolin-4-amine, tetrahydroquinolin-4-amine, naphthyridin-4-amine, and tetrahydronaphthyridin-4-amine compounds as well as certain analogous thiazolo and oxazolo compounds were synthesized and found to be useful as immune response modifiers (IRMs), rendering them useful in the treatment of a variety of disorders.
There continues to be interest in and a need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
SUMMARY The present invention provides a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Such compounds are of the following Formula
I:
Figure imgf000003_0001
I and, more particularly, compounds of the following Formula TJ:
Figure imgf000003_0002
π
wherein: R', RA, RB, RAI, RBI, RI, R2, R2a, X, and Y' are as defined below.
The compounds of Formulas I and II are useful as immune response modifiers (IRMs) due to their ability to induce cytokine biosynthesis (e.g., induce the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions, such as viral diseases and neoplastic diseases, that are responsive to such changes in the immune response. In another aspect, the present invention provides pharmaceutical compositions containing the immune response modifier compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral disease in an animal, and treating a neoplastic disease in an animal, by administering an effective amount of one or more compounds of Formula I and/or Formula II and/or pharmaceutically acceptable salts thereof to the animal. In another aspect, the invention provides methods of synthesizing compounds of
Formulas I and II and intermediates useful in the synthesis of these compounds.
As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably.
The terms "comprising" and variations thereof do not have a limiting meaning where these terms appear in the description and claims. The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION The present invention provides compounds of the following Formulas I through
VI:
Figure imgf000004_0001
Figure imgf000004_0002
π
Figure imgf000004_0003
Figure imgf000005_0001
ma
Figure imgf000005_0002
rv
Figure imgf000005_0003
IVa
Figure imgf000005_0004
V R,
Figure imgf000006_0001
VI
wherein: R, R', R'", RA, RB, RAI, RBI, RA2, B2, RI, R2, R2a, R3, n, m, p, X, and Y' are as defined below.
hi one aspect of the invention, compounds are provided that are of the following Formula I:
Figure imgf000006_0002
I wherein:
X is Cι-10 alkylene or C2.10 alkenylene;
RA and RB are each independently selected from the group consisting of: hydrogen, halogen, alkyl, aikenyl, alkoxy, alkylthio, and -N(R9)2; or when taken together, RA and RB form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R'" groups; or when taken together, RA and RB form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups; R. is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
-N(R9)2; Y"' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
-S(O)2-, -S(O)2-N(R8)-,
Figure imgf000007_0001
-C(O)-O-, -C(O)-N(R8)-
-C(S)-N(R8)-, -C(O)-N(R8)-S(O)2-, -C(O)-N(R8)-C(O)-, -C(S)-N(R8)-C(O)-,
Figure imgf000007_0002
-C(O)-C(O)-, -C(O)-C(O)-O-, and -C(=NH)-N(R8)-; R2 and R2a are 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, halo alkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(O)o-2-alkyl,
-S(O)o-2-aryl, -NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and
-C(O)-alkyl; or R and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R6) -N- S(0)2
V and R ; R' is hydrogen or a non-interfering substituent;
R'" is a non-interfering substituent;
R6 is selected from the group consisting of =O and =S;
R is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, CMQ alkyl, C2.10 alkenyl, C O alkoxy- -io al ylenyl, and aryl-d-io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; and
R10 is C3-8 alkylene; or a pharmaceutically acceptable salt thereof.
In one aspect of the invention, compounds are provided that are of the following
Formula II:
π wherein: X is Cι-10 alkylene or C2-10 alkenylene;
RA1 and RB1 are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and
-N(R9)2; or when taken together, RAΪ and Rβi form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R groups, or substituted by one R3 group, or substituted by one R3 group and one R group; or when taken together, RAΪ and RBΪ form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; R3 is selected from the group consisting of: -Z-R4, -Z-X'-R^
-Z-X'-Y-R4, -Z-X'-Y-X'-Y-R^ and -Z-X'-R5; Y' is selected from the group consisting of: a bond,
-C(O)-, -C(S)-,
-S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000011_0001
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000011_0002
-C(O)-C(O)-, -C(0)-C(0)-O-, and
-C(=NH)-N(R8)-; Ri is selected from the group consisting of:
-R4,
Figure imgf000011_0003
-X'-Y-R4,
-X'-Y-X'-Y-T , -X*-R5,
-X"-O-NRia-Y'-Rib, and
Figure imgf000011_0004
Ria, Rib, Ri', Ri", R-2, and R2a are 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,
-S(O)0-2-aryl, -NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and -C(O)-alkyl; or Rla and R^ and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of:
-N- C(R6) -N— S(0)2 7 and or K\ and R^' can join together to form a ring system selected from the group consisting of:
Figure imgf000013_0001
wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000013_0002
wherein the total number of atoms in the ring is 4 to 9;
Re and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(R13)-alkylene- or -CH(R13)-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of: -S(O)o-2-,
-S(O)2-N(R8)-,
-C(R6)-,
-C(R6)-O-,
-O-C(R6)-, -O-C(0)-O-,
-N(R8)-Q-, -C(R6)-N(R8>,
-O-C(R6)-N(R8K -C(R6)-N(OR9)-,
Figure imgf000014_0001
Z is a bond or -O-; R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of allcyl, 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;
R5 is selected from the group consisting of:
- -NIN-— C(R6) - γN
Figure imgf000014_0002
R6 is selected from the group consisting of =O and =S;
R7 is C2_7 alkylene;
R8 is selected from the group consisting of hydrogen, Cμio alkyl, C2-10 alkenyl, C1-10 alkoxy-C o alkylenyl, and aryl-Ci.-i.o alkylenyl; R9 is selected from the group consisting of hydrogen and alkyl;
R10 is C -8 alkylene;
Rπ is C1-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
R13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
A is selected from the group consisting of-CH -, -O-, -C(O)-, -S(O)0-2-, and -NOE )-;
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)- -, -S(0)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
hi one aspect of the invention, compounds are provided that are of the following Formula IH:
Figure imgf000016_0001
rπ wherein:
X is C O alkylene or C2-10 alkenylene; Y' is selected from the group consisting of: a bond,
-C(O)-,
-C(S)-,
-S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000016_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000016_0003
Ho
-C(O)-C(O)-, -C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R2 and R2a are 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)o-2-alkyl, -S(O)o-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl;
R8 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-io alkenyl, CMO alkoxy-Ci-io alkylenyl, and aryl-C1.1o alkylenyl; R10 is C3-8 alkylene; n is an integer from 0 to 4; R'" is a non-interfering substituent; and
R' is hydrogen or a non-interfering substituent; or a pharmaceutically acceptable salt thereof.
In one aspect of the invention, compounds are provided that are of the following Formula UTa:
Figure imgf000018_0001
ma wherein:
X is Ci-io alkylene or C2-10 alkenylene; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O)2-, -S(O)2-N(R8)-,
Figure imgf000018_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000019_0001
-C(O)-C(O)-, -C(O)-C(O)-O-, and -C(=NH)-N(R8)-;
R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
-N(R9)2; R\ is selected from the group consisting of:
-R4,
-X--R4, -X'-Y-R,,
Figure imgf000019_0002
-X'-R5,
-X"-O-NRla-Y'-Rlb, and -X"-O-N=C(R1')(Rι"); Ria, Rib, Ri', Ri", R_, and R a are 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)o-2-alkyl, -S(O)o-2-aryl, -NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
-C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl; or Rla and Rlb and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R6) -N- S(0)2
or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
the total number of atoms in the ring is 4 to 9, and
Figure imgf000021_0001
wherein the total number of atoms in the ring is 4 to 9;
Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
R3 is selected from the group consisting of:
-Z-R4, -Z-X'-R4,
-Z-X'-Y-R4, -Z-X'-Y-X'-Y-R^ and
-Z-X'-R5; n is an integer from 0 to 4; m is 0 or 1 ; with the proviso that when m is 1, then n is 0 or 1 ; X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(R13)-alkylene- or -CH(R13)-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups; Y is selected from the group consisting of:
-S(O)o-2-,
-S(O)2-N(R8)-,
-C(R6)-,
-C(R6)-O-, -O-C(R6)-,
-O-C(O)-O-,
-N(R8)-Q-,
-C(R6)-N(R8)-,
-O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000022_0001
Z is a bond or -O-; 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 ;
R5 is selected from the group consisting of:
-N
Figure imgf000023_0001
R6 is selected from the group consisting of =O and =S;
R7 is C2_7 alkylene;
R8 is selected from the group consisting of hydrogen, Ci.in alkyl, C2-l0 alkenyl, Cι-ιo alkoxy-d-K) alkylenyl, and aryl-CMo alkylenyl; R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
Rπ is Cι-6 alkylene or C2.6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, C1.5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
R13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o-2-, and
A' is selected from the group consisting of -O-, -S(O)o-2-, -N^Q-R^-, and -CH -;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(Rδ)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R<s)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -0-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
In one aspect of the invention, compounds are provided that are of the following Fonnula a:
Figure imgf000024_0001
wherein:
X is Ci-io alkylene or C2-ιo alkenylene; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
-S(O)2-, -S(O)2-N(R8)-,
Figure imgf000024_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000025_0001
-C(O)-C(O)-, -C(O)-C(O)-O-, and
Figure imgf000025_0002
R2 and R2a are 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, -S(O)o-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and
-C(O)-alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2;
Ri is selected from the group consisting of:
Figure imgf000026_0001
-X'-R4, -X-Y-R^ -X'-Y-X'-Y-R^
-X'-Rs, -X"-O-NH-Y*-Rι', and
-X"-O-N=C(Rι')(R1"); R3 is selected from the group consisting of: -Z-R4,
Figure imgf000026_0002
Figure imgf000027_0001
-Z-X'-Y-X'-Y-R^ and -Z-X'-R5; n is an integer from 0 to 4; m is 0 or 1 ; with the proviso that when m is 1 , then n is 0 or 1 ;
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups; X" is -CH(R )-alkylene- or -CH(Rι3)-alkenylene-;
Y is selected from the group consisting of: -S(O)0.2-, -S(O)2-N(R8)-, -C(R6)-, -C(R6)-O-,
-O-C(R6)-, -O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-, -O-C(R6)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000027_0002
Figure imgf000028_0001
Z is a bond or -O-;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, 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 ;
R5 is selected from the group consisting of:
-N
Figure imgf000028_0002
Ri' and R\" axe independently the same as R , or Ri' and RΪ" can join together to form a ring system selected from the group consisting of:
the total number of atoms in the ring is 4 to 9, and
Figure imgf000028_0003
wherein the total number of atoms in the ring is 4 to 9; Re and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms; R6 is selected from the group consisting of =O and =S;
R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, Cι-10 alkyl, C2-10 alkenyl, Cι-10 alkoxy-Ci-io alkylenyl, and aryl-C1-10 alkylenyl; R is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
R11 is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
R12 is selected from the group consisting of a bond, Cι-5 alkylene, and C -5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o-2-, and -NOR4)-;
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)- -, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R($)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
In one aspect of the invention, compounds are provided that are of the following
Formula TV:
Figure imgf000029_0001
TV wherein:
X is Ci-io alkylene or C2.1o alkenylene; Y' is selected from the group consisting of: a bond,
-C(O)-,
-C(S)-,
-S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000030_0001
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000030_0002
-C(O)-C(O)-,
-C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
-N(R9)2; n is an integer from 0 to 4;
R2 and R2a are 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, -S(O)o-2-aryl, -NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy; -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and -C(O)-alkyl; R8 is selected from the group consisting of hydrogen, Ci-io alkyl, C -ι0 alkenyl, Cι-ι0 alkoxy-Ci-io alkylenyl, and aryl-Q-io alkylenyl; R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene; and R' is hydrogen or a non-interfering substituent; or a pharmaceutically acceptable salt thereof.
In one aspect of the invention, compounds are provided that are of the following
Formula (IVa):
Figure imgf000032_0001
IVa wherein: X is Ci-io alkylene or C2.10 alkenylene;
Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000033_0001
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000033_0002
-C(O)-C(O)-, -C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2;
Ri is selected from the group consisting of:
-R4,
-X'-R4, -X-Y-R4, -X'-Y-X'-Y-R4,
-X'-R5,
-X"-O-NRla-Y'-Rib, and -X"-O-N=C(R1')(R1"); Ria, Rib, Ri', Ri", R2, and R2a are 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, -S(O)o-2-aryl, -NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and -C(O)-alkyl; or Rla and Rιb and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R6) -N- S(0)2 V and ; or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Figure imgf000035_0001
wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000035_0002
wherein the total number of atoms in the ring is 4 to 9; Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Rς and
Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms; n is an integer from 0 to 4; X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(R13)-alkylene- or -CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of: -S(O)0-2-, -S(O)2-N(R8)-, -C(R6)-, -C(R6)-O-, -O-C(R6)-,
-O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-, -O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000036_0001
Rύ, 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;
R5 is selected from the group consisting of:
Figure imgf000037_0001
R6 is selected from the group consisting of =O and =S;
R7 is C -7 alkylene;
R8 is selected from the group consisting of hydrogen, Cι-10 alkyl, C -ι0 alkenyl,
Ci-io alkoxy-Ci-io alkylenyl, and aryl-Cι-ιo alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rw is C3.8 alkylene;
Rπ is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι2 is selected from the group consisting of a bond, Cι-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o- -, and
-N(R4>; A' is selected from the group consisting of -O-, -S(O)o-2-,
Figure imgf000037_0002
and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-,
-S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9 ;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and
-S(O)2-; W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof. In one aspect of the invention, compounds are provided that are of the following Formula IVa:
Figure imgf000038_0001
IVa wherein:
X is Ci-io alkylene or C2-ιo alkenylene; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
-S(O)2-, -S(O)2-N(R8)-,
Figure imgf000038_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000038_0003
-C(O)-C(O)-, -C(O)-C(O)-O-, and
Figure imgf000038_0004
R2 and R a are 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)o-2-alkyl, -S(O)o-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy; -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl;
R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; n is an integer from 0 to 4;
R\ is selected from the group consisting of:
-R4, -X'-R ,
Figure imgf000040_0001
-X'-Y-X'-Y-Ri,
-X'-R5,
Figure imgf000040_0002
_χ-..0-N=C(R1')(R1"); X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups; X" is -CH(R13)-alkylene- or -CH(R13)-alkenylene-; Y is selected from the group consisting of: -S(O)o_2-,
-S(O)2-N(R8)-, I -C(R6)-,
-C(R6)-O-,
-O-C(R6)-,
-O-C(O)-O-,
-N(R8)-Q-,
-C(R6)-N(R8)-,
-O-C(R6)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000041_0001
R4 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, diallcylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo; R5 is selected from the group consisting of:
Figure imgf000042_0001
Ri' and Ri" are independently R2, or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Figure imgf000042_0002
^R 1 π wherein the total number of atoms in the ring is 4 to 9,
Figure imgf000042_0003
wherein the total number of atoms in the ring is 4 to 9;
Re and Ra are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
R6 is selected from the group consisting of =O and =S; R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, Cι-10 alkyl, C2.1o alkenyl, Ci-io alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl; R is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
Rn is Ci.6 alkylene or C2.6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι2 is selected from the group consisting of a bond, Cι_5 alkylene, and C _5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
R13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)0-2-, and -N(R4)-; A' is selected from the group consisting of -O-, -S(O)o-2-,
Figure imgf000043_0001
and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O) -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ≤ 7; or a pharmaceutically acceptable salt thereof.
In one aspect of the invention, compounds are provided that are of the following Formula V:
Figure imgf000043_0002
V wherein:
X is C MO alkylene or C2-ι0 alkenylene; Y' is selected from the group consisting of: a bond,
-C(O)-,
-C(S)-,
-S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000043_0003
-C(O)-O-, -C(O)-N(R8)-, -C(S)-N(R8)-, -C(O)-N(R8)-S(O)2- -C(O)-N(R8)-C(O)-, -C(S)-N(R8)-C(O)-,
Figure imgf000044_0001
-C(O)-C(O)-, -C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, aikylthio, and -N(R9)2;
Ri is selected from the group consisting of:
-R4, -X'-R4,
-X'-Y-R4, -X'-Y-X'-Y-R^
-X'-R5,
-X"-O-NRιa-Y'-Rlb, and
Figure imgf000044_0002
Ria, Rιb, Ri', Ri", R2, and R2a are 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)o-2-alkyl, -S(O)o-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and
-C(O)-alkyl; or Rla and RJb and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of:
Figure imgf000046_0001
or Ri' and R n together ; to form a ring system selected from the group consisting of:
the total number of atoms in the ring is 4 to 9, and
Figure imgf000046_0002
wherein the total number of atoms in the ring is 4 to 9;
Re and d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
R3 is selected from the group consisting of:
-Z-R ,
-Z-X*-R4, -Z-X'-Y-R4,
-Z-X'-Y-X'-Y-Rt, and
-Z-X'-R5; p is an integer from 0 to 3; m is 0 or 1, with the proviso that when m is 1, p is 0 or 1; X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or tenninated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of: -S(O)o-2",
-S(O)2-N(R8)-, -C(R6)-, -C(R6)-O-, -O-C(R6)-,
-O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-, -O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000047_0001
Z is a bond or -O-;
RA 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 ;
R5 is selected from the group consisting of:
Figure imgf000048_0001
R6 is selected from the group consisting of =O and =S; R is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, Ci-io alkyl, C2-ιo alkenyl, Ci-io alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl; R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3.8 alkylene;
Rii is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι is selected from the group consisting of a bond, C1-5 alkylene, and C -5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
R13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o-2-, and
A' is selected from the group consisting of -O-, -S(O)o-2-, -N^Q-R*)-, and -CH2-; Q is selected from the group consisting of a bond, -C(Re)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof. In one aspect of the invention, compounds are provided that are of the following Formula VI:
Figure imgf000049_0001
VI wherein:
X is C i-io alkylene or C2-ιo alkenylene; A2 and Rβ2 are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R9)2; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O)2-, -S(O)2-N(R8)-,
Figure imgf000049_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-, -C(0) _ N J V_ Rιo
-C(O)-C(O)-,
-C(O)-C(O)-O-, and
-C(=NH)-N(R8)-;
Ri is selected from the group consisting of:
-R4,
-X--R4,
-X'-Y-RA,
-X'-Y-X'-Y-R4,
-X'-Rs,
-X"-O-NRιa-Y'-Rιb, and
-X"-O-N=C(Rι')(Rι");
Ri a, Rι , Ri', Ri", R2, and R2a are 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)o-2-alkyl,
-S(O)o-2-aryl, -NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, ' arylalkyleneoxy,
-C(O)-O-alkyl,
-C(O)-N(R8)2,
-N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and -C(O)-alkyl; or Rla and Rlb and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R6) -N- S(O)2
V and ; or Ri' and Ri" can join together to form a ring system selected from the group consisting of: R11 \
A'
-R
11 wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000052_0001
wherein the total number of atoms in the ring is 4 to 9;
Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or e and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
-S(O)o-2-, -S(O)2-N(R8)-,
-C(R6)-,
-C(R6)-O-,
-O-C(R6)-,
-O-C(O)-O-, -N(R8)-Q-,
-C(R6)-N(R8)-,
-O-C(R6)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000052_0002
Figure imgf000053_0001
R4 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;
R5 is selected from the group consisting of:
Figure imgf000053_0002
R6 is selected from the group consisting of =O and =S; R7 is C _7 alkylene; R8 is selected from the group consisting of hydrogen, Cι-10 alkyl, C _ιo alkenyl,
Cι-10 alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
R is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene; Rii is Cι-6 alkylene or C2.6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι2 is selected from the group consisting of a bond, Cι-5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o- -, and
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-;
Q is selected from the group consisting of a bond, -C(Rδ)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-; W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
Certain embodiments of the present invention include non-interfering substituents. For example, in certain embodiments, R' is hydrogen or a non-interfering substitutent, and in certain embodiments, R'" is a non-interfering substituent.
Herein, "non-interfering" means that the ability of the compound or salt, which includes a non-interfering substituent, to modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not destroyed by the non-interfering substitutent. Illustrative non-interfering R' groups include those described herein for Ri. Illustrative non- interfering R'" groups include those described herein for R and R .
As used herein, the terms "alkyl", "alkenyl", "alkynyl" and the prefix "alk-" are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms, hi 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.
Unless otherwise specified, "alkylene", "alkenylene", and "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. For example, an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached.
The term "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. The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems.
Examples of aryl groups include phenyl, naphthyl, biphenyl, fiuorenyl and indenyl.
Unless otherwise indicated, the term "heteroatom" refers to the atoms O, S, or N. The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidiiiyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on. The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tefrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, dihydroisoquinolin-(lH)-yl, octahydroisoquinolin-(lH)-yl, dihydroquinolin- (2H)-yl, octahydroquinolin-(2H)-yl, dihydro-lH-imidazolyl, and the like. When "heterocyclyl" contains a nitrogen atom, the point of attachment of the heterocyclyl group may be the nitrogen atom.
The terms "arylene," "heteroarylene," and "heterocyclylene" are the divalent forms of the "aryl," "heteroaryl," and "heterocyclyl" groups defined above. The terms,
"arylenyl", "heteroarylenyl", and "heterocyclylenyl" are used when "arylene," "heteroarylene," and "heterocyclylene", respectively, are substituted. For example, an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
When a group (or substituent or variable) is present more than once in any Formula described herein, each group (or substituent or variable) is independently selected, whether explicitly stated or not. For example, for the formula -C(O)-N(R8)2 each R8 group is independently selected, hi another example, when an Ri and an R3 group both contain an R4 group, each R group is independently selected. In a further example, when more than one Y group is present (i.e., Ri and R both contain a Y group) and each Y group contains one or more R7 groups, then each Y group is independently selected, and each R7 group is independently selected.
The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers. It should be understood that the term "compound" includes any or all of such forms, whether explicitly stated or not (although at times, "salts" are explicitly stated).
For any of the compounds presented herein, each one of the following variables (e.g., R, R', R'", RA, RB, RAι, RBI, RI, R2, R2a, R3, n, X, Y, Y', Z 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. hi some embodiments, R is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2. hi certain embodiments, R is selected from the group consisting of halogen and hydroxy.
In some embodiments, RA and RB are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R9)2.
Alternatively, when taken together, RA and RB form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R'" groups. Alternatively, when taken together, RA and RB form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups. i some embodiments, particularly embodiments of Formula I, RA and RB are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R9)2. hi some embodiments, particularly embodiments of Formula I, RA and RB form a fused aryl or heteroaryl ring. h some embodiments, particularly embodiments of Formula I, RA and RB form a fused 5 to 7 membered saturated ring. h some embodiments, RAι and RBI are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R9)2.
Alternatively, RAI. and RB1 form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R groups, or substituted by one R3 group, or substituted by one R3 group and one R group. Alternatively, when taken together, RAI and RBI form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups.
In some embodiments, particularly embodiments of Formula TJ, RAI and RBι form a fused benzene ring which is unsubstituted. h some embodiments, particularly embodiments of Formula II, RAI and RBι fonn a fused pyridine ring which is unsubstituted. In some embodiments, particularly embodiments of Formula jT, RAI and RBI form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, wherein the ring is unsubstituted.
In some embodiments, R 2 and B2 are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R9)2. hi certain of these embodiments, RA2 and Rβ2 are each independently alkyl. In some embodiments, RA2 and RB2 are each methyl.
In some embodiments, Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can j oin to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms. In certain embodiments, at least one of Re or Rd is aryl.
In some embodiments, Ri is selected from the group consisting of -Rt, -X'-R^ -X-Y-R4, -X'-Y-X'-Y-RA, -X'-RS, -X"-O-NRla-Y*-Rι , and -X"-O-N=C(Rι')(Rι"). hi some embodiments, Ri is selected from the group consisting of -R , -X'-R4, -X'-Y-Ri,
-X'-Y-X'-Y-R4, -X'-R5, -X"-O-NH-Y'-Rι', and -X"-O-N=C(Ri')(Ri").
In some emdobiments, Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, -X'-Y-Ri, and -X'-R5. h some embodiments, Ri is 2-methylpropyl, 2-hydroxy-2-methylpropyl, or -X'-Y-R In some embodiments, Ri is 2-methylpropyl or -X'-Y-R^ In some embodiments, Ri is 2-methylpropyl or 2-hydroxy-2-methylpropyl. In some embodiments, Ri is 2-methyl-2-[(methylsulfonyl)amino]propyl or 4-[(methylsulfonyl)amino]butyl.
In some embodiments, R' is hydrogen or a non-interfering substituent. In some embodiments, R' is selected from the group consisting of -Rj, -X'-R4, -X'-Y-Ri, -X'-Y-X'-Y-R^ -X'-R5, -X"-O-NH-Y'-Rι', and -X"-O-N=C(Rι')(Rι"). hi some embodiments, R' is selected from the group consisting of -R , -X'-R^ -X'-Y-Ri, -X'-Y-X'-Y-R^ -X'-R5, -X"-O-NRιa-Y'-Rι , and -X"-O-N=C(Rι')(Rι"). h some embodiments, Ri' and Ri" are independently the same as R2.
In some embodiments, R\ and Ri" are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, as well as 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, -S(O)0-2-aryl, -NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl.
In some embodiments, Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Figure imgf000059_0001
Alternatively, Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Figure imgf000059_0002
1 η wherein the total number of atoms in the ring is 4 to 9,
Figure imgf000059_0003
wherein the total number of atoms in the ring is 4 to 9.
In some embodiments, Rιa and Rιb are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, as well as 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, -S(O)0-2-aryl, -NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
-C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl. Alternatively, Rιa and Rιb together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of -N- C(R6) -N- S(0)2 R R /
7 and 7 . In some embodiments, Rιa is hydrogen. hi some embodiments, R2 and R2a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, heterocyclylalkylenyl, as well as alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of hydroxy (i.e., hydroxyl), alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, -S(O)0-2-alkyl, -S(O)o-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano (i.e., nitrile), nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2,
-N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl. Herein, this list of substituents is being referenced when an R2 or R2a group is refened to as substituted or optionally substituted.
Alternatively, R and R a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of
-N- C(R6) -N- S(O)2
^ R7 and ^ R K?7 In some embodiments, particularly embodiments of Formulas ma and IVa, R2 and
R2a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, wherein the alkyl, alkenyl, aryl, and heteroaryl are each optionally substituted with one or more substitutents selected from the group consisting of Ci-io alkyl, aryl, heteroaryl, Ci-io alkoxy, -O-C(O)-Ci-io alkyl, -C(O)-O-Ci-io alkyl, halogen, and cyano (i.e., nitrile).
In some embodiments, R2 is alkyl or substituted alkyl. In some embodiments, R2 is methyl or cyclopropyl.
In some embodiments, R2 is alkenyl or substituted alkenyl. In some embodiments, R2 is aryl, arylalkylenyl, substituted aryl, or substituted arylalkylenyl. hi some embodiments, R2 is heteroaryl , heteroarylalkylenyl, substituted heteroaryl, or substituted heteroarylalkylenyl. In some embodiments, R is heterocyclyl, heterocyclylalkylenyl, substituted heterocyclyl, or substituted heterocyclylalkylenyl.
In some embodiments, R2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2- (ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3- methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3-ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tetrahydrofuranyl, tetrahydrofuran-3 -ylmethyl, 2- (methylthio)ethyl, 3-(methylthio)propyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6- dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4- (dimethylamino)phenyl, 3-hydroxy-4-methoxyphenyl, 4-acetamidophenyl, 4- (methoxycarbonyl)phenyl, 4-(trifluoromethyl)phenyl, biphenyl, benzyl, 2-methylbenzyl, 3- methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4- cyanobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4- dimethylaminobenzyl, 3-hydroxy-4-methoxybenzyl, 4-acetamidobenzyl, 4- (methoxycarbonyl)benzyl, 4-(trifluoromethyl)benzyl, 1-phenylethyl, 2-phenylethyl, 2- phenylpropyl, 3-phenylpropyl, 2-phenylethenyl, phenoxymethyl, 2-pyridyl, 3 -pyridyl, 4- pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethy, l-methylpynol-2-yl, 1- methylpyrrol-2-ylmethyl, l-methylimidazol-2-yl, l-methylimidazol-2-ylmethyl, 1- methylimidazol-4-yl, l-methylimidazol-4-ylmethyl, 3-cyclohexen-l-yl, 3-cyclohexen-l- ylmethyl, 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-2-ylmethyl, 1- methylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-benzylpiperidin-4-yl, 2-thienyl, 3-thienyl, thien-2-ylmethyl, thiazol-2-yl, thiazol-2-ylmethyl, 5-isoxazolyl, 5-isoxazolylmethyl, quinolin-2-yl, quinolin-2-ylmethyl, pyrrolidinyl, 3,4-dichlorophenyl, α-methylbenzyl, methoxymethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.
In some embodiments, R2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2- (ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3- methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3-ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tefrahydrofuranyl, tetrahydrofuran-3-ylmethyl, 2- (methylthio)ethyl, 3-(methylthio)propyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6- dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4- (dimethylamino)phenyl, 3-hydroxy-4-methoxyphenyl, 4-acetamidophenyl, 4- (methoxycarbonyl)phenyl, 4-(trifluoromethyl)phenyl, biphenyl, benzyl, 2-methylbenzyl, 3- methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4- cyanobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4- dimethylaminobenzyl, 3-hydroxy-4-methoxybenzyl, 4-acetamidobenzyl, 4- (methoxycarbonyl)benzyl, 4-(trifluoromethyl)benzyl, 1-phenylethyl, 2-phenylethyl, 2- phenylpropyl, 3-phenylpropyl, 2-phenylethenyl, phenoxymethyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethy, l-methylpyrrol-2-yl, 1- methylpynol-2-ylmethyl, l-methylimidazol-2-yl, l-methylimidazol-2-ylmethyl, 1- methylimidazol-4-yl, l-methylimidazol-4-ylmethyl, 3-cyclohexen-l-yl, 3-cyclohexen-l- ylmethyl, 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-2-ylmethyl, 1- methylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-benzylpiperidin-4-yl, 2-thienyl, 3-thienyl, thien-2 -ylmethyl, thiazol-2-yl, thiazol-2-ylmethyl, 5-isoxazolyl, 5-isoxazolylmethyl, quinolin-2-yl, quinolin-2-ylmethyl, and pyrrolidinyl.
In some embodiments, particularly embodiments of Formulas ma and IVa, 2a is hydrogen.
In some embodiments, R'" is a non-interfering substituent. In some embodiments, R'" is R3. In some embodiments, particularly embodiments of Formula , R'" is R or R3 when n is 1 , R or one R and one R3 when n is 2, or R when n is 3 to 4.
In some embodiments, R3 is selected from the group consisting of -Z-R4, -Z-X'-R4, -Z-X'-Y-Ri, -Z-X'-Y-X'-Y-R^ and -Z-X'-R5. hi some embodiments, R3 is selected from the group consisting of -Z-R4 and -Z-X'-Y-R
In some embodiments, R4 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.
In some embodiments, is hydrogen, alkyl, alkenyl, aryl, or heteroaryl. In some embodiments, R4. is hydrogen, alkyl, alkenyl, aryl, or heteroaryl, wherein alkyl and alkenyl are optionally substituted by aryl or aryloxy and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen. In some embodiments, * is selected from the group consisting of aryl or heteroaryl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, cyano, hydroxyalkyl, dialkylamino, and alkoxy.
In some embodiments, R5 is selected from the group consisting of
Figure imgf000063_0001
In some embodiments, R5 is
Λ(CH2)a -N- C(R6) -N- S(0)2 _N(R8)_c(θ)-N A R7 RT , or (CH^b--7
In some embodiments, R6 is selected from the group consisting of =O and =S. In some embodiments, R is =O.
In some embodiments, R7 is C2-7 alkylene. In some embodiments, R7 is ethylene. i some embodiments, R7 is propylene. In some embodiments, R8 is selected from the group consisting of hydrogen,
C1-10 alkyl, C2-10 alkenyl, CMO alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl. h some embodiments, R8 is hydrogen or methyl. In some embodiments, R8 is hydrogen.
In some embodiments, R is selected from the group consisting of hydrogen and alkyl. In some embodiments, Rio is C3.8 alkylene. In some embodiments, Rio is pentylene.
In some embodiments, Rn is C3.9 alkylene or C3.9 alkenylene, optionally interrupted by one hetero atom. In some embodiments, Rn is d-β alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom. In some embodiments, Rπ is methylene; in some embodiments, Rπ is ethylene. i some embodiments, R12 is C2-7 alkylene or C2-7 alkenylene, optionally interrupted by one hetero atom. In some embodiments, Rι2 is selected from the group consisting of a bond, Cι-5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom. In some embodiments, R12 is ethylene.
In some embodiments, Rι3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- -groups, h some embodiments, Rι3 is hydrogen.
In some embodiments, A is selected from the group consisting of -CH2-, -O-, -C(O)-, -S(O)o-2-, and -NCR4)-. In some embodiments, A is selected from the group consisting of-CH2- and -O-. hi some embodiments, A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-. hi some embodiments, A' is -CH2-, -O-, or -N(-Q-R4)-.
In some embodiments, Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-. h some embodiments, Q is selected from the group consisting of -C(O)-, -S(O)2-, and -C(O)-N(R8)-W-. In some embodiments, V is selected from the group consisting of -C(R6)-,
-O-C(R6)-, -N(R8)-C(Re)-, and -S(O)2-. In some embodiments, V is -N(R8)-C(O)-.
In some embodiments, W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-. hi some embodiments, W is selected from the group consisting of a bond and -C(O)-. hi some embodiments, X is C1-10 alkylene or C2-ιo alkenylene. Preferably, X is
Ci-io alkylene or C3-1o alkenylene. In some embodiments, particularly embodiments of Formulas a and IVa, X is Cι-4 alkylene. In some embodiments, X is methylene.
In some embodiments, X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups, hi some embodiments, X' is alkylene. i some embodiments, X' is ethylene, propylene, or butylene (including isobutylene).
In some embodiments, X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups. In some embodiments, particularly in embodiments of Formula ma and TVa, X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-.
In some embodiments, Y is selected from the group consisting of -S(O)o-2-, -S(O)2-N(R8)-, -C(R6)-, -C(R6)-O-, -O-C(R6)-, -O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-, -O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000065_0001
In some embodiments, Y is selected from the group consisting of -S(O)o-2-, -S(O)2-N(R8>, -C(R6)-, -C(R6)-O-, -O-C(R6)-, -O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-, -O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000065_0002
hi some embodiments, Y is -N(R8)-C(O)-, -N(R8)-S(O)2-, -N(R8)-S(O)2-N(R8)-, -N(R8)-C(O)-N(R8)-, -N(R8)-C(O)-N(R8)-C(O)-,
Figure imgf000065_0003
In some embodiments, Y is -NH-C(O)-, -NH-S(O)2-, -NH-S(O)2-N(R8)-, -NH-C(O)-N(R8)-, -NH-C(O)-NH-C(O)-, or — H- C(O)-N
In some embodiments, Y' is selected from the group consisting of a bond, -C(O)-, -C(S)-, -S(O)2-, -S(O)2-N(R8)-,
Figure imgf000066_0001
-C(O)-O-, -C(O)-N(R8)-, -C(S)-N(R8)-, -C(O)-N(R8)-S(O)2-, -C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000066_0002
R 10 -C(O)-C(O)-, -C(O)-C(O)-O-, and -C(=NH)-N(R8)-
In some embodiments, Y' is selected from the group consisting of a bond, -C(O)-, -C(O)-O-, -S(O)2-, -S(O)2-N(R8)-, -C(O)-N(R8)-, -C(S)-N(R8)-, -C(O)-N(R8)-C(O)-, and
Figure imgf000066_0003
In some embodiments, particularly embodiments of Formulas ma and IVa, Y' is selected from the group consisting of a bond, -C(O)-, -C(O)-O-, -S(O)2-, -S(O)2-N(R8)-, -C(O)-N(R8)-, -C(O)-N(R8)-C(O)-, and
Figure imgf000066_0004
hi some embodiments, Y' is selected from the group consisting of -C(O)-, -S(O)2-, and -C(O)-N(R8)-. i some embodiments, Z is a bond or -O-. hi some embodiments, Z is a bond. In some embodiments, Z is -O-.
In some embodiments, a and b are independently integers from 1 to 6 with the proviso that a + b is < 7. In some embodiments, a and b are each 2. hi some embodiments, n is an integer from 0 to 4. In some embodiments, n is 0 or 1. In some embodiments, particularly embodiments of Formula IVa, n is 0. In some embodiments, m is 0 or 1. In some embodiments m is 1. In some embodiments, m is 0. h some embodiments, m is 0 or 1 ; with the proviso that when m is 1, then n is 0 or 1. In some embodiments, particularly embodiments of Formula ma, m and n are 0. hi some embodiments, n is 0 or m is 0.
In some embodiments, p is an integer from 0 to 3. In some embodiments, p is 0 or 1. In some embodiments, p is 0.
In some embodiments, m is 0 or 1, with the proviso that when m is 1, p is 0 or 1. In some embodiments, p and m are 0.
In some embodiments, particularly embodiments of Formula HT, R' is selected from the group consisting of:
-R4,
-X'-R,, -X'-Y-R ,
-X'-Y-X'-Y-R4,
-X'-R5,
-X"-O-NH-Y'-Rι', and -X"-O-N=C(Rι')(Rι"); wherein X*, X", Y, Y', Ri1, Ri", R4, and R5, are as defined above.
In some embodiments, particularly embodiments of Formula m, R'" is R or R3 when n is 1 , R or one R and one R3 when n is 2, or R when n is 3 to 4; wherein:
R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; R3 is selected from the group consisting of: -Z-R4, -Z-X'-R4, -Z-X'-Y-R4,
-Z-X'-Y-X'-Y-R4, and -Z-X'-R5; n is an integer from 0 to 4; Z is a bond or -O-; and X', Y, R4, R5, and R9 are as defined above.
In some embodiments, particularly embodiments of Formulas ma and IVa, R2 is alkyl or substituted alkyl, and R2a is hydrogen. hi some embodiments, R2 is methyl or cyclopropyl, and R2a is hydrogen. In some embodiments, particularly embodiments of Formulas ma and IVa, R2 is alkenyl or substituted alkenyl, and R2a is hydrogen.
In some embodiments, particularly embodiments of Formulas ma and IVa, R2 is aryl, arylalkylenyl, substituted aryl, or substituted arylalkylenyl, and R2a is hydrogen. hi some embodiments, particularly embodiments of Formulas ma and IVa, R2 is heteroaryl, heteroarylalkylenyl, substituted heteroaryl, or substituted heteroarylalkylenyl, and R2a is hydrogen.
In some embodiments, particularly embodiments of Formulas ma and IVa, R2 is heterocyclyl, heterocyclylalkylenyl, substituted heterocyclyl, or substituted heterocyclylalkylenyl, and R2a is hydrogen. i some embodiments, R2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-
(ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3- methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3 -ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tetrahydrofuranyl, tefrahydrofuran-3 -ylmethyl, 2- (methylthio)ethyl, 3-(methylthio)propyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6- dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4- (dimethylamino)phenyl, 3-hydroxy-4-methoxyphenyl, 4-acetamidophenyl, 4- (methoxycarbonyl)phenyl, 4-(trifluoromethyl)phenyl, biphenyl, benzyl, 2-methylbenzyl, 3- methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4- cyanobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4- dimethylaminobenzyl, 3-hydroxy-4-methoxybenzyl, 4-acetamidobenzyl, 4- (methoxycarbonyl)benzyl, 4-(trifluoromethyl)benzyl, 1-phenylethyl, 2-phenylethyl, 2- phenylpropyl, 3-phenylpropyl, 2-phenylethenyl, phenoxymethyl, 2-pyridyl, 3 -pyridyl, 4- pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethy, l-methylpyrrol-2-yl, 1- methylpynol-2-ylmethyl, l-methylimidazol-2-yl, l-methylimidazol-2-ylmethyl, 1- methylimidazol-4-yl, l-methylimidazol-4-ylmethyl, 3-cyclohexen-l-yl, 3-cyclohexen-l- ylmethyl, 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-2-ylmethyl, 1- methylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-benzylpiperidin-4-yl, 2-thienyl, 3-thienyl, thien-2 -ylmethyl, thiazol-2-yl, thiazol-2-ylmethyl, 5-isoxazolyl, 5-isoxazolylmethyl, quinolin-2-yl, quinolin-2-ylmethyl, pynolidinyl, 3,4-dichlorophenyl, α-methylbenzyl, methoxymethyl, trifluoromethyl, and 2,2,2-trifluoroethyl; and R2a is hydrogen.
In some embodiments, particularly embodiments of Formulas ma and IVa, R2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-(ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3 -methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3- ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tetrahydrofuranyl, tetrahydrofuran-3- ylmethyl, 2-(methylthio)ethyl, 2-(methylthio)propyl, phenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4- (dimethylamino)phenyl, 3-hydroxy-4-methoxyphenyl, 4-acetamidophenyl, 4- (methoxycarbonyl)phenyl, 4-(trifluoromethyl)phenyl, biphenyl, benzyl, 2-methylbenzyl, 3- methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4- cyanobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4- dimethylaminobenzyl, 3-hydroxy-4-methoxybenzyl, 4-acetamidobenzyl, 4- (methoxycarbonyl)benzyl, 4-(trifluoromethyl)benzyl, 1-phenylethyl, 2-phenylethyl, 2- phenylpropyl, 3-phenylpropyl, 2-phenylethenyl, phenoxymethyl, 2-pyridyl, 3 -pyridyl, 4- pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethy, l-methylpynol-2-yl, 1- methylpynol-2 -ylmethyl, l-methylimidazol-2-yl, l-methylimidazol-2 -ylmethyl, 1- methylimidazol-4-yl, l-methylimidazol-4-ylmethyl, 3-cyclohexen-l-yl, 3-cyclohexen-l- ylmethyl, 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-2-ylmethyl, 1- methylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-benzylpiperidin-4-yl, 2-thienyl, 3-thienyl, thien-2-ylmethyl, thiazol-2-yl, thiazol-2-ylmethyl, 5-isoxazolyl, 5-isoxazolylmethyl, quinolin-2-yl, quinolin-2-ylmethyl, and pyrrolidinyl; and R2a is hydrogen.
In some embodiments of Formulas ffla and IVa, Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, -X'-Y-R^ and -X*-R5; wherein X' is alkylene; Y is -N(R8)-C(O)-, -N(R8)-S(O)2-, -N(R8)-S(O)2-N(R8)-, -N(R8)-C(O)-N(R8)-, -N(R8)-C(O)-N(R8)-C(O)-,
Figure imgf000070_0001
; R4 is hydrogen, alkyl, alkenyl, aryl, or heteroaryl; and R5 is
/"(CΗ2)a -N- C(R6) -N- S(0)2 _N(R8)_C(0)-N A or V(CH2)b-^
In some embodiments, Ri is 2-methylpropyl or -X'-Y-Ri; X' is ethylene, propylene, or butylene; Y is -NH-C(O)-, -NH-S(O)2-, -NH-S(O)2-N(R8)-, -NH-C(O)-N(R8)-, -NH-C(O)-NH-C(O)-, or
-NH- C(O)-N ^T
; and R8 is hydrogen or methyl.
In some embodiments, R\ is 2-methylpropyl, 2-hydroxy-2-methylpropyl, or
-X'-Y-R4; X' is ethylene, propylene, or butylene (including isobutylene); Y is -NH-C(O)-,
-NH-S(O)2-, -NH-S(O)2-N(R8)-, -NH-C(O)-N(R8)-, -NH-C(O)-NH-C(O)-, or
— NH- C(O)-N ; and R8 is hydrogen or methyl. In some embodiments, Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, -X'-Y-R-t, and -X'-R5; wherein X' is alkylene; Y is -N(R8)-C(O)-, -N(R8)-S(O)2-, -N(R8)-S(O)2-N(R8)- -N(R8)-C(O)-N(R8)-, -N(R8)-C(O)-N(R8)-C(O)-,
Figure imgf000071_0001
, or ; R4 is hydrogen, alkyl, alkenyl, aryl, or heteroaryl, wherein alkyl and alkenyl are optionally substituted by aryl or aryloxy and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen; and R5 is
^(CH2)a ^
-N— C(R6) — N— S(0)2 -N(R8)-C(0)-N A . \, 7 , ' , or (C 2)b— ^ .
In some embodiments, Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Figure imgf000071_0002
wherein A' is selected from the group consisting of
-O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-; Rπ is C3-9 alkylene or C3-9 alkenylene, optionally interrupted by one hetero atom; R12 is C2-7 alkylene or C2-7 alkenylene, optionally interrupted by one heteroatom; and Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to fonn a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms.
Alternatively, Ri' and Ri" can join together to form a ring system selected from the group consisting of:
total number of atoms in the ring is 4 to 9, and
Figure imgf000071_0003
wherein the total number of atoms in the ring is 4 to 9; and further wherein A' is selected from the group consisting of -O-, -S(O)0-2-, -N^Q-R^-, and -CH2-; Rπ is Cι-6 alkylene or C -6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom; Rι2 is selected from the group consisting of a bond, Cι- alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom; and Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms.
Preparation of the Compounds
Compounds of the invention can be prepared according to Reaction Scheme I where R, Ri, X, and n are as defined above, Hal is chloro, bromo, or iodo, and R2' and R2" are the same as Ri' and Ri" as defined above. In step (1) of Reaction Scheme I, a quinoline-3,4-diamine of Formula X is reacted with a carboxylic acid or an equivalent thereof to provide a lH-imidazo[4,5-c]quinoline of Formula XI. Suitable equivalents to a carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired -X-Hal substituent in a compound of Formula XI. For example, Hal-X-CO2H or Hal-X-C(O-alkyl) will provide a compound with the desired -X-Hal substitutent at the 2-position. The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction. Optionally a catalyst such as pyridine hydrochloride can be included.
Alternatively, step (1) can be carried out by (i) reacting a compound of Formula X with an acyl halide of formula Hal-X-C(O)Cl or Hal-X-C(O)Br and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of a compound of Formula X in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature. A catalyst such as pyridine hydrochloride can be included. Alternatively, the reaction can be carried out in the presence of triethylamine. In part (ii) the product of part (i) is heated in pyridine. The two steps can be combined into a single step when the reaction is run in pyridine or solvents such as dichloromethane or dichloroethane in the presence of triethylamine. Many compounds of Formula X are known and can be readily prepared using known synthetic routes; see for example, U.S. Patent Nos. 4,689,338 (Gerster), 4,929,624 (Gerster et al.), 5,268,376 (Gerster), 5,389,640 (Gerster et al.), 6,331,539 (Crooks et al.), 6,451,810 (Coleman et al.), 6,541,485 (Crooks et al), 6,660,747 (Crooks et al.), 6,670,372 (Charles et al), 6,683,088 (Crooks et al.), 6,656,938 (Crooks et al), and 6,664,264
(Dellaria et al.).
In step (2) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline of Formula XI is oxidized to provide an N-oxide of Formula XII using a conventional oxidizing agent that is capable of forming N-oxides. The reaction can be carried out by treating a solution of a compound of Formula XI in a suitable solvent such as chloroform or dichloromethane with
3-chloroperoxybenzoic acid at ambient temperature.
In step (3) of Reaction Scheme I an N-oxide of Formula XII is animated to provide a lH-imidazo[4,5-c]quinoline-4-amine of Formula Xm. The reaction is carried out in two parts. In part (i) a compound of Formula XII is reacted with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride, or/?-toluenesulfonyl chloride). In part (ii) the product of part (i) is reacted with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g. in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). The reaction can be carried out by dissolving a compound of Formula XE in a suitable solvent such as dichloromethane or chloroform, adding ammonium hydroxide to the solution, and then adding >-toluenesulfonyl chloride. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (4) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline-4-amine of Formula Xm is treated with N-hydroxyphthalimide to provide an N-phthalimide-protected lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIV. The reaction is conveniently carried out by adding a base, such as triethylamine, to a solution of N- hydroxyphthalimide in a suitable solvent such as N,N-dimethylformamide (DMF); and then adding the lH-imidazo[4,5-c]quinoline-4-amine of Formula XUI in a suitable solvent (for example, DMF) to the resulting mixture. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (5) of Reaction Scheme I an N-phthalimide-protected lH-imidazo[4,5- c]quinolin-2-yl hydroxylamine of Formula XIV is converted to a lH-imidazo[4,5- c]quinolin-2-yl hydroxylamine of Formula XV. Removal of the N-phthalimide protecting group is conveniently carried out by adding hydrazine to a suspension of anN- phthalimide-protected lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIV in a suitable solvent such as ethanol. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods .
In step (6) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XV is reacted with an aldehyde or ketone of formula R2'C(O)R2" to provide a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XVI. Numerous aldehydes and ketones of formula R2'C(O)R2" are commercially available; others can be readily prepared using known synthetic methods. The reaction can be conveniently carried out by adding the aldehyde or ketone of formula R2'C(O)R2" to a lH-imidazo[4,5-c]quinolin-4-amine of Formula XV in a suitable solvent such as methanol. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. In step (7) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-2-yl oxime of
Formula XVI is reduced to provide a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XVII, which is a subgenus of Formulas I, II, m, and ma. The reduction is conveniently carried out by treating a lH-imidazo[4,5-c]quinolin-2-yl oxime of Fonnula XVI with excess sodium cyanoborohydride in a suitable solvent or solvent mixture such as methanol/acetic acid. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Reaction Scheme I
Figure imgf000075_0001
Compounds of the invention can be prepared according to Reaction Scheme II where R, R4, R8, Q, X, X', Hal, and n are as defined above, Boc is tert-butoxycarbonyl, R •5a
-N S(0)2 N C(O) (CH '22),a
-V-N A
-R,
IS R7 or (CH2)b - ^ wherein V is -N(R8)-C(R6)-, and R2' and R2" are the same as Ri' and R " as defined above. In step (1) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-l-yl tert-butylcarbamate of Formula XVm is treated with N-hydroxyphthalimide to provide an N-phthalimide-protected 1H- imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIX. The reaction is conveniently carried out by adding a base, such as triethylamine, to N-hydroxyphthalimide dissolved in a suitable solvent such as DMF; and then adding the lH-imidazo[4,5-c]quinolin-l-yl tgrt- butylcarbamate of Formula XV in a suitable solvent (for example, DMF) to the resulting mixture. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Compounds of Formula XVLU can be readily prepared using known synthetic routes; see for example, U.S. Patent No. 6,451,485 (Crooks et al.), and 6,660,747 (Crooks et al to prepare a quinoline-3,4-diamine that can be treated according to steps (1) to (3) of Reaction Scheme I. h step (2) of Reaction Scheme II an N-phthalimide-protected lH-imidazo[4,5- c]quinolin-2-yl hydroxylamine of Formula XLX is converted to a lH-imidazo[4,5- e]quinolin-2-yl hydroxylamine of Formula XX. Removal of the N-phthalimide protecting group is conveniently carried out by adding hydrazine to a suspension of an N- phthalimide-protected lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XIX in a suitable solvent such as ethanol. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (3) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XX is reacted with an aldehyde or ketone of formula R2'C(O)R2" to provide a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXI. Numerous aldehydes and ketones of formula R2'C(O)R2" are commercially available; others can be readily prepared using known synthetic methods. The reaction can be conveniently carried out by adding the aldehyde or ketone of formula R2'C(O)R2" to a solution of the lH-imidazp[4,5-c]quinolin- 4-amine of Formula XX in a suitable solvent such as methanol. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (4) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXI is deprotected to provide an amino group at the 1 -position of a 1H- imidazo[4,5-c]quinolin-2-yl oxime of Formula XXII. The reaction can be conveniently carried out by dissolving a compound of Formula XXI in a mixture of trifluoroacetic acid and a suitable solvent such as dichloromethane. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof, including the trifluoro acetate salt, can be isolated using conventional methods.
In steps (5) and (5a) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXLI is converted to a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXm or XXIV, using conventional methods. For example, sulfonamides of
Formula XXTH (Q is -S(O)2-) can be prepared by reacting a compound of Formula XXII with a sulfonyl chloride of formula R4S(O)2Cl. The reaction can be carried out at ambient temperature in an inert solvent such as chloroform or dichloromethane by adding the sulfonyl chloride to a compound of Formula XXLI in the presence of a base such as N,N- diisopropylethylamine, triethylamine, or pyridine. Sulfamides of Fonnula XXTfl (Q is, for example, -S(O)2-Ν(R8)-) can be prepared by reacting a compound of Formula XXJT with a sulfamoyl chloride of formula R4(R8)NS(O)2Cl or by reacting a compound of Formula XXπ with sulfuryl chloride to generate a sulfamoyl chloride in situ, and then reacting the resulting sulfamoyl chloride with an amine of formula ΗN(R8)R4. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Some sulfamoyl chlorides of formula R4(R8)NS(O)2θ and many sulfonyl chlorides of formula 4S(O)2Cl and amines of formula HN(R8)R4 are commercially available; others can be prepared using known synthetic methods.
In another example, using step (5a) of Reaction Scheme II, a lH-imidazo[4,5- c]quinolin-2-yl oxime of Formula XXII is reacted with a chloroalkanesulfonyl chloride of formula Cl-R7-S(O)2Cl to provide a compound of Formula XXIV, wherein R5a is a ring having the structure
Figure imgf000077_0001
The reaction is preferably carried out by adding the chloroalkanesulfonyl chloride to a solution of a compound of Formula XXII in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. The intermediate chloroalkanesulfonamide may optionally be isolated before treatment with a stronger base such as 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) at ambient temperature. If the intermediate chloroalkanesulfonamide is isolated, the reaction with DBU can be carried out in a suitable solvent such as DMF. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Amides of Formulas XXm (Q is, for example, -C(O)-) and XXIV can be prepared from lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXII using conventional methods. For example, a compound of Formula XXLI can be reacted with an acid chloride of formula 4C(O)Cl to provide a compound of Formula XXHI. The reaction can be carried out by adding the acid chloride to a solution of a compound of Formula XXLI in a suitable solvent such as chloroform, optionally in the presence of a base such as N,N- diisopropylethylamine, triethylamine, or pyridine, at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In another example shown in step (5a), a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXII is reacted with a chloroalkanoyl chloride compound of formula Cl-R7-C(O)Cl to provide a compound of Formula XXIV, wherein R5a is a ring having the structure
Figure imgf000078_0001
The reaction is preferably carried out by adding the chloroalkanoyl chloride compound to a compound of Formula XXII in a suitable solvent such as dichloromethane in the presence of a base such as N,N-diisopropylethylamine. The intermediate chloroalkanamide may optionally be isolated before treatment with a stronger base such as DBU at ambient temperature. If the intermediate chloroalkanamide is isolated, the reaction with DBU can be carried out in a suitable solvent such as DMF. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Ureas and thioureas of Formula XXHI (Q is, for example, -C(O)-Ν(R8)- or -C(S)-N(R8)-) and XXIV can be prepared from lH-imidazo[4,5-c]quinolin-2-yl oximes of Formula XXII using conventional methods. For example, a compound of Formula XXLI can be reacted with an isocyanate of formula R4N=:C:=O. The reaction can be carried out by adding the isocyanate to a solution of a compound of Formula XXII in a suitable solvent such as chloroform, optionally in the presence of a base such as N,N- diisopropylethylamine, or triethylamine, at ambient temperature. Alternatively, a compound of Formula XXII can be reacted with, for example, a thioisocyanate of formula R N=C=S, a sulfonyl isocyanate of formula R4S(O)2N=C=O or a carbamoyl chloride of formula R4j (R8)C(0)Cl. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. hi steps (6) and (6a) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXTH or Formula XXIV is reduced to provide a lH-imidazo[4,5- c]quinolin-2-yl hydroxylamine of Formula XXV or Formula XXVI, each of which is a subgenus of Formulas I, π, HI, and ma. The reduction is conveniently carried out by treating a liϊ-imidazo[4,5-c]quinolin-2-yl oxime of Fonnula XXHI or Formula XXIV with excess sodium cyanoborohydride in a suitable solvent or solvent mixture such as methanol/acetic acid. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme II
Figure imgf000080_0001
Compounds of the invention can be prepared according to Reaction Scheme where n is as defined above; each RB is independently selected from the group consisting of hydroxy, alkyl, alkoxy, -N(R9)2; Xc is C O alkylene; P is a removable protecting group, such as an alkanoyloxy group (e.g., acetoxy) or an aroyloxy group (e.g., benzoyloxy); R2' and R2" are the same as Ri' and Ri" as defined above; and Rlc is a subset of Ri as defined above, which does not include those groups that one skilled in the art would recognize as being susceptible to reduction in step (5). These groups include, for example, alkenyl, alkynyl, and aryl groups, and groups bearing nitro and -S- substitutents. hi step (1) of
Reaction Scheme HI a quinoline-3,4-diamine of Formula Xa is reacted with a carboxylic acid of the formula, HO-X-CO2H, with a trialkyl orthoester of the formula HO-X-C(O-Ci_ alkyl)3, or with a combination thereof (wherein "alkyl" is a straight or branched chain) to provide a lH-imidazo[4,5-c]quinolin-2-yl alcohol of Formula XXVII. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction. Optionally a catalyst such as pyridine hydrochloride can be included. Compounds of Formula Xa are a subset of compounds of Formula X, which are shown in Reaction Scheme I.
In step (2) of Reaction Scheme HI the hydroxyl group of a lH-imidazo[4,5- c] quinoline of Formula XXVII is protected with a removable protecting group such as an alkanoyloxy group (e.g., acetoxy) or aroyloxy group (e.g., benzoyloxy) to provide a 1H- imidazo[4,5-c]quinoline of Formula XXVHI. Suitable protecting groups and reactions for their placement and removal are well known to those skilled in the art. See, for example, U.S. Patent No. 4,689,338 (Gerster), Examples 115 and 120 and 5,389,640 (Gerster et al), Examples 2 and 3.
For some embodiments, it is possible to combine steps (1) and (2) when an acid chloride of the Formula PO-X-CO2Cl is used under the conditions of step (1). Some acid chlorides of this type, for example, acetoxyacetyl chloride, are commercially available, hi step (3) of Reaction Scheme HI a lH-imidazo[4,5-c]quinoline of Formula XXViπ is oxidized to provide an N-oxide of Formula XXIX using a conventional oxidizing agent that is capable of forming N-oxides. The reaction can be carried out by treating a solution of a compound of Formula XXVLTI in a suitable solvent such as chloroform or dichloromethane with 3-chloroperoxybenzoic acid at ambient temperature. In step (4) of Reaction Scheme HI an N-oxide of Formula XXIX is aminated and the protecting group removed to provide a lH-imidazo[4,5-c]quinoline-4-amine of
Formula XXX. The animation reaction is carried out in two parts, hi part (i) a compound of Formula XXTX is reacted with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chorides (e.g., benzenesulfonyl choride, methanesulfonyl choride, or j9-toluenesulfonyl chloride). In part (ii) the product of part (i) is reacted with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g. in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). The reaction can be carried out by dissolving a compound of Formula XXIX in a suitable solvent such as dichloromethane or chloroform, adding ammonium hydroxide to the solution, and then adding -toluenesulfonyl chloride. The protecting group is removed using well-known methods. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. In step (5) of Reaction Scheme HI a lH-imidazo[4,5-c]quinoline-4-amine of Formula XXX is reduced to provide a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinoline-4- amine of Formula XXXI. The reaction can be conveniently carried out by suspending or dissolving a compound of Formula XXX in ethanol, adding a catalytic amount of rhodium on carbon, and hydrogenating. Alternatively, the reaction can be carried out by suspending or dissolving a compound of Formula XXX in trifluoroacetic acid, and adding platinum(lV) oxide, and hydrogenating. The reaction can be carried out in a Pan apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. i step (6) of Reaction Scheme m a 6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinoline-4-amine of Formula XXXI is treated with N-hydroxyphthalimide under Mitsunobu reaction conditions to provide an N-phthalimide-protected 6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXII. The reaction is conveniently carried out by adding triphenylphosphine and N-hydroxyphthalimide to a solution of a compound of Formula XXXI in a suitable solvent such as tetrahydrofuran, and then slowly adding diethyl azodicarboxylate or diisopropyl azodicarboxylate. The reaction can be carried out at ambient temperature or at an elevated temperature, such as 60 °C. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Alternatively, step (6) may be carried out in two parts by (i) converting the hydroxy group in a compound of Formula XXXI to a leaving group and (ii) displacing the leaving group with N-hydroxyphthalimide in the presence of a base. Part (i) of step (6) is conveniently carried out by treating the hydroxy-substituted 6,7,8,9-tetrahydiO-lH- imidazo[4,5-c]quinoline-4-amine of Formula XXXI with thionyl chloride in a suitable solvent such as 1,2-dichloroethane. The reaction may be carried out at ambient temperature, and the product can be isolated by conventional methods. Part (ii) of step (6) may be carried out under the conditions described in step (4) of Reaction Scheme I, and the product of Formula XXXII or phannaceutically acceptable salt thereof can be isolated using conventional methods.
In step (7) of Reaction Scheme m an N-phthalimide-protected 6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXΗ is converted to a
6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXΗL Removal of the N-phthalimide protecting group is conveniently carried out by adding hydrazine to a suspension of an N-phthalimide-protected 6,7,8,9-tetrahydro-lH- imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXLI in a suitable solvent such as ethanol. The reaction can be carried out at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (8) of Reaction Scheme m a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin- 2-yl hydroxylamine of Formula XXXLΗ is reacted with an aldehyde or ketone of formula R2'C(O)R2" to provide a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXXIV as in step (3) of Reaction Scheme Η. The product or phannaceutically acceptable salt thereof can be isolated using conventional methods.
In step (9) of Reaction Scheme HI a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXXIV is reduced to provide a lH-imidazo[4,5-e]quinolin-2-yl hydroxylamine of Formula XXXV, which is a subgenus of Formulas I, H, IV and IVa. The reduction is carried out as described in step (7) of Reaction Scheme I. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods. Reaction Scheme IH
Figure imgf000084_0001
Compounds of the invention can be prepared according to Reaction Scheme TV where Ri, R, X, and Hal are as defined above, p is 0 to 3, R2' and R2" are the same as Rj.' and Ri" as defined above, and R3a is -R^, -X R4, -X' -Y-R4, or -X'b-R5; where X'a is alkenylene; X'b is arylene, heteroarylene, and alkenylene interrupted or terminated by arylene or heteroarylene; R4b is aryl or heteroaryl where the aryl or heteroaryl groups can be unsubstituted or substituted as defined in R4 above; and R4, R5, and Y are as defined above, h step (1) of Reaction Scheme IV a halogen substituted lH-imidazo[4,5- c]quinolin-2-yl oxime of Formula XXXVI is coupled with a boronic acid of the formula R3a-B(OΗ)2 (or the conesponding anhydride or esters, R a-B(O-alkyl)2, thereof) using Suzuki coupling conditions to provide a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXXVΗ. A compound of Formula XXXVI is combined with a boronic acid of the fomiula R3a-B(OΗ)2 in the presence of palladium (LT) acetate, triphenylphosphine and a base such as aqueous sodium carbonate in a suitable solvent such as n-propanol or «-propanol and water. The reaction can be canied out at an elevated temperature (e.g., 80 °C-100 °C).
The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Halogen substituted lH-imidazo[4,5-c]quinolin-2-yl oximes of Formula XXXVI can be prepared as described above in steps (l)-(6) of Reaction Scheme I or steps (1) - (5) or (5a) or Reaction Scheme π, wherein one of the R groups is Hal. Numerous boronic acids of Formula R3a-B(OH)2, anhydrides thereof, and boronic acid esters of Formula R3a-B(O-alkyl) are commercially available; others can be readily prepared using known synthetic methods. i step (2) of Reaction Scheme IV a lH-imidazo[4,5-c]quinolin-2-yl oxime of Formula XXXVΗ is reduced to provide a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXVm, which is a subgenus of Formulas I, Η, , and ma. The reduction is carried out as described in step (7) of Reaction Scheme I. The product or a phannaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
Figure imgf000086_0001
XXXVI
Figure imgf000086_0002
Compounds of the invention can be prepared according to Reaction Scheme V where R, Rl5 R2, X, and n are as defined above, and Ya' is Y' defined above, excluding a bond. In step (1) of Reaction Scheme V, a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XV is converted to a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XXXLX, a subgenus of Formulas I, Η, m, and a, using conventional methods. For example, sulfonamides of Formula XXXLX (Ya' is -S(O)2-) can be prepared by reacting a compound of Formula XV with a sulfonyl chloride of formula R2S(O)2θ. The reaction can be carried out at ambient temperature in an inert solvent such as chloroform or dichloromethane by adding the sulfonyl chloride to a compound of Formula XV in the presence of a base such as iV,N-diisopropylethylamine, triethylamine, or pyridine.
— S(0)2 — Ν" Sulfamides of Formula XXXLX (Ya' is -S(O)2-Ν(R8)- or ^ • R1i0, ) can be prepared by reacting a compound of Formula XV with sulfuryl chloride to generate a sulfamoyl chloride in situ, and then reacting the sulfamoyl chloride with an amine of
ΗN -R, formula ΗN(R8)R2, or R, , or by reacting a compound of Formula XV with a
Cl- S(0)2— N - ,
. R sulfamoyl chloride of formula R2(R8)NS(O)2θ or 10 . The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Many sulfonyl chlorides of formula R2S(O)2Cl, amines of formulas HN(R8)R2, and
HN -j — R2
10 , and some sulfamoyl chlorides of formulas R2(R8)NS(O)2Cl and
Cl— S(0)2— N — 2
10 are commercially available; others can be prepared using known synthetic methods.
Amides of Formula XXXIX (Ya' is -C(O)-) can be prepared from lH-imidazo[4,5- c]quinolin-2-yl hydroxylamines of Formula XV using conventional methods. For example, a compound of Formula XV can be reacted with an acid chloride of formula
R2C(O)Cl to provide a compound of Formula XXXLX. The reaction can be carried out by adding the acid chloride to a solution of a compound of Formula XV in a suitable solvent such as chloroform, optionally in the presence of a base such as NJV- diisopropylethylamine, triethylamine, or pyridine, at ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Ureas and thioureas of Formula XXXLX (Ya' is -C(O)-Ν(R8)-, -C(S)-N(R8)-, -C(O)-N(R8)-S(O)2-, -C(O)-N(R8)-C(0)-, -C(S)-N(R8)-C(O)-, or
— C(0)-N
10 ) can be prepared from lH-imidazo[4,5-c]quinolin-2-yl hydroxylamines of Formula XV using conventional methods. For example, a compound of Formula XV can be reacted with an isocyanate of formula R2N=C=O. The reaction can be carried out by adding the isocyanate to a solution of a compound of Formula XV in a suitable solvent such as chloroform, optionally in the presence of a base such as N,N- diisopropylethylamine, or triethylamine, at ambient temperature. Alternatively, a compound of Formula XV can be reacted with a thioisocyanate of formula R2Ν=C=S, a sulfonyl isocyanate of formula R2S(O)2N=C=:O or a carbamoyl chloride of formula
Cl— C(O)— N Η — R, - R„
R2N(R8)C(O)Cl or "~ 100 . The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods Reaction Scheme V
Figure imgf000088_0001
Compounds of the invention wherein R2a is other than hydrogen can be prepared according to Reaction Scheme VI where R, Rls R2, X, Y', and n are as defined above, hi step (1) of Reaction Scheme VI, a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XL, a subgenus of Formulas I, II, HI, and a, is prepared by reductive alkylation of a lH-imidazo[4,5-cjquinolin-2-yl hydroxylamine of Formula XV. The reaction is carried out in two steps, (i) reacting a compound of Formula XV with the appropriate aldehyde to provide an oxime and (ii) reducing the oxime, using the methods of steps (6) and (7), respectively, of Reaction Scheme I.
In step (2) of Reaction Scheme VI, a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XL is converted to a lH-imidazo[4,5-c]quinolin-2-yl hydroxylamine of Formula XLI, a subgenus of Formulas I, Η, and Id. Compounds of Formula XLI wherein Y' is a bond are prepared by subjecting the compound of Formula
XL to a second alkylation. Compounds of Formula XLI wherein Y' is other than a bond are prepared using the methods of Reaction Scheme V. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VI
Figure imgf000089_0001
For some embodiments, tetrahydroquinolines of the invention can be prepared according to Reaction Scheme VII, wherein RB, RIC, XC, Ya', R2, and n are as defined above. The reaction in Reaction Scheme VH can be carried out according to one of the methods described in Reaction Scheme V to provide a tetrahydroquinoline of Formula XLE, a subgenus of Formulas I, U, TV, and IVa. The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods. Tetrahydroquinolines of Formula XXXm can also be treated according to the methods described in Reaction Scheme V to provide compounds of the invention.
Reaction Scheme VH
Figure imgf000089_0002
Compounds of the invention can be prepared according to Reaction Scheme Vm where R, R1? R2, R2', R2", R2a, X, Y', and Hal are as defined above; E is carbon (imidazoquinoline ring) or nitrogen (imidazonaphthyridine ring); n is an integer from 0 to 4 (imidazoquinoline ring) or 0 to 3 (imidazonaphthyridine ring) with the proviso that when m is 1, then n is 0 or 1; and D is -Br, -I, or -OCH2PI1; wherein Ph is phenyl. hi step (1) of Reaction Scheme VIII, an aniline or aminopyridine of Formula XLILL is treated with the condensation product generated from 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid) and triethyl orthoformate to provide an imine of Formula XLTV. The reaction is conveniently carried out by adding a solution of an aniline or aminopyridine of Formula XLiπ to a heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an elevated temperature. The product can be isolated using conventional methods. Many anilines and aminopyridines of Formula XLIH are commercially available; others can be prepared by known synthetic methods. For example, benzyloxypyridines of Formula XLIH can be prepared using the method of Holladay et al., Biorg. Med. Chem. Lett, 8, pp. 2797-2802, (1998).
In step (2) of Reaction Scheme Vm, an imine of Formula XLTV undergoes thermolysis and cyclization to provide a compound of Formula XLV. The reaction is conveniently carried out in a medium such as DOWTHERM A heat transfer fluid at a temperature of 200 °C to 250 °C. The product can be isolated using conventional methods. Isomers of the compound of Formula XLIH or Formula XLV, wherein E is nitrogen, can also be synthesized and can be used to prepare compounds of the invention. In step (3) of Reaction Scheme Vm, a compound of Formula XLV is nitrated under conventional nitration conditions to provide a compound of Formula XLVI. The reaction is conveniently carried out by adding nitric acid to the compound of Formula XLV in a suitable solvent such as propionic acid and heating the mixture at an elevated temperature. The product can be isolated using conventional methods. In step (4) of Reaction Scheme VHL a 3-nitro[l,5]naphthyridin-4-ol or 3- nitroquinolin-4-ol of Formula XLVI is chlorinated using conventional chlorination chemistry to provide a 4-chloro-3-nitro[l,5]naphthyridine or 4-chloro-3-mtroquinoline of Formula XLVH The reaction is conveniently carried out by treating the compound of Formula XLVI with phosphorous oxychloride in a suitable solvent such as DMF. The reaction can be carried out at ambient temperature or at an elevated temperature such as
100 °C, and the product can be isolated using conventional methods. The 4-chloro-3-nitro[l,5]naphthyridine of Formula XLVH wherein m and n are both 0 is known and can be readily prepared using a known synthetic route; see for example, U.S. Patent No. 6,194,425 (Gerster et al.).
In step (5) of Reaction Scheme VILL, a 4-chloro-3 -nitro [l,5]naphthyridine or 4- chloro-3-nitroquinoline of Formula XLVH is treated with an amine of Formula R1-NH2 to provide a compound of Formula XX Vm. Several amines of Formula Rι-NH2 are commercially available; others can be prepared by known synthetic methods. The reaction is conveniently carried out by adding the amine of Formula Rι-NH2 to a solution of the 4- chloro-3-nitro[l,5]naphthyridine or 4-chloro-3-nitroquinoline of Formula XLVII in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine. The reaction can be carried out at ambient temperature or at a sub-ambient temperature such as, for example, 0 °C. The reaction product can be isolated using conventional methods.
In step (6) of Reaction Scheme VIH, a compound of Formula XLVm is reduced to provide a diamine of Formula XLEX. The reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as palladium on carbon or platinum on carbon. The hydrogenation is conveniently carried out in a Parr apparatus in a suitable solvent such as toluene, methanol, acetonitrile, or ethyl acetate. For compounds of the Formula XLVHI wherein m is 1 and D is -OCH2Ph, the prefened catalyst is platinum on carbon. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
Alternatively, the reduction in step (6) can be carried out using nickel boride, prepared in situ from sodium borohydride and nickel(II) chloride. The reduction is conveniently carried out by adding a solution of a compound of Formula XLVm in a suitable solvent or solvent mixture such as dichloromethane/methanol to a mixture of excess sodium borohydride and catalytic nickel(H) chloride in methanol. The reaction can be carried out at ambient temperature. The product can be isolated using conventional methods.
In step (7) of Reaction Scheme VflT, a diamine of Formula XLLX, is reacted with a carboxylic acid equivalent to provide a lH-imidazo[4,5-c][l,5]naphthyridine or 1H- imidazo[4,5-c]quinoline of Formula L. The carboxylic acid or equivalent is selected such that it will provide the desired -X-Hal substituent in a compound of Formula L and the reaction can be carried out as described in step (1) of Reaction Scheme I. When an acid chloride, for example chloroacetyl chloride, is used as the carboxylic acid equivalent, the reaction can be carried out in two steps. Part (i) of step (7) is conveniently carried out by adding the acid chloride to a solution of a diamine of Formula XLIX in a suitable solvent such as dichloromethane, chloroform, or acetonitrile. Optionally, a tertiary amine such as triethylamine, pyridine, or 4-dimethylaminopyridine can be added. The reaction can be carried out at ambient temperature. The amide product or the salt thereof can be isolated and optionally purified using conventional techniques. Part (ii) of step (7) involves heating the amide prepared in part (i) in the presence of base to provide a lH-imidazo[4,5- c][l,5]naphthyridine or lH-imidazo[4,5-c]quinoline of Formula L. The reaction is conveniently carried out in a suitable solvent such as ethanol in the presence of a base such aqueous sodium hydroxide, aqueous potassium carbonate, or triethylamine at elevated temperature, hi some instances, the product of Formula L may be obtained directly from Part (i). Alternatively, a diamine of Formula XLIX can be treated with ethyl chloroacetimidate hydrochloride as the carboxylic acid equivalent to provide a compound wherein X is methylene. The reaction is carried out in a suitable solvent such as chloroform at ambient temperature and the product of Formula L can be isolated using conventional methods. Ethyl chloroacetimidate hydrochloride is a known compound that can be prepared according to the literature procedure: Stillings, M. R. et al., J. Med.
Chem., 29, pp. 2280-2284 (1986).
In steps (8) - (10) of Reaction Scheme VIA, a halogen-substituted lH-imidazo[4,5- c][l,5]naphthyridine or lH-imidazo [4, 5 -c] quinoline of Formula L can be converted into phthalimide-substituted lH-imidazo[4,5-c][l,5]naphthyridin-4-amine or lH-imidazo[4,5- c]quinolin-4-amine of Formula Lm using the chemistry described in steps (2) - (4) of
Reaction Scheme I. Steps (8) and (9) can alternatively be combined and carried out as a one-pot procedure by adding 3-chloroperoxybenzoic acid to a solution of a compound of Formula L in a solvent such as dichloromethane or chloroform and then adding ammomum hydroxide and j-toluenesulfonyl chloride without isolating the N-oxide of Formula LL Compounds of Formula LI, LΗ, and Lm or their pharmaceutically acceptable salts can be isolated using conventional methods. In steps (11) and (12) of Reaction Scheme V, a phthalimide-substituted \H- imidazo[4,5-c][l,5]naphthyridin-4-amine or lH-imidazo[4,5-c]quinolin-4-amine of Formula Lm is converted to a hydroxylamine-subsitituted lH-imidazo[4,5- c][l,5]naphthyridin-4-amine or lH-imidazo[4,5-c]quinolm-4-amine of Formula LIV which is condensed with an aldehyde or ketone to form an oxime of Formula LV, sequentially using the chemistry described in steps (5) and (6) of Reaction Scheme I. Compounds of Formula LIV and LV or their pharmaceutically acceptable salts can be isolated using conventional methods. i step (13) of Reaction Scheme Vm, an oxime of Formula LV is reduced to provide a hydroxylamine of Formula LVI, a subgenus of Formulas I and II. The reduction is conveniently carried out by treating the oxime of Formula LV with excess sodium cyanoborohydride in a suitable solvent or solvent mixture such as methanol/acetic acid. Optionally, hydrochloric acid may be added. The reaction can be carried out at ambient temperature or at elevated temperature. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (14) of Reaction Scheme VAX a hydroxylamine of Formula LVI is converted to a compound of Formula LVH, a subgenus of Formulas I and H The reaction is carried out using one of the methods described in Reaction Scheme V or step (2) of Reaction Scheme VI. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Alternatively, a compound of Formula LIV can be converted to a compound of Formula LVLH, a subgenus of Formulas I and H, as shown in step (12a) of Reaction Scheme VIH. The transformation is conveniently carried out by using the conditions described in Reaction Scheme V and step (2) of Reaction Scheme VI. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (13a) of Reaction Scheme VIH, a compound of Formula LVm is alkylated to provide a compound of Formula LVH. The reaction can be carried out with an alkylating agent that is generated in situ from an alcohol of Formula R2a-OH under Mitsunobu reaction conditions (described in step (6) of Reaction Scheme HT) or an alkylating agent of Formula R2a-Br or ∑ -I in the presence of a base such as cesium carbonate in a suitable solvent such as DMF. The latter reaction may be carried out at ambient temperature for reactive alkylating agents such as, for example, methyl iodide, benzyl bromide, and substituted benzyl bromides, or at an elevated temperature. Optionally, catalytic tetrabutylammonium hydrogensulfate can be added. The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods. One skilled in the art would recognize that the reactions described for the alkylation step would probably not be successful for R2a groups that are difficult to introduce via bimolecular nucleophihc substitution reactions. These groups include, for example, sterically hindered alkyl groups.
A compound of Formula LVHI in which R2a and R2 together with the nitrogen atom and Y' group to which they are bonded j oin together to form a ring of Formula
-N- C(O) -N- S(0)2
7 or 7 , can be prepared in a two-step procedure from a compound of Formula LTV using the methods described in step 5a of Reaction Scheme H. Alternatively, a reagent of the Formula P-0-R.7C(O)Cl, wherein P is a protecting group, may react with a compound of Formula LIV to generate an isolable intermediate that can then be deprotected to yield a hydroxyalkanamide. The isolable hydroxyalkanamide is cyclized under Mitsunobu conditions, described in step (6) of Reaction Scheme HI. The product or phannaceutically acceptable salt thereof can be isolated using conventional methods.
For some embodiments, compounds shown in Reaction Scheme VIE can be further elaborated using conventional synthetic methods. For example, an amine of Formula
R1-NH2, used in step (5) of Reaction Scheme VIH, may contain a protected functional group, such as a tert-butoxycarbonyl-protected amino group. The protecting group maybe removed after step (14) of Reaction Scheme V to reveal an amine on the Ri group. An amino group introduced in this manner may be further functionalized using the chemistry described in steps (5) and (5a) of Reaction Scheme H to provide compounds of the
Formula LVH in which Ri is -X'-N(R8)-Q-& or -X'-R5a. Alternatively, the protecting group may be removed after step (7) in Reaction Scheme VIH and the resulting amino group may be functionalized as described above before step (8). The resulting compound of Formula L can be subjected to steps (8) - (14) of Reaction Scheme VIH to provide a compound of Formula LVH wherein i is -X'-NCR^-Q^ or -X'-R5a. Alternatively, the amine of Formula R1-NH2 used in step (5) of Reaction Scheme Vm may contain an appropriately-protected hydroxyl group, for example, a tert- butyldimethylsilyl-protected hydroxyl group. The protecting group may be removed after step (14) in Reaction Scheme VIH to provide an alcohol on the Ri group. An alcohol introduced in this manner into a compound of Formula LVH may be converted into a hydroxylamine upon treatment with N-hydroxyphthalimide using the Mitsunobu reaction conditions described in step (6) of Reaction Scheme HI, followed by deprotection of the resulting phthalimide-protected hydroxylamine with hydrazine in ethanol. A hydroxylamine on the Ri group can undergo reaction with a ketone or aldehyde of Fonnula Rι'C(O)Rι" to form an oxime using the reaction conditions described in step (6) of
Reaction Scheme I to yield a compound of Formula LVH in which Ri is -X"-O-Ν=C(Rι')(Rι") where X", Rx', and Rj" are as defined above.
A hydroxylamine on the Ri group of a compound of Formula LVH, prepared as described above, can also be further functionalized to a compound of the Formula LVH in which Ri is -X"-O-NRιa-Y'-Rιb wherein Y' is -C(O)-, -S(O)2-, -C(O)-N(R8>,
-C(S)-N(R8)-, -C(O)-N(R8)-S(O)2-, -C(O)-N(R8)-C(O)-, -S(O)2-N(R8)-; Ria is hydrogen, and Rιb is as defined above using, respectively, an acid chloride, a sulfonyl chloride or a sulfonic anhydride; an isocyanate; an acyl isocyanate, an isothiocyanate, a sulfonyl isocyanate, a carbamoyl chloride, or a sulfamoyl chloride. The reaction can be carried out using the conditions described in step (5) of Reaction Scheme H. A large number of the reagents listed above are commercially available; others can be readily prepared using known synthetic methods.
A compound of Formula LVH in which Ri is -X"-O-NRιa-Y'-Rιb wherein Y' is a bond, -C(O)-, -C(S)-, -S(O)2-, or -C(O)-C(O)-; Rl is defined above, and R is hydrogen, can be derivatized further upon treatment with an alkylating agent that is generated in situ from an alcohol of Formula Rιa-OH under Mitsunobu reaction conditions or an alkylating agent of Formula Rιa-Br or Rιa-I as described in step (13a) above.
A compound of Formula LVH in which Ri is -X"-O-NRιa-Y'-Rιb, where Rιa and Rιb together with the nitrogen atom and Y' group to which they are bonded join together to form a ring of Fonnula -N- C(O) -N- S(0)2 J R ;
R7 or 7 , can be prepared in a two-step procedure from a compound of Formula LVH in which Ri is -X"-0-NH2, using one of the methods described in step 5a of Reaction Scheme H or step 13a above.
Reaction Scheme VIH
Figure imgf000097_0002
Figure imgf000097_0003
XLlll
Figure imgf000097_0001
XLVI
Figure imgf000097_0004
Compounds of the invention can be prepared according to Reaction Scheme LX, wherein D, E, R, Ri, R2, R2a, X, and Y'are as defined above, m is 1, n is 0 or 1, and R3b and R3c are as defined below. In Reaction Scheme DC, when D is -Br or -I, step (1) is used to react a lH-imidazo[4,5-c]quinoline-4-amine or lH-imidazo[4,5-c][l,5]naphthyridine-4- amine of Formula LVΗ using known palladium-catalyzed coupling reactions such as the Suzuki coupling and the Ηeck reaction. For example, a bromo or iodo-substituted compound of Fonnula LVΗ undergoes Suzuki coupling with a boronic acid of Formula
R3a-B(OΗ)2, an anhydride thereof, or a boronic acid ester of Formula R3a-B(O-alkyl)2, wherein R a is as defined above, according to the method described in Reaction Scheme IV. The product of Formula LIX, a subgenus of Formulas I and H wherein R3b is the same as R a, or a pharmaceutically acceptable salt thereof, can be isolated by conventional methods.
The Heck reaction can also be used in step (1) of Reaction Scheme IX to provide compounds of Formula LLX, wherein R3 is -X R^ and -XVY-R4, wherein X'a, Y, R4 , and φ are as defined above. The Heck reaction is carried out by coupling a compound of Formula LVH with a compound of the Formula H2C=C(H)-R4 or H2C=C(H)-Y-R4. Several of these vinyl-substituted compounds are commercially available; others can be prepared by known methods. The reaction is conveniently carried out by combining the compound of Formula LVH and the vinyl-substituted compound in the presence of palladium (TT) acetate, triphenylphosphine or tri-ortAo-tolylphosphine, and a base such as triethylamine in a suitable solvent such as acetonitrile or toluene. The reaction can be carried out at an elevated temperature such as 100 °C -120 °C under an inert atmosphere.
The product of Formula LIX or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Compounds of Formula LIX, wherein R3b is — XO-R4, X'c is alkynylene, and ^ is as defined above, can also be prepared by palladium catalyzed coupling reactions such as the Stille coupling or Sonogashira coupling. These reactions are carried out by coupling a compound of Formula LVH with a compound of the Formula
Figure imgf000098_0001
(alkyl)3Si-C≡C-R4, or H-C≡C-R^
Compounds of Formula LLX prepared as described above by palladium-mediated coupling reactions, wherein R3b is -XVR4, -X Y-R4, -X'b2-Y-R4, -X'b2-R5, or -XVR4, where X'b2 is alkenylene interrupted or terminated by arylene or heteroarylene, and X'a, X'c, Y, R > and R5 are as defined above, can undergo reduction of the alkenylene or alkynylene group present to provide compounds of Formula LIX wherein R3b is -X'd-R^ -XVY-R4, or-X'e-R5, where X'd is alkylene; X'e is alkylene interrupted or terminated by arylene or heteroarylene; and R4, R5, and Y are as defined above. The reduction can be carried out by hydrogenation using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon. The reaction can conveniently be carried out on a Pan apparatus in a suitable solvent such as ethanol, methanol, or mixtures thereof. The product or pharmaceutically acceptable salt thereof can be isolated using conventional methods. Compounds of Formula LVH wherein D is -OCH2Ph can be converted in Reaction
Scheme IX to compounds of Formula LXI wherein R3c is -O-R4b, -O-X'-R , -O-X'-Y-Rφ, or -O-X'-R5; wherein R4, R41,, R5, X', and Y are as defined above. In step (la) of Reaction Scheme DC, the benzyl group in a lH-imidazo[4,5-c]quinoline-4-amine or 1H- imidazo[4,5-c][l,5]naphthyridine-4-amine of Formula LVΗ, wherein D is -OCΗ2Ph, is cleaved to provide a hydroxy group. The cleavage is conveniently carried out on a Pan apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as palladium or platinum on carbon in a solvent such as ethanol. Alternatively, the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst. The transfer hydrogenation is conveniently carried out by adding ammomum formate to a solution of a compound of Formula LVH in a suitable solvent such as ethanol in the presence of a catalyst such as palladium on carbon. The reaction is carried out at an elevated temperature, for example, the refluxing temperature of the solvent. The product of Formula LX, a subgenus of Formulas I and H, or pharmaceutically acceptable salt thereof can be isolated using conventional methods. In step (2) of Reaction Scheme IX, a hydroxy-substituted lH-imidazo[4,5- c]quinoline-4-amine or lH-imidazo[4,5-c][l,5]naphthyridine-4-amine of Formula LX is converted to a compound of Formula LXI, a subgenus of Formula I and Η wherein R3c is -O-Rft, -O-X'-R/j, -O-X'-Y-Ri, or -O-X'-R5, using a Williamson-type ether synthesis. The reaction is effected by treating a hydroxy-substituted lH-imidazo[4,5-c]quinoline-4-amine or lH-imidazo[4,5-c][l,5]naphthyridine-4-amine of Formula LX with an aryl, alkyl, or arylalkylenyl halide of Formula Halide-Rn,, Halide-alkylene-R^, Halide-alkylene-Y-R4, or Halide-alkylene-R5 in the presence of a base. Numerous alkyl, arylalkylenyl, and aryl halides of these formulas are commercially available, including substituted benzyl bromides and chlorides, substituted or unsubstituted alkyl or arylalkylenyl bromides and chlorides, and substituted fluorobenzenes. Other halides of these formulas can be prepared using conventional synthetic methods. The reaction is conveniently carried out by combining an alkyl, arylalkylenyl, or aryl halide with the hydroxy-substituted compound of Fonnula LX in a solvent such as DMF in the presence of a suitable base such as cesium carbonate. Optionally, catalytic tetrabutylammonium bromide can be added. The reaction can be carried out at ambient temperature or at an elevated temperature, for example 65 °C or 85 °C, depending on the reactivity of the halide reagent. Alternatively, step (2) may be carried out using the Ullmann ether synthesis, in which an alkali metal aryloxide prepared from the hydroxy-substituted compound of Formula LX reacts with an aryl halide in the presence of copper salts, to provide a compound of Formula LXI, where R3c is -O-R^, -O-XVR4, or -O-X Y-R45 wherein X'f is an arylene or heteroarylene. Numerous substituted and unsubstituted aryl halides are commercially available; others can be prepared using conventional methods. The product of Formula LXI, prepared by either of these methods, or pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IK
Figure imgf000101_0001
(1 ) (2)
Figure imgf000101_0002
For some embodiments, compounds of the invention are prepared according to Reaction Scheme X, where Rls R2, R2', R2", R2a, X, Y' , RA2, RB2, and Hal are as defined above, and Ph is phenyl. In step (1) of Reaction Scheme X, a 2,4-dichloro-3-nitropyridine of Formula LXH is reacted with an amine of the Formula
Figure imgf000101_0003
to form a 2-chloro-3- nitropyridine of Formula LXH The reaction is conveniently carried out by combining an amine of Fonnula ^N-Ri and a 2,4-dichloro-3-nitropyridine of Formula LXH in the presence of a base such as triethylamine in an inert solvent such as DMF. The reaction can be carried out at ambient temperature, and the product can be isolated from the reaction mixture using conventional methods. Many amines of Formula
Figure imgf000101_0004
are commercially available; others can be prepared by known synthetic methods. Many 2,4-dichloro-3- nitropyridines of the Formula LXH are known and can be readily prepared using known synthetic methods (see, for example, Dellaria et al, U.S - Pat. No. 6,525,064 and the references cited therein).
In step (2) of Reaction Scheme X, a 2-chloro-3-nitropyridine of Formula LXTH is reacted with an alkali metal azide to provide an 8-nitrotetrazolo[l,5-α]pyridin-7-amine of Formula LXTV. The reaction can be carried out by combining the compound of Formula LXTH with an alkali metal azide, for example, sodium azide, in a suitable solvent such as acetonixrile/water, preferably 90/10 acetonitrileΛvater, in the presence of cerium(m) chloride, preferably cerium(IH) chloride heptahydrate. Optionally, the reaction can be carried out with heating, for example, at the reflux temperature. Alternatively, the reaction can be carried out by combining the compound of Formula LXTH with an alkali metal azide, for example, sodium azide, in a suitable solvent such as DMF and heating, for example to about 50 °C -60 °C, optionally in the presence of ammonium chloride. The product can be isolated from the reaction mixture using conventional methods.
In step (3) of Reaction Scheme X, an 8-nitrotetrazolo[l,5-α]pyridin-7-amine of Fomiula LXTV is reduced to provide a compound of Formula LXV. The reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as palladium on carbon or platinum on carbon. The hydrogenation is conveniently carried out in a Pan apparatus in a suitable solvent such as toluene, methanol, acetonitrile, or ethyl acetate. The reaction can be carried out at ambient temperature, and the product can be isolated using conventional methods.
In step (4) of Reaction Scheme X, a tetrazolo[l,5-a]pyridine-7,8-diamine of Formula LXV, is reacted with a carboxylic acid or an equivalent thereof to provide a 7H- imidazo[4,5-c]tetrazolo[l,5-α]pyridine of Formula LXVI. The carboxylic acid or equivalent is selected such that it will provide the desired -X-Ηal substituent in a compound of Formula LXVI. The reaction can be carried out as described in step (7) of
Reaction Scheme VΗL The product can be isolated using conventional methods. h step (5) of Reaction Scheme X, a 7H-imidazo[4,5-c]tetrazolo[l,5-α]pyridine of Formula LXVI is treated with N-hydroxyphthalimide to provide a compound of Formula LXVΗ, which contains a N-phthalimide-protected hydroxylamine. The reaction is conveniently carried out as described in step (4) of Reaction Scheme I. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (6) of Reaction Scheme X, the N-phthalimide-protected hydroxylamine of Formula LXVΗ is treated with hydrazine in a suitable solvent such as ethanol to provide a hydroxylamine of Formula LXVΗI. The reaction can be carried out at ambient temperature and the product can be isolated from the reaction mixture using conventional methods. In step (7) Reaction Scheme X, the hydroxylamine group in a 7H-imidazo[4,5- c]tetrazolo[l,5-fl]pyridine of Formula LXVΗI reacts with an aldehyde or ketone of Formula R2'C(O)R2 M to provide an oxime of Formula LXIX. The reaction can be carried out using the conditions described above in step (6) of Reaction Scheme I and the product can be isolated from the reaction mixture using conventional methods.
In step (8) of Reaction Scheme X, the tetrazolo ring is removed from a 7H- imidazo[4,5-c]tetrazolo[l,5-α]pyridine of Formula LXIX by reaction with triphenylphosphine to form an N-triphenylphosphinyl intermediate of Formula LXX. The reaction with triphenylphosphine can be run in a suitable solvent such as toluene or 1,2- dichlorobenzene under an atmosphere of nitrogen with heating, for example at the reflux temperature. hi step (9) of Reaction Scheme X, an N-triphenylphosphinyl intermediate of Formula LXX is hydrolyzed to provide an oxime-substituted lH-imidazo[4,5-c]pyridin-4- amine of Formula LXXI. The hydrolysis can be carried out by general methods well known to those skilled in the art, for example, by heating in a lower alkanol or an alkanol/water solution in the presence of an acid such as trifluoroacetic acid, acetic acid, or hydrochloric acid. The product can be isolated from the reaction mixture using conventional methods as the compound of Formula LXXI or as a pharmaceutically acceptable salt thereof. A compound of the Formula LXXI may also be obtained through an alternative two-step route from a compound of Formula LXVΗ. In step (6a) of Reaction Scheme X, a compound of Formula LXVΗ is treated sequentially according to the reaction conditions described in steps (8) and (9) of Reaction Scheme X using hydrochloric acid as the acid in step (9). Under these reaction conditions, the N-phthalimide is removed to provide the hydroxylamine-substituted lH-imidazo[4,5-c]pyridin-4-amine of Formula LXXΗ. The product can be isolated and purified using conventional methods.
In step (7a) of Reaction Scheme X, a hydroxylamine-substituted lH-imidazo[4,5- c]pyridin-4-amine of Formula LXXΗ reacts with an aldehyde or ketone of Formula R2'C(O)R2" to provide an oxime of Formula LXXI. The reaction can be earned out using the conditions described above in step (6) of Reaction Scheme I, and the product or the pharmaceutically acceptable salt thereof can be isolated from the reaction mixture using conventional methods.
In step (10) of Reaction Scheme X, the oxime of Formula LXXI is reduced using the conditions described in step (7) of Reaction Scheme I to afford a compound of Formula LXXIH, a subgenus of Formulas I, H, and VI. The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
In step (11) of Reaction Scheme X, a hydroxylamine of Formula LXXIH is converted into a compound of Formula LXXIV, a subgenus of Formulas I, H, and VI, using the reagents and conditions described in Reaction Scheme V or step (2) of Reaction Scheme VI. The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
Alternatively, in steps (10a) and (Ila) of Reaction Scheme X, a hydroxylamine of Formula LXXH is converted into a compound of Formula LXXIV using the reagents and methods described in steps (12a) and (13a), respectively, of Reaction Scheme VHL The product or pharmaceutically acceptable salt thereof can be isolated by conventional methods.
For some embodiments, compounds shown in Reaction Scheme X can be further elaborated using conventional synthetic methods. For Example, amines of Formula Rι-NH2, used in step (1) of Reaction Scheme X, may contain a protected functional group, such as a tert-butoxycarbonyl-protected amino group. The protecting group may be removed later in Reaction Scheme X after step (4) to reveal, for example, an amine on the Ri group of a compound of Formula LXVI. An amino group introduced in this manner maybe further functionalized by applying the chemistry described in steps (5) and (5a) of Reaction Scheme H to provide compounds of the Formula LXVI in which Ri is -X'-N(R8)-Q-R4 or X'-R5a, which can be converted into compounds of the Formula
LXXm or LXXIV using the chemistry described in steps (5) - (10) or (11), respectively, of Reaction Scheme X. Alternatively, the protecting group may be removed after step (7) of Reaction Scheme X to reveal an amine on the Ri group of a compound of Formula LXIX. The amino group may be further functionalized as described above to provide compounds of the Formula LXDC in which Ri is -X'-N(R8)-Q-R4 or -X'-R5a, which can be converted into compounds of the Fonnula LXXIH or LXXIV using the chemistry described in steps (8) - (10) or (11) of Reaction Scheme X.
Compounds of the Formula LXXIH, LXXIV, or LXXV in which Ri is -X"-O-N=C(Rι')(Rι") or -X"-O-NRιa-Y'-Rib can be synthesized from compounds shown in Reaction Scheme X using the chemistry described above in association with Reaction Scheme VTH.
Reaction Scheme X
Figure imgf000105_0001
Lxxiii LXXIV LXXV
Pharmaceutical Compositions and Biological Activity
Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound or salt of the invention as described above in combination with a pharmaceutically acceptable carrier.
The terms "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. Although the exact amount of active 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, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably about 10 micrograms per kilogram (μg/kg) to about 5 mg/kg, of the compound or salt to the subject. A variety of dosage forms maybe used, such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds or salts of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.
Compounds or salts of the invention have been shown to induce the production of certain cytokines and certain compounds or salts of the invention may inhibit the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds or salts are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
Cytokines whose production may be induced by the administration of compounds or salts of the invention generally include interferon-α (IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certain interleukins (TL). Cytokines whose biosynthesis may be induced by compounds or salts of the invention include IFN-α, TNF-α, IL-1, TL-6, EL- 10 and H-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds or salts useful in the treatment of viral diseases and neoplastic diseases. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal. The animal to which the compound or salt or composition is administered for induction of cytokine biosynthesis may have a disease as described infra, for example a viral disease or a neoplastic disease, and administration of the compound or salt may provide therapeutic treatment. Alternatively, 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.
In addition to the ability to induce the production of cytokines, compounds or salts of the invention can affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. The compounds or salts may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, the compounds or salts may cause proliferation and differentiation of B-lymphocytes.
Compounds or salts of the invention can also have an effect on the acquired immune response. For example, the production of the T helper type 1 (TRT) cytokine IFN- γ may be induced indirectly and the production of the T helper type 2 (TH2) cytokines IL-4,
H-5 and H-13 maybe inhibited upon administration of the compounds or salts.
Other cytokines whose production may be inhibited by the administration of compounds or salts of the invention include tumor necrosis factor-α (TNF-α). Among other effects, inhibition of TNF-α production can provide prophylaxis or therapeutic treatment of TNF-α mediated diseases in animals, making the compounds or salt useful in the treatment of, for example, autoimmune diseases. Accordingly, the invention provides a method of inhibiting TNF-α biosynthesis in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal. The animal to which the compound or salt or composition is administered for inhibition of TNF-α biosynthesis may have a disease as described infra, for example an autoimmune disease, and administration of the compound or salt may provide therapeutic treatment. Alternatively, 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. Whether for prophylaxis or therapeutic treatment of a disease, and whether for effecting innate or acquired immunity, 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. When administered with other components, the compound or salt and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.
Conditions for which IRMs identified herein may be used as treatments include, but are not limited to:
(a) viral diseases such as, for example, diseases resulting from infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-H, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus
(e.g., rhinovirus or enterovirus), an orthomyxoviras (e.g., influenzavims), a paramyxovirus (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus (RSV)), a coronavims (e.g., SARS), a papovaviras (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), or a retrovirus (e.g., a lentivirus such as HIV);
(b) bacterial diseases such as, for example, diseases resulting from infection by bacteria of, for example, the genus Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus,
Corynebacterium, Mycobacterium, Campylobacter, Vibrio, Senatia, Providencia, Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
(c) other infectious diseases, such 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;
(d) neoplastic diseases, such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemias including but not limited to myelogeous leukemia, chronic lymphocytic leukemia, multiple myeloma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and other cancers; (e) Tκ2-mediated, atopic diseases, such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
(f) certain autoimmune diseases such as systemic lupus erythernatosus, essential thrombocythaemia, multiple sclerosis, discoid lupus, alopecia areata; and (g) 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).
Additionally, an IRM compound or salt of the present invention maybe 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, meningococcal and pneumococcal vaccines, adenovirus, HTV, chicken pox, cytomegalovirus, dengue, feline leukemia, fowl plague, HSV-1 and HSV-2, hog cholera, apanese encephalitis, respiratory syncytial virus, rotavirus, papilloma virus, yellow fever, and Alzheimer's Disease.
Certain IRM compounds or salts of the present invention maybe particularly helpful in individuals having compromised immune function. For example, certain compounds or salts may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HTV patients.
Thus, one or more of the above diseases or types of diseases, for example, a viral disease or a neoplastic disease may be treated in an animal in need thereof (having the disease) by administering a therapeutically effective amount of a compound or salt of the invention to the animal. An amount of a compound or salt effective to induce or inhibit cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, T -6, TL-10 and H-12 that is increased (induced) or decreased (inhibited) over a background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount that is effective for such treatment will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/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 μg/kg to about 5 mg/kg.
Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.
EXAMPLES Example 1 O-{[4-Amino-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolm-2-yl]methyl}hydroxylamine
Figure imgf000111_0001
Part A
N4-(2-Methylpropyl)quinoline-3,4-diamine (41 g), dichloromethane (550 mL), triethylamine (40 mL, 1.5 eq), and chloroacetyl chloride (16.7 mL, 1.1 eq.) were combined and then stined at ambient temperature over the weekend. The reaction mixture was diluted with 1,2-dichloroethane (75 mL) and then washed with saturated aqueous sodium bicarbonate (3 x 400 mL). The organic layer was dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 52.81 g of 2-chloromethyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinoline as a brown solid.
Part B 3-Chloroperoxybenzoic acid (mCPBA) (16.4 g of 77% max, 73.1 mmol) was added to a solution of 2-chloromethyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quijnoline (10 g, 36.5 mmol) in chloroform (250 mL). The reaction mixture was stined at ambient temperature overnight. Ammonium hydroxide (100 mL) was added and the reaction was stined vigorously for 15 minutes. P rα-toluenesulfonyl chloride (8.4 g, 43.8 mmol) was added in portions over a period of 10 minutes. The reaction mixture was stirred at ambient temperature for 1 hour and then filtered to remove a precipitate. The filtrate was transfened to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 16 g of crade product as a yellow foam. The foam was dissolved in 10% methanol in dichloromethane (20 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g), (available from Biotage, Inc, Charlottesville, Virginia, USA). The cartridges were eluted sequentially with IL 1 :1 ethyl acetate:hexanes, 2% methanol in 1:1 ethyl acetate :hexanes, and 5% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and then concentrated under reduced pressure to provide 6.4 g of 2-chloromethyl-l -(2-methylpropyl)- 1H- imidazo[4,5-c]quinolin-4-amine as an orange foam.
Part C
Triethylamine (536 mg, 5.19 mmol) was added to a solution of N- hydroxyphthalimide (678 mg, 4.16 mmol) in N,N-dimethylformamide (DMF); after 5 minutes a solution of 2-chloromethyl-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-4- amine (1 g) in DMF (10 mL) was added. The reaction mixture was stined at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL) and then washed with water (1 x 100 mL). The aqueous layer was extracted with dichloromethane (2 x 50 mL) and ethyl acetate (1 x 50 mL). The combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 1.8 g of crade product as a yellow solid.
The solid was dissolved in 5% methanol in chloroform (10 mL) and loaded onto a FLASH 40+M silica cartridge (90 g). The cartridge was eluted sequentially with IL 1% methanol in chloroform and 3% methanol in chloroform. The fractions containing the desired product were combined and then concentrated under reduced pressure to provide 950 mg of a yellow solid. This material was recrystallized from acetonitrile, isolated by filtration, washed sequentially with acetonitrile and diethyl ether, and then dried in a vacuum oven at 65 °C overnight to provide 640 mg of 2-{[4-amino-l-(2-methylpropyl)-lH-imidazo[4,5- c]quinolin-2-yl]methoxy}isoindole-l,3-dione as a yellow crystalline solid, mp 221-222 °C. 1H ΝMR (300 MHz, DMSO-d6) δ 8.10 (d, J= 1.6 Hz, IH), 7.88 (s, 4H), 7.63 (dd, J= 8.3 Hz, 1.2 Hz, IH), 7.48 (m, IH), 7.32 (m, IH), 6.69 (br s, 2H), 5.51 (s, 2H), 4.73 (d, J= 1.6
Hz, 2H), 2.35 (m, IH), 1.01 (d, J= 6.6 Hz, 6H); MS (APCI) m/z 448.0 (M + H)+;
Anal. Calc'd for C23H2ιΝ5O3»0.5CH3CΝ •0.5H2O: C, 64.78; H, 5.32; N, 17.31. Found: C, 64.87; H, 5.28; N, 17.63. Part D
Hydrazine (15 mL) was added to a solution of 2-{[4-amino-l-(2-methylpropyl)- lH-imidazo[4,5-c]quinolin-2-yl]methoxy}isoindole-l,3-dione (51 g of crade material from a large scale reaction) in ethanol (200 mL) and a precipitate formed almost immediately. The reaction mixture was stirred at ambient temperature for 1.5 hours and then filtered.
The filter cake was washed with several portions of dichloromethane. The filtrate was concentrated under reduced pressure to provide 40 g of crude product as a brown semi- solid. The solid was partitioned between IM aqueous hydrochloric acid (300 mL) and dichloromethane (100 mL). The layers were separated. The aqueous layer was extracted with dichloromethane (2 x 100 mL). Analysis by liquid chromatography/mass spectroscopy (LCMS) showed that the organics did not contain product. The aqueous layer was made basic (pH -10) with solid sodium carbonate and then extracted with dichloromethane (3 x 100 mL). The combined extracts were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 9.29 g of product as a brown foam. A portion (1.7 g) of this material was purified on a FLASH 40+S silica cartridge (40 g), (available from Biotage, Inc, Charlottesville, Virginia, USA), eluting sequentially with 500 mL of 2%, 5%, 5%, and 10% methanol in ethyl acetate. The fractions containing product were combined and then concentrated under reduced pressure to provide 950 mg of an oil. The oil was dissolved in dichloromethane and then combined with 4M hydrochloric acid in dioxane. The resulting precipitate was isolated by filtration and then partitioned between dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The combined organics were concentrated under reduced pressure to provide 500 mg of a foam. This material was dissolved in dichloromethane (50 mL) and then combined with 4M hydrochloric acid in dioxane (30 mL). A precipitate formed. The mixture was concentrated and then dissolved in hot ethanol. The solution was allowed to cool to ambient temperature, chilled (-10 °C) in a freezer overnight, and then allowed to warm to ambient temperature. A precipitate was isolated by filtration, washed with ethanol and acetonitrile, and then dried under high vacuum overnight to provide 261 mg of 0-{{4- amino-l-(2-methylproρyl)-lH-imidazo[4,5-c]quinolin-2-yl]methyl}hydroxylamine dihydrochloride as a white crystalline solid, mp 205-207 °C. 1H NMR (300 MHz, DMSO-d6) δ 8.23 (d, J- 8.0 Hz, IH), 7.86 (dd, J= 8.3 Hz, 1.0 Hz, IH), 7.75 (dd, J= 7.3, 7.3 Hz, IH), 7.62 (m, IH), 5.57 (s, 2H), 4.64 (d, J= 1.6 Hz, 2H), 2.20 (m, IH), 0.98 (d, J= 6.6 Hz, 6H);
13C NMR (75 MHz, DMSO-d6) δ 149.6, 149.2, 135.8, 134.4, 130.4, 125.5, 125.3, 122.7, 119.0, 112.9, 66.9, 52.5, 29.1, 19.3 (2);
MS (APCI) m/z 286.1 (M + H)+;
Anal. Calc'd for Cι5Hι9N5O«2.0 HCl «0.3 H2O: C, 49.54; H, 5.99; N, 19.26. Found: C, 49.87; H, 6.36; N, 18.94.
Example 2
N- { [4-Amino- 1 -(2-methylpropyl)- lH-imidazo[4,5-c] quinolin-2- yljmethoxy} methanesulfonamide
Figure imgf000114_0001
Triethylamine (1.47 mL, 10.5 mmol) was added to a solution of O-{[4-amino-l-(2- methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methyl}hydroxylamine (1.5 g, 5.3 mmol) in dichloromethane (50 mL). Methanesulfonyl chloride (0.448 mL, 5.78 mmol) was added and the reaction mixture was stined at ambient temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (1 x 30 mL) and brine (1 x 30 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 2.16 g of crade product as a brown foam. This material was dissolved in dichloromethane (10 mL) and then loaded onto a FLASH 40+S silica cartridge (4O g). The cartridge was eluted sequentially with 500 mL ethyl acetate, 2%, 3%, and 5% methanol in ethyl acetate. The fractions containing product were combined and then concentrated under reduced pressure to provide 850 mg of a yellow solid. The material was recrystallized from 3:2 ethanol: acetonitrile and dried under high vacuum to provide 206 mg of N- {[4-amino-l -(2-methylpropyl)- lH-imidazo[4,5-c]quinolin-2- yl]methoxy} methanesulfonamide as a yellow crystalline solid, mp 215-216 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.3 (br s, IH), 8.04 (d, J= 8.0 Hz, IH), 7.63 (d, J= 7.4 Hz, IH), 7.46 (m, IH), 7.29 (m, IH), 6.69 (br s, 2H), 5.23 (s, 2H), 4.50 (d, J= 7.6 Hz, 2H), 3.05 (s, 3H), 2.25 (m, IH), 0.93 (d, J= 6.6 Hz, 6H);
13C NMR (75 MHz, DMSO-d6) δ 152.9, 147.8, 146.3, 134.0, 127.9, 127.6, 127.3, 122.1, 121.5, 115.6, 70.9, 52.7, 37.6, 29.6, 20.1 (2);
MS (APCI) m/z 364.1 (M + H)+;
Anal. Calc'd for d6H2ιN5O3S: C, 52.88; H, 5.82; N, 19.27. Found: C, 52.96; H, 5.81; N, 19.04.
Example 3
N- { [4- Amino- 1 -(2-methylpropyl)- lH-imidazo [4, 5 -c] quinolin-2-yl]methoxy } -N '- isopropylurea
Figure imgf000115_0001
Isopropyl isocyanate (0.620 mL, 6.31 mmol) was added to a solution of O- {[4- amino-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methyl}hydroxylamine (1.5 g, 5.3 mmol) in dichloromethane (50 mL). The reaction mixture was stined at ambient temperature for 1 hour and then concentrated under reduced pressure to provide crude product as a brown foam. This material was dissolved in dichloromethane (10 mL) and then loaded onto a FLASH 40+S silica cartridge (40 g). The cartridge was eluted sequentially with 500 mL 2%, 4%, 6%, and 8% methanol in ethyl acetate. The fractions containing product were combined and then concentrated under reduced pressure to provide 880 mg of a yellow solid. This solid was recrystallized from acetonitrile, isolated by filtration, washed with acetonitrile and diethyl ether, and then dried under high vacuum to provide 365 mg of N-{[4-amino-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2- yl]methoxy}-N '-isopropylurea as a light yellow crystalline solid, mp 218-219 °C. 1H ΝMR (300 MHz, DMSO-d6) δ 9.21 (s, IH), 8.02 (d, J= 8.1 Hz, IH), 7.62 (d, J= 7.4 Hz, IH), 7.45 (dd, J= 7.3, 7.3 Hz, IH), 7.28 (dd, J= 7.1, 7.1 Hz, IH), 6.66 (br s, 2H), 6.49 (d, J= 8.1 Hz , IH), 5.07 (s, 2H), 4.49 (d, J= 7.5 Hz, 2H), 3.71 (m, IH), 2.22 (m, IH), 1.01 (d, J= 6.5 Hz, 6H), 0.93 (d, J= 6.6 Hz, 6H); MS (APCI) m/z 371.1 (M + H)+;
Anal. Calc'd for d9H26N6O2: C, 61.60; H, 7.07; N, 22.69. Found: C, 61.41; H, 7.40; N, 22.37.
Examples 4 - 42 An acid chloride, sulfonyl chloride, sulfamoyl chloride, carbamoyl chloride or isocyanate from the table below (1.1 equivalents) was added to a test tube containing a solution of O-{[4-amino-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2- yljmethyl} hydroxylamine (30 mg) and triethylamine (2.0 eq.) in dichloromethane (1 mL). The test tube was capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). The reaction was quenched by adding 2 drops of water and then vortexing the test tube. The solvent was removed by vacuum centrifugation. The compounds were purified by preparative high performance liquid chromatography (prep
ΗPLC) using a Waters Fraction Lynx automated purification system. The prep ΗPLC fractions were analyzed using a Micromass LC-TOFMS, and the appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the desired compound. Column: Phenomenex LUNA C18(2), 21.2 x 50 millimeters (mm), 10 micron particle size, 100 Angstroms (A) pore; flow rate: 25 mL/min; non-linear gradient elution from 5-
95% B in 9 min, then hold at 95% B for 2 min, where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic acid/acetonitrile; fraction collection by mass- selective triggering. The table below shows the acid chloride, sulfonyl chloride, sulfamoyl chloride, carbamoyl chloride or isocyanate used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Examples 43 - 68 Part A Triethylamine (9 mL, 64.7 mmol) was added to a solution of tert-butyl [3-(3- aminoquinolin-4-ylamino)propyl]carbamate (13.65 g, 43.1 mmol) in dichloromethane (150 mL). Chloroacetyl chloride (3.8 mL, 47.5 mmol) was added dropwise over a period of 10 minutes. The reaction mixture was stined at ambient temperature over the weekend and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and 1 : 1 water: saturated aqueous sodium bicarbonate. The organic layer was washed with brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (2 x 100 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 14.1 g of crude product as a brown foam. The foam was dissolved in a mixture of dichloromethane (15 mL) and methanol (0.5 mL). The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g). The cartridges were eluted sequentially with 1 L 1:1 ethyl acetate :hexanes, 5% methanol in 1:1 ethyl acetate :hexanes, and 10% methanol in 1:1 ethyl acetate :hexanes. The fractions containing product were combined and concentrated under reduced pressure to provide 8.96 g of tert-butyl [3-(2-chloromethyl-lH-imidazo[4,5- c] quinolin- 1 -yl)propyl] carbamate as a light brown foam.
Part B
3-Chloroperoxybenzoic acid (13.3 g of 7% max, 59.4 eq.) was added in portions over a period of 5 minutes to a solution of tert-butyl [3-(2-chloromethyl-lH-imidazo[4,5- e]quinolin-l-yl)propyι]carbamate (8.9 g, 23.7 mmol) in chloroform (200 mL). The reaction mixture was allowed to stir at ambient temperature overnight. Ammonium hydroxide (50 mL) was added and the reaction mixture was stined vigorously. Para- toluensulfonyl chloride (5.43 g, 28.5 mmol) was added over a period of 5 minutes. The reaction mixture was stined at ambient temperature for 2 hours; an additional 1 g of para- toluensulfonyl chloride was added and the reaction mixture was stined for another hour. The reaction mixture was filtered to remove solids. The filtrate was transfened to a separatory funnel and the layers were separated. The organic layer was washed with 1:1 water: saturated aqueous sodium bicarbonate (2 x 150 mL). The combined aqueous was extracted with dichloromethane (2 x 150 mL) and ethyl acetate (1 x 100 mL). The combined organic extracts were concentrated under reduced pressure to provide 13.6 g of crade product as a brown foam. The foam was dissolved in dichloromethane (20 mL).
The solution was divided and loaded onto two FLASH 40+M silica cartridges (90 g). The first cartridge was eluted sequentially with IL 1 :1 ethyl acetate :hexanes, 5% methanol in 1:1 ethyl acetate :hexanes, and 10% methanol in 1:1 ethyl acetate:hexanes. The second cartridge was eluted sequentially with IL 1:1 ethyl acetate :hexanes, 7% methanol in 1:1 ethyl acetate :hexanes, and 7% methanol in 1:1 ethyl acetate:hexanes. The fractions containing product were combined and then concentrated under reduced pressure to provide 4.3 g of tert-butyl [3-(4-amino-2-chloromethyl-lH-imidazo[4,5-c]quinolin-l- yl)propyl]carbamate as a light yellow foam. Part C Triethylamine (4.6 mL, 33.1 mmol) was added to a solution of N- hydroxyphthalimide (2.16 g, 13.2 mmol) in DMF (10 mL). A solution of tert-butyl [3-(4- amino-2-chloromethyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]carbamate (4.3 g, 11.0 mmol) in DMF (20 ml) was added. The reaction was stined at ambient temperature for 3.5 hours and then diluted with water (100 mL). The resulting precipitate was isolated by filtration, washed with water, and then dried in a vacuum oven at 60°C over the weekend to provide 4.25 g of tert-butyl (3-{4-amino-2-[(l,3-dioxo-l,3-dihydroisoindol-2- yl)oxymethyl]-lH-imidazo[4,5-c]quinolin-l-yl}propyl)carbamate as a light yellow solid. 1H ΝMR (300 MHz, DMSO-d6) δ 8.2 (d, J = 8.0 Hz, IH), 7.9 (s, 4H), 7.7 (m, IH), 7.5 (m, IH), 7.3 (m, IH), 7.2 (m, IH), 6.7 (br s, 2H), 5.5 (s, 2H), 4.8 (m, 2H), 3.2 (m, 2H), 2.2 (m, 2H), 1.4 (s, 9H);
MS (APCI) m/z 517.3 (M + H)+. Part D
Hydrazine hydrate (8 mL of 55%) was added to a suspension of tert-butyl (3-{4- amino-2-[(l,3-dioxo-l,3-dihydroisoindol-2-yl)oxymethyl]-lH-imidazo[4,5-c]quinolin-l- yl}propyl)carbamate (4.25 g, 8.23 mmol) in ethanol (70 mL). The reaction became homogeneous after about 2 minutes. A precipitate started forming after about 1 hour.
After stirring at ambient temperature for a total of 2 hours the reaction mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was azeotroped twice with toluene to provide 3.63 g of tert- butyl [3-(4-amino-2-aminooxymethyl- lH-imidazo [4,5-c] quinolin- 1 -yι)propyι] carbamate as a white solid.
Part E
Acetone (20 mL) was added to a solution of tert-butyl [3-(4-amino-2- aminooxymethyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]carbamate (3.6 g) in methanol (70 mL). The reaction mixture was stined at ambient temperature overnight and then concentrated under reduced pressure to provide 4.12 g of tert-butyl [3-(4-amino-2- isopropylideneaminoxymethyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]carbamate as a light yellow foam.
Part F
Trifluoroacetic acid (7 mL) was added to a suspension of tert-butyl [3-(4-amino-2- isopropylideneaminoxymethyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]carbamate (4.12 g) in dichloromethane (70 mL). The reaction became homogeneous and was stined at ambient temperature for 2.5 hours. More trifluoroacetic acid (10 mL) was added and the reaction was stined for another hour. The reaction mixture was concentrated under reduced pressure and placed under high vacuum overnight to provide 7.68 g of propan-2- one O-{[4-amino-l-(3-aminopropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methyl}oxime a white solid. Based on the weight this material was assumed to contain 5 equivalents of trifluoroacetic acid. Part G
An acid chloride, sulfonyl chloride, sulfamoyl chloride, carbamoyl chloride or isocyanate from the table below (1.1 equivalents) was added to a test tube containing proρan-2-one O-{[4-amino-l-(3-aminopropyl)-lH-imidazo[4,5-c]quinolin-2- yljmethyl} oxime trifluoroacetate (~90 mg) prepared in Part F, N,N-diisopropylethylamine (350 μL, 10 equivalents), and chloroform (2 mL). The test tube was capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). Water (1 drop) was added to the test tube and then the solvent was removed by vacuum centrifugation. The residue was dissolved in methanol (5 mL). Part H
A portion (2.5 mL) of the solution from Part G was transfened to a fresh test tube and then the solvent was removed by vacuum centrifugation. Methanol (1 mL), glacial acetic acid (1 mL), and 400 μL of a 1.0 M solution of sodium cyanoborohydride in • tefrahydrofuran were added to the test tube. The test tube was capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). The solvent was removed by vacuum centrifugation. The compounds were purified by preparative high performance liquid chromatography (prep HPLC) using a Waters Fraction Lynx automated purification system using the method described above for Examples 4 - 42. The table below shows the acid chloride, sulfonyl chloride, sulfamoyl chloride, carbamoyl chloride or isocyanate used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Examples 69 - 97
Part A Using the general method of Examples 43 - 68 Part A, tert-butyl [2-(3- aminoquinolin-4-ylamino)ethyl]carbamate (43.5 g, 144 mmol) was reacted with chloroacetyl chloride (17.72 g, 158 mmol) to provide 37.39 g of tert-butyl [2-(2- chloromethyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]carbamate. Part B Using the general method of Examples 43 - 68 Part B, a solution of tert-butyl [2-
(2-chloromethyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]carbamate (27.45 g, 76.1 mmol) in chloroform (500 mL) was treated with 3-chloroperoxybenzoic acid (25.6 g of 77% max, 114 mmol) and the resulting 5-oxide was aminated using ammonium hydroxide (150 mL) and αr -toluenesulfonyl chloride (17.4 g, 91.3 mmol) to provide 41.83 g of crude tert- butyl [2-(4-amino-2-chloromethyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]carbamate as a brown solid. A portion (-32 g) of the crude material was dissolved in dichloromethane and then washed with 1 Ν hydrochloric acid (x3). The organic layer was allowed to stand for several days and a precipitate formed. This material was isolated by filtration to provide 7.0 g of tert-butyl [2-(4-amino-2-chloromethyl-lH-imidazo[4,5-c]quinolin-l- yl)ethyl]carbamate as an off white solid. Part C Using the general method of Examples 43 - 68 Part C, tert-butyl [2-(4-amino-2- chloromethyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]carbamate (7 g, 19 mmol)) was reacted with N-hydroxyphthalimide (3.65 g, 22.3 mmol) to provide 6.37 g of tert-butyl (2- {4-amino-2-[(l,3-dioxo-l,3-dihydroisoindol-2-yl)oxymethyl]-lH-imidazo[4,5-c]quinolin- l-yl}ethyl)carbamate as a yellow solid. 1H ΝMR (300 MHz, DMSO-d6) δ 8.3 (d, J = 8.5 Hz, IH), 7.9 (s, 4H), 7.6 (m, IH), 7.5 (m,
IH), 7.3 (m, IH), 7.1 (m, IH), 6.6 (br s, 2H), 5.5 (s, 2H), 4.9 (m, 2H), 3.6 (m, 2H), 1.3 (s, 9H);
MS (APCI) m/z 503.2 (M + H)+. Part D Using the general method of Examples 43 - 68 Part D, the N-phthalimide protecting group was removed from tert-butyl (2-{4-amino-2-[(l,3-dioxo-l,3- dihydroisoindol-2-yl)oxymethyl]-lH-imidazo[4,5-c]quinolin-l-yl}ethyl)carbamate (6.35 g) to provide crade tert-butyl [2-(4-amino-2-aminooxymethyl-lH-imidazo[4,5-c]quinolin- 1 -yl)ethyl]carbamate. Part E
Acetone (25 mL) was added to a suspension of the crude material from Part D in methanol (100 mL). The resulting solution was stined at ambient temperature for 3 hours and then concentrated under reduced pressure. The residue was azeotroped once with toluene, slurried with ethanol (100 mL) and then filtered. The filter cake was washed with additional ethanol. The filtrate was concentrated under reduced pressure to provide 3.9 g of product as a yellow solid. Additional product (0.9 g) was obtained by extracting the filter cake with dichloromethane. The two lots were combined to provide 4.8 g of tert- butyl [2-(4-amino-2-isopropylideneaminooxymethyl-lH-imidazo[4,5-c]quinolin-l- yl)ethyl] carbamate. Part F
Trifluoroacetic acid (10 mL) was added to a suspension of tert-butyl [2-(4-amino- 2-isopropylideneaminooxymethyl-lH-imidazo[4,5-c]quinolin-l-yl)ethyl]carbamate (4.8 g) in dichloromethane (100 mL). The reaction became homogeneous and was stined at ambient temperature. At 2.5 hours and 3.5 hours more trifluoroacetic acid (10 mL and 5 mL respectively) was added. After a total reaction time of 4 hours the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (x3) and then placed under high vacuum overnight to provide 9.97 g of propan-2-one O-{[4- amino-l-(2-aminoethyl)-lH-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as a yellow solid. Based on the weight this material was assumed to contain 5 equivalents of trifluoroacetic acid. Part G
An acid chloride, sulfonyl chloride, sulfamoyl chloride, carbamoyl chloride or isocyanate from the table below (1.1 equivalents) was added to a test tube containing propan-2-one O-{[4-amino-l-(2-aminoethyl)-lH-imidazo[4,5-c]quinolin-2- yljmethyl} oxime trifluoroacetate (-90 mg) prepared in Part F, N^V-diisopropylethylamine (350 μL, 10 equivalents), and chloroform (2 mL). The test tube was capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). Part Η A portion (1 mL) of the solution from Part G was transfened to a fresh test tube and then the solvent was removed by vacuum centrifugation. Methanol (1 mL), glacial acetic acid (1 mL), and 300 μL of a 1.0 M solution of sodium cyanoborohydride in tetrahydrofuran were added to the test tube. The test tube was capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). The solvent was removed by vacuum centrifugation. The compounds were purified by preparative high performance liquid chromatography (prep ΗPLC) using a Waters Fraction Lynx automated purification system using the method described above for Examples 4 - 42. The table below shows the acid chloride, sulfonyl chloride, sulfamoyl chloride, carbamoyl chloride or isocyanate used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Example 98 N-[4-(4-Amino-2-{[(isopropylamino)oxy]methyl}-6,7-dimethyl-lH-imidazo[4,5- cjpyridin- 1 -yl)butyl]benzamide
Figure imgf000133_0001
Part A
A solution of tert-butyl 4-aminobutylcarbamate (8.50 g, 45.2 mmol) in DMF (20 mL) in an addition funnel was added over 1 hour to a stined solution of 2,4-dichloro-5,6- dimethyl-3-nitropyridine (10.0 g, 45.2 mmol) and triethylamine (9.30 mL, 67.8 mmol) in DMF (100 mL). The addition funnel was rinsed with DMF (17 mL) and the solution was added to the reaction vessel. After the reaction solution was stined overnight at room temperature, additional tert-butyl 4-aminobutylcarbamate (0.1 equivalent) was added. The solution was allowed to stir an additional 2 hours, then was concentrated under reduced pressure. The resulting oil was partitioned between ethyl acetate (400 mL) and water (100 mL). The organic phase was washed with water (4 x 50 mL), then was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crade product was purified by flash chromatography (silica gel, elution with 33% ethyl acetate in hexanes followed by 66% ethyl acetate in hexanes) to afford 9.2 g of tert-butyl 4-[(2-chloro-5,6- dimethyl-3-nitropyridin-4-yl)amino]butylcarbamate.
Part B
The purified tert-butyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridm-4- yl)amino]butylcarbamate from A was combined with crade tert-butyl 4-[(2-chloro-5,6- dimethyl-3-nitropyridin-4-yl)amino]butylcarbamate from a similar experiment to yield 38 g (approximately 101 mmol) of material, wliich was combined with sodium azide (13.0 g, 202 mmol), cerium(IΗ) chloride heptahydrate (19.0 g, 51.0 mmol), and 9:1 acetontrile/water (300 mL). The reaction mixture was heated at reflux for 3 days, then was allowed to cool to room temperature and was filtered. The filter cake was rinsed with DMF. The filtrate was concentrated under reduced pressure to yield an oil that was purified by flash chromatography (silica gel, elution with 2:1:1 ethyl acetate/hexanes/chloroform, followed by 4:1 ethyl acetate/chloroform) to afford 23 g of tert-butyl 4-[(5,6-dimethyl-8-nitrotetraazolo[l,5-α]pyridin-7-yl)amino]butylcarbamate.
Part C
A mixture of tert-butyl 4-[(5,6-dimethyl-8-nitrotetraazolo[l,5-α]pyridin-7- yl)amino]butylcarbamate (9.00 g, 23.7 mmol), 10% palladium on carbon (900 mg), and acetontrile (100 mL) was hydrogenated on a Pan apparatus for 5 hours. The mixture was filtered through CELITE filter agent, which was rinsed afterwards with methanol. The filtrate was concentrated under reduced pressure to yield 6.70 g of tert-butyl 4-[(8-amino- 5 ,6-dimethyltefraazolo [1,5 -α]pyridin-7-yl)amino]butylcarbamate.
Part D
Ethyl 2-chloroethanimidoate hydrochloride (ethyl chloroacetimidate hydrochloride) (2.58 g, 16.4 mmol) was added to a solution of tert-butyl 4-[(8-amino-5,6- dimethyltetraazolo[l,5- ]pyridin-7-yl)amino]butylcarbamate (3.80 g, 10.9 mmol) in chloroform (75 mL). The solution was stined for 3 days, then saturated aqueous sodium bicarbonate (40 mL) was added. The aqueous phase was extracted with chloroform (3 x
40 mL). The organic phases were combined, washed with water (2 x 20 mL) and saturated aqueous sodium bicarbonate (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 4.3 g of tert-butyl 4-[8-(chloromethyl)-5,6- dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5-α]pyridin-7-yl]butylcarbamate, which was used in the next step without purification.
Part E
Concentrated hydrochloric acid (10 mL) was added to a suspension of tert-butyl 4- [8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5-α]pyridin-7- yljbutylcarbamate (1.00 g, 2.30 mmol) in methanol (23 mL). The reaction mixture was stined at room temperature for 2 hours, then was concentrated under reduced pressure to yield a residue. The residue was concentrated twice from toluene to remove residual water, then was triturated with methanol. A solid was isolated by filtration and was dried under vacuum to provide 0.68 g of 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5- c]tetraazolo[l,5- ]pyridin-7-yl]butan-l-amine hydrochloride.
Part F
Benzoic anhydride (3.1 g, 13.8 mmol) was added to a flask containing 4-[8- (chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5-β]pyridin-7-yl]butan-l- amine hydrochloride (4.30 g, 12.5 mmol), triethylamine (3.70 mL, 26.3 mmol), and dichloromethane (100 mL) at 0 °C. The reaction mixture was stined at room temperature for 1 day and additional triethylamine (0.5 mL) and benzoic anhydride (0.8 g) were added. The reaction mixture was stined for 6 hours at room temperature. The volatiles were removed under reduced pressure and water (50 mL) followed by ethyl acetate (50 mL) were added to the solid residue. The mixture was sonicated for 1 minute, then the solid was isolated by filtration, washed with water and ethyl acetate, and dried under vacuum to afford 4.7 g of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5- α]pyridin-7-yl]butyl}benzamide.
Part G N-Ηydroxyphthalimide (2.60 g, 16.0 mmol) and triethylamine (2.20 mL, 16.0 mmmol) were added to a suspension of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H- imidazo[4,5-c]tetraazolo[l,5-α]pyridin-7-yl]butyl}benzamide (4.70 g, 11.4 mmol) in DMF (285 mL). The reaction mixture was allowed to stir for 3 days, then was concentrated under reduced pressure to a white slurry. Methanol was added and a white solid was isolated by filtration, washed with methanol, and dried under vacuum to afford 5.70 g of
N-[4-(8-{[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H- imidazo[4,5-c]tetraazolo[l,5- ]pyridin-7-yl)butyl]benzamide.
Part Η Anhydrous hydrazine (0.47 mL, 15 mmol) was added to a stined suspension of N-
[4-(8-{[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H- imidazo[4,5-c]tetraazolo[l,5-α]pyridin-7-yl)butyl]benzamide (2.8 g, 5.0 mmol) in ethanol (50 mL). After two hours, a solid was isolated by filtration and the filter cake was washed with ethanol. Acetone (25 mL) and methanol (25 mL) were added to the solid and the mixture was stined overnight. The volatiles were removed under reduced pressure to afford a solid that was triturated with 1 M aqueous sodium hydroxide (10 mL) and 1 : 1 methanol/acetone (4 mL). The solid was isolated by filtration, washed with water, and dissolved in chloroform (100 mL). The solution was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford 1.9 g of a N-{4-[5,6-dimethyl-8-({[(l-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5- c]tetraazolo[ 1 ,5-α]pyridin-7-yl]butyl}benzamide as a white solid.
Part i
A mixture of N-{4-[5,6-dimethyl-8-({[(l-methylethylidene)amino]oxy}methyl)- 7H-imidazo[4,5-c]tetraazolo[l,5-Ω]pyridin-7-yl]butyl}benzamide (1.9 g, 4.2 mmol), triphenylphosphine (2.2 g, 8.4 mmol), and 1,2-dichlorobenzene (40 mL) was heated at 125
°C for 2 days. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and 1 M aqueous hydrochloric acid (20 mL) and heated at 40 °C for 6 hours. The reaction was allowed to stand at room temperature overnight and a white precipitate formed that was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (20 mL) and chloroform (10 mL). The aqueous layer was extracted with chloroform (3 x 10 mL). The organic layers were combined, washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by chromatography using a HORIZON HPFC system (an automated, modular high- performance flash purification product available from Biotage, ie, Charlottesville, Virginia, USA) (silica gel, gradient elution with 10-35% CM A in chloroform, where CM A is 80:18:2 chloroform/methanol/concentrated ammonium hydroxide). The appropriate fractions were combined and concentrated under reduced pressure. The solid was triturated with ethyl acetate and was isolated by filtration, washed with ethyl acetate, and dried under vacuum at 50 °C overnight to provide 0.85 g of N-{4-[4-amino-6,7-dimethyl- 2-( { [( 1 -methylethylidene)amino] oxy } methyl)- lH-imidazo [4,5 -cjpyridin- 1 - yl]butyl}benzamide as a white powder, mp 206.0-208.0 °C. Anal. Calcd for C23Η3oN6θ2*0.06 CHC13: C, 64.46; H, 7.05; N, 19.56; Found: C, 64.31; H, 7.06; N, 19.55.
Part i
A solution of sodium cyanoborohydride in tetrahydrofuran (1 M, 6 mL) was added to a solution ofN-{4-[4-amino-6,7-dimethyl-2-({[(l- methylethylidene)amino]oxy}methyl)-lH-imidazo[4,5-c]pyridin-l-yl]butyl}benzamide (260 mg, 0.62 mmol) in 1:2 acetic acid/methanol (9 mL). The reaction mixture was stined overnight, concentrated under reduced pressure, and partitioned between 1 M aqueous hydrochloric acid (20 mL) and chloroform (5 mL). After the bubbling subsided, the layers were separated and the aqueous phase was washed with chloroform (2 x 5 mL). The organic layers were combined and back-extracted with 1 M aqueous hydrochloric acid (2 x 5 mL). The aqueous layers were combined and adjusted to pΗ 10 with 1 M aqueous sodium hydroxide, then were extracted with chloroform (4 x). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a foam. The foam was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 3-35%) CM A in chloroform) followed by crystallization from acetonitrile. The crystals were isolated by filtration and dried under vacuum at 70 °C to yield 80 mg of N-
[4-(4-amino-2-{[(isopropylamino)oxy]methyl}-6,7-dimethyl-lH-imidazo[4,5-c]pyridin-l- yl)butyl]benzamide as a white powder, mp 161.0-162.0 °C.
Anal. Calcd for C23Η32Ν6O2: C, 65.07; H, 7.60; N, 19.80; Found: C, 64.85; H, 7.92; N, 20.00.
Example 99
N-[4-(4-Amino-2-{[(isopropylamino)oxy]methyl}-6,7-dimethyl-lH-imidazo[4,5- cjpyridin- 1 -yι)butyl] -2-methylpropanamide
Figure imgf000138_0001
Part A
Isobutyric anhydride (2.28 mL, 13.8 mmol) was added to a flask containing 4-[8- (chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5-α]pyridin-7-yl]butan-l- amine hydrochloride (prepared as described in Parts A-E of Example 98, 4.30 g, 12.5 mmol), triethylamine (3.66 mL, 26.3 mmol), and dichloromethane (100 mL) at 0 °C. The reaction mixture was stined at room temperature for 3 hours. The solution was concentrated under reduced pressure and water (50 mL) followed by ethyl acetate (50 mL) were added to the solid residue. The mixture was sonicated for 1 minute, then the solid was isolated by filtration, washed with water and ethyl acetate. Toluene was added to the solid and the mixture was concentrated under reduced pressure. The solid was dried under vacuum to afford 4.12 g of N- {4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5- cjtetraazolo [ 1 ,5- ]pyridin-7-yl]butyl} -2-methylpropanamide.
Part B
The general method described in Part G of Example 98 was used to convert 4.10 g N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5-β]pyridin-7- yljbutyl} -2-methylpropanamide into 4.92 g ofN-[4-(8-{[(l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[l,5-α]pyridin-7- yl)butyl] -2-methylpropanamide. Part C
Anhydrous hydrazine (0.91 mL, 29 mmol) was added to a stined suspension of N- [4-(8-{[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H- imidazo[4,5-c]tetraazolo[l,5- ]pyridin-7-yl)butyl]-2-methylpropanamide (4.90 g, 9.71 mmol) in ethanol (100 mL). Dichloromethane (50 mL) was added. After four hours, acetone (50 mL) was added and the reaction mixture was stined overnight. A solid was removed by filtration and washed with methanol. The filtrate was concentrated to provide a solid that was triturated with 1 : 1 saturated aqueous sodium bicarbonate/water. The solid was isolated by filtration, washed with water, and dissolved in chloroform (300 mL). The solution was washed with water (2 x 50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford N- {4-[5,6- dimethyl-8-({[(l-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[l,5- α]pyridin-7-yl]butyl} -2-methylpropanamide that was used in the next experiment.
Part D
A mixture of N-{4-[5,6-dimethyl-8-({[(l-methylethylidene)amino]oxy} methyl)- 7H-imidazo[4,5-c]tetraazolo[l,5-a]pyridin-7-yl]butyl}-2-methylpropanamide (from Part C, approximately 9.71 mmol), triphenylphosphine (5.1 g, 19 mmol), and 1,2- dichlorobenzene (97 mL) was heated at 125 °C for 2 days, then stined at room temperature for 3 days, then heated at 130 °C for 5 hours. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in methanol (80 mL) and 1 M aqueous hydrochloric acid (40 mL) and heated at 40 °C for 6 hours. The reaction was allowed to stir at room temperature overnight and a white precipitate formed that was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid
(20 mL) and chloroform (10 mL). The aqueous layer was extracted with chloroform (3 x 10 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-55% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure. The resulting solid was triturated with acetonitrile and then was recrystallized from acetonitrile to provide N-{4-[4-amino- 6,7-dimethyl-2-({[(l-methylethylidene)amino]oxy}methyl)-lH-imidazo[4,5-c]pyridin-l- yljbutyl} -2-methylpropanamide as a white powder, mp 180.0-181.0 °C. Anal. Calcd for C20Η32Ν6O2: C, 61.83; H, 8.30; N, 21.63; Found: C, 61.65; H, 8.65; N, 21.70.
Part E
A modification on the method described in Part J of Example 98 was used to convert 1.10 g of N-{4-[4-amino-6,7-dimethyl-2-({[(l- methylethylidene)amino] oxy} methyl)- lH-imidazo[4,5-c]pyridin- 1 -yfjbutyl} -2- methylpropanamide into 0.052 g of N-[4-(4-amino-2-{[(isopropylamino)oxy]methyl}-6,7- dimethyl-lH-imidazo[4,5-c]pyridin-l-yl)butyl]-2-methylpropanamide. After the work-up, the crade material was not purified by chromatography, rather by trituration with acetonitrile. The purified product was isolated by filtration and was dried under vacuum to afford N-[4-(4-amino-2-{[(isopropylamino)oxy]methyl}-6,7-dimethyl-lH-imidazo[4,5- cjpyridin- 1 -yl)butyl]-2-methylpropanamide as a white powder, mp 156.0-157.0 °C.
Anal. Calcd for C20Η34Ν6O2*0.2 H2O«0.03 CH3CN: C, 60.91; H, 8.80; N, 21.38; Found: C, 60.94; H, 9.20; N, 21.77.
Example 100 l-{4-Amino-2-[(aminooxy)methyl]-lH-imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol
Figure imgf000140_0001
Part A
Triethylamine (50.0 mL, 360 mmol) was added to a suspension of 4-chloro-3- nitroquinoline (50.0 g, 240 mmol) in DMF (200 mL), followed by dropwise addition of a solution of l-amino-2-methyl-propan-2-ol (23.5 g, 264 mmol) in DMF (50 mL). The reaction mixture was stined overnight at room temperature, then water (500 mL) was added and stirring was continued for 30 minutes. A solid was isolated by filtration, washed with water, and dried to yield 60.9 g of 2-methyl-l-[(3-mtroquinolin-4- yl)amino]propan-2-ol, which was used without further purification.
Part B A mixture of 2-methyl-l-[(3-nitroquinolin-4-yl)amino]propan-2-ol (60.9 g, 233 mmol), 5% platinum on carbon (6.1 g), and ethanol (500 mL) was hydrogenated on a Parr apparatus at 30 psi (2.1 x 105 Pa) for 3 hours. The mixture was filtered through CELITE filter agent, which was subsequently rinsed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to yield an oil that was concentrated twice from toluene to afford 56.6 g of a brown oil that was used directly in the next step.
Part C
Triethylamine (49.0 mL, 350 mmol) was added to a stined suspension of the material from Part B in dichloromethane (450 mL). A solution of chloroacetyl chloride (21.0 mL, 257 mmol) in dichloromethane (50 mL) was added dropwise over 45 minutes.
The reaction mixture was stined for approximately 3 days at room temperature. The solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and 1:1 saturated aqueous sodium bicarbonate/water (500 mL). The aqueous layer was extracted with ethyl acetate (3 x 250 mL) and chloroform (250 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale brown solid was crystallized from dichloromethane (80 mL) to afford 25.7 g of l-[2-(chloromethyl)-lH-imidazo[4,5- c]quinolin-l-yl]-2-methylpropan-2-ol as pale yellow crystals. The mother liquor was concentrated and crystallized from dichloromethane (40 mL) to yield an additional 3.56 g of product. The mother liquor was concentrated under reduced pressure and the resulting residue was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 3-13% methanol in ethyl acetate) to afford 15.5 g of l-[2- (chloromethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol. Part D mCPBA (77% pure, 36.5 g, 163 mmol) was added over 10 minutes to a stined suspension of l-[2-(chloromethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol (23.6 g, 81.4 mmol) in chloroform (500 mL). The resulting solution was stined at room temperature for 1.5 hours. Concentrated ammonium hydroxide (200 mL) was added.
After 5 minutes, /7-toluenesulfonyl chloride (18.6 g, 97.7 mmol) was added in portions. The mixture was stined at room temperature for 2.3 hours, then was transfened to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL, then 3 x 200 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a foam.
The crade product was purified in portions by chromatography on a HORIZON HPFC system (silica gel, elution with 5% methanol in chloroform followed by gradient elution with 5-15%) methanol in chloroform) to yield 9.42 g of l-[4-amino-2-(chloromethyl)-lH- imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol as a pale yellow solid.
Part E
A solution of l-[4-amino-2-(chloromethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2- methylpropan-2-ol (1.00 g, 3.28 mmol) in DMF (3.0 mL) was added to a solution of N- hydroxyphthalimide (642 mg, 3.94 mmol) and triethylamine (0.915 mL, 6.56 mmol) in DMF (3.0 mL). The flask containing the solution of l-[4-amirio-2-(chloromethyl)-lH- imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol was rinsed with DMF (3.0 mL), wliich was added to the reaction solution. The solution was stined at room temperature for 3 hours and a solid formed. The solid was isolated by filtration, washed with dichloromethane, and dried. The off-white solid was dissolved in hot DMF (20 mL). Acetonitrile (50 mL) was added to the solution, which was then placed in a freezer.
Crystals formed and were isolated by filtration, washed with acetonitrile, and dried to provide 288 mg of 2-{[4-amino-l-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5- c]quinolin-2-yl]methoxy}-lH-isoindole-l,3(2H)-dione as orange crystals, mp 270-272 °C. 1H ΝMR (300 MHz, DMSO-d6) δ 8.36 (d, J= 8.1 Hz, IH), 7.85 (s, 4H), 7.60 (dd, J= 8.3, 1.3 Hz, IH), 7.44 (ddd, J- 8.1, 7.0, 1.1 Hz, IH), 7.24 (ddd, J= 8.1, 7.2, 1.3 Hz, IH), 6.57
(br s, 2H), 5.67 (br s, 2H), 4.97 (s, IH), 4.96 (br s, 2H), 1.24 (br s, 6H); MS (APCI) m/z 432.0 (M + H)+;
Anal, calcd for C23H21N5O4: C, 64.03; H, 4.91; N, 16.23. Found: C, 63.65; H, 4.65; N,
16.50.
Part F
Hydrazine (20 mL) was added to a stined suspension of 2-{[4-amino-l-(2- hydroxy-2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methoxy}-lH-isoindole- l,3(2H)-dione (14.0 g, 32.4 mmol) in ethanol (100 mL). The mixture was stined at room temperature and after 5 minutes a solution formed. After 1 hour, a solid began to fonn and additional ethanol (100 mL) was added. After 4.5 hours, the solid was isolated by filtration, washed with dichloromethane, and dried to yield 9.30 g of l-{4-amino-2- [(aminooxy)methyl]-lH-imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol as a yellow solid, some of which was used without further purification in the next step. Two batches of the product (6.63 g and 1.00 g) were purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% of 2 M NH3 in methanol/chloroform) to provide 4.45 g and 650 mg of l-{4-amino-2-[(aminooxy)methyl]-lH-imidazo[4,5- c]quinolin-l-yl}-2-methylpropan-2-ol as a yellow solid, respectively. Some of the chromatographed product (650 mg) was crystallized from acetonitrile to yield 377 mg of l-{4-amino-2-[(aminooxy)methyl]-lH-imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol as pale yellow crystals, mp 178-179 °C.
1H NMR (300 MHz, DMSO-d6) δ 8.28 (d, J= 8.1 Hz, IH), 7.60 (dd, J= 8.3, 0.9 Hz, IH), 7.40 (m, IH), 7.21 (m, IH), 6.58 (br s, 2H), 6.24 (br s, 2H), 5.02 (br s, 2H), 4.85, (s, IH) 4.71 (br s, 2H), 1.17 (br s, 6H); MS (APCI) m/z 302.2 (M + H)+; Anal, calcd for C15H19N5O2: C, 59.79; H, 6.36; N, 23.24. Found: C, 59.93; H, 6.38; N,
23.40. Example 101 N-{[4-Amino-l-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methoxy}-
N-isopropylurea
Figure imgf000144_0001
Isopropyl isocyanate (0.234 mL, 2.39 mmol) was added to a stined solution of 1-
{4-amino-2-[(aminooxy)methyl]-lH-imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 600 mg, 1.99 mmol) in DMF (5 mL). After 5 minutes, a solid formed. The mixture was stined for 1 hour and 45 minutes, then additional isopropyl isocyanate (0.234 mL) and DMF (2 mL) was added. The mixture was stined at room temperature for 45 minutes. Water (40 mL) was added and a solid was isolated by filtration. The solid was washed with water and dried under vacuum to provide 272 mg ofN-{[4-amino-l-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2- yl]methoxy}-N-isopropylurea as a white solid. The filtrate was allowed to stand overnight at room temperature and crystals formed. The crystals were isolated by filtration, washed with acetontrile, and dried in a vacuum oven at 60 °C to afford additional 38 mg of N-{[4- amino- 1 -(2-hydroxy-2-methylpropyl)- lH-imidazo [4,5-c] quinolin-2-yl]methoxy} -N- isopropylurea, as yellow crystals, mp 231-233 °C.
1H ΝMR (300 MHz, DMSO-d6) δ 9.16 (s, IH), 8.27 (d, J= 7.7 Hz, IH), 7.60 (dd, J= 8.4, 1.3 Hz, IH), 7.41 (m, IH), 7.22 (ddd, J= 8.3, 7.3, 1.4 Hz, IH), 6.62 (br s, 2H), 6.46 (d, J= 8.1 Hz, IH), 5.17 (br s, 2H), 4.93 (s, IH), 4.70 (br s, 2H), 3.67 (m, IH), 1.17 (br s, 6H),
0.97 (d, J= 6.7 Hz, 6H); MS (APCI) m/z 387.1 (M + H)+;
Anal, calcd for C19H26Ν6O3: C, 59.05; H, 6.78; N, 21.75. Found: C, 58.78; H, 6.86; N, 21.64. Example 102 N- { [4- Amino- 1 -(2-hydroxy-2-methylpropyl)- lH-imidazo[4,5-c] quinolin-2-yl]methoxy} -
N-methylurea
Figure imgf000145_0001
Methyl isocyanate (0.148 mL, 2.39 mmol) was added to a stined solution of 1 - {4- amino-2- [(aminooxy)methyl] - lH-imidazo [4,5 -c] quinolin- 1 -yl} -2-methylpropan-2-ol (prepared as described in Example 100, 600 mg, 1.99 mmol) in DMF (5 mL). A solid formed immediately. The mixture was stined for 2 hours at room temperature, then was heated to form a solution to which acetonitrile (10 mL) was added. Crystals formed that were isolated by filtration and purified by chromatography using a HORIZON HPFC
(silica gel, gradient elution with 5-20% 2 M NH3 in methanol/chloroform). The appropriate fractions were combined and concentrated to a solid that was dried in a vacuum oven overnight to afford N-{[4-amino-l-(2-hydroxy-2-methylpropyι)-lH- imidazo[4,5-c]quinolin-2-yl]methoxy}-N-methylurea as white crystals, mp 206-207 °C. 1H ΝMR (300 MHz, DMSO-d6) δ 9.17 (s, IH), 8.26 (d, J= 8.1 Hz, IH), 7.60 (dd, J= 8.3,
1.3 Hz, IH), 7.41 (ddd, J= 8.1, 7.0, 1.1 Hz, IH), 7.21 (ddd, J- 8.3, 6.9, 1.3 Hz, IH), 7.04 (q, J= 4.7Hz, IH), 6.60 (br s, 2H), 5.17 (br s, 2H), 4.92 (s, IH), 4.67 (br s, 2H), 2.60 (d, J = 4.7 Hz, 3H), 1.17 (br s, 6H); MS (APCI) m/z 359.0 (M + H)+; Anal, calcd for Cι7H22Ν6O3: C, 56.97; H, 6.19; N, 23.45. Found: C, 56.80; H, 6.27; N,
23.45.
Example 103
N-{[4-Amino-l-(2-hydroxy-2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2- yljmethoxy} methanesulfonamide
Figure imgf000146_0001
Triethylamine (0.634 mL, 4.55 mmol) and methanesulfonyl chloride (0.211 mL,
2.73 mmol) were added to a solution of l-{4-amino-2-[(aminooxy)methyl]-lH- imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). A solid formed immediately. The mixture was stined for 3.5 hours at room temperature, then additional triethylamine (0.634 mL) and methanesulfonyl chloride (0.211 mL) were added. The reaction mixture was stined for an additional 1.5 hours, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2 x 30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration to provide 40 mg of N-{[4-amino-l-(2-hydroxy-2- methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methoxy} methanesulfonamide. Additional crystals were isolated from the mother liquor after a seed crystal was added. The two crops were combined and dried in a vacuum oven to provide 160 mg of N-{[4-amino-l-(2- hydroxy-2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2-yl]methoxy} methanesulfonamide as pale yellow crystals, mp 232-234 °C. 1H ΝMR (300 MHz, DMSO-d6) δ 10.1 (br s, IH), 8.30 (d, J= 8.4 Hz, IH), 7.60 (dd, J=
8.3, 1.3 Hz, IH), 7.41 (ddd, J= 8.1, 7.0, 1.1 Hz, IH), 7.21 (ddd, J= 8.1, 7.2, 1.3 Hz, IH), 6.62 (br s, 2H), 5.35 (br s, 2H), 4.91 (s, IH), 4.72 (br s, 2H), 3.01 (s, 3H), 1.17 (br s, 6H); MS (APCI) m/z 380.1 (M + H)+; Anal, calcd for Cι6H2lΝ5O4S: C, 50.65; H, 5.58; N, 18.46. Found: C, 50.69; H, 5.89; N, 18.76. Example 104
N- { [4- Amino- 1 -(2-hydroxy-2-methylpropyl)- lH-imidazo [4, 5 -c] quinolin-2- yl]methoxy}cyclopropanecarboxamide
Figure imgf000147_0001
Triethylamine (0.634 mL, 4.55 mmol) and cyclopropanecarbonyl chloride (0.248 mL, 2.73 mmol) were added to a solution of l-{4-amino-2-[(aminooxy)methyl]-lH- imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). The cloudy mixture was stined for 2 hours at room temperature, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2 x 30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration, washed with dichloromethane and acetonitrile, and dried in a vacuum oven to provide 442 mg of N-{[4-Amino-l-(2-hydroxy-2-methylpropyl)-lH- imidazo[4,5-c]quinolin-2-yl]methoxy}cyclopropanecarboxamide as a hydrate, white crystals, mp 209-210 °C.
1H ΝMR (300 MHz, DMSO-d6) δ 11.3 (br s, IH), 8.30 (d, J= 8.1 Hz, IH), 7.60 (dd, J= 8.4, 1.3 Hz, IH), 7.41 (m, IH), 7.22 (m, IH), 6.62 (br s, 2H), 5.27 (br s, 2H), 4.86 (s, IH), 4.81 (br s, 2H), 1.38 (m, IH), 1.18 (br s, 6H), 0.70 (d, J= 6.4 Hz, 4H); MS (APCI) m/z 370.0 (M + H)+; Anal, calcd for Cι9H23Ν5O3Η2O: C, 58.90; H, 6.50; N, 18.08. Found: C, 59.08; H, 6.87;
N, 18.48.
Examples 105-122 A reagent from the table below (1.1 equivalents, 0.10 mmol) was added to a test tube containing a solution of 1- {4-amino-2-[(aminooxy)methyl]-lH-imidazo[4,5- c]quinolin-l-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 29 mg, 0.09 mmol) and triethylamine (26 μL, 0.20 mmol) in DMF (1 mL). The test tubes were capped and placed on a shaker at ambient temperature overnight (approximately 18 hours). The solvent was removed from the test tubes by vacuum centrifugation. The compounds were purified by preparative high perfonnance liquid chromatography (prep HPLC) using a Waters FractionLynx automated purification system. The prep HPLC fractions were analyzed using a Waters LC/TOF-MS, and the appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the desired compound. Reversed phase preparative liquid cliromatography was performed with non-linear gradient elution from 5- 95%) B where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic acid/acetonitrile. Fractions were collected by mass-selective triggering. The table below shows the reagent used for each example, the stracture of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Examples 105-122
Figure imgf000148_0001
Figure imgf000149_0001
Example 123
2-[(Aminooxy)methyl] - 1 -(2-methylpropyl)-6,7, 8,9-tetrahydro- lH-imidazo [4,5-c] quinolin-
4-amine
Figure imgf000150_0001
Part A
A mixture of [4-amino-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-2- yljmethanol (15.2 g, 56.2 mmol, U.S. Pat. No. 5,389,640 Example 9), platinum(IV) oxide (7.6 g), and trifluoroacetic acid (75 mL) was hydrogenated at 50 psi (3.5 x 105 Pa) of hydrogen on a Pan apparatus for 2 days. The mixture was diluted with dichloromethane and filtered through CELITE filter agent, which was rinsed afterwards with dichloromethane and methanol. The filtrate was concentrated under reduced pressure and the residue was partitioned between dichloromethane (250 mL) and 1:1 saturated aqueous sodium bicarbonate/water (250 mL). Some solid formed that was isolated by filtration. The aqueous layer was extracted with dichloromethane (2 x 200 mL). The solid was dissolved in methanol and the resulting solution was combined with the organic layers, concentrated under reduced pressure, and purified by cliromatography using a HORIZON HPFC system (silica gel, elution with 10% 1 M NH3 in methanol/dichloromethane) to afford 4.98 g of [4-amino-l-(2-methylpropyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-2-yl]methanol as a grey solid.
Part B
Thionyl chloride (2.65 mL, 36.2 mmol) was added dropwise to a stined suspension of [4-amino-l-(2-methylpropyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-2- yljmethanol (4.97 g, 18.1 mmol) in 1,2-dichloroethane (200 mL). The suspension dissolved, then a precipitate formed after 5 minutes. The reaction mixture was stined at room temperature for 6 hours, then was concentrated under reduced pressure to yield crade 2-(chloromethyl)-l-(2-methylpropyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4- amine hydrochloride, all of which was used in the next step. Part C
A solution of N-hydroxyphthalimide (3.54 g, 21.7 mmol) and triethylamine (7.6 mL, 54.3 mmol) in DMF (25 mL) was added to a suspension of the material from Part B in DMF (25 mL) at room temperature. The reaction mixture was stined at room temperature overnight, then was concentrated under reduced pressure and used without purification in the next step.
Part D Hydrazine hydrate (8.8 mL, 181 mmol) was added to a solution of the material from Part C in ethanol (180 mL). The reaction mixture was stined overnight and a solid formed that was removed by filtration. The filtrate was concentrated under reduced pressure, then was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-10% 1 M NH3 in methanol/dichloromethane) to afford 4.52 g of2-[(aminooxy)methyl]-l-(2-methylpropyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-4-amine as a pale yellow foam. MS (APCI) m/z 290.2 (M + Η)+;
1H NMR (300 MHz, DMSO-d6) δ 6.26 (br s, 2H), 5.85 (br s, 2H), 4.77 (s, 2H), 4.14 (d, J = 7.6 Hz, 2H), 2.91 (m, 2H), 2.67 (m, 2H), 2.00 (m, IH), 1.76 (m, 4H), 0.84 (d, J- 6.7 Hz, 6H).
Example 124
N-{[4-Amino-l-(2-methylpropyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-2- yljmethoxy} methanesulfonamide hydrochloride
Figure imgf000151_0001
A solution of methanesulfonyl chloride (0.253 mL, 3.27 mmol) in dichloromethane (10 mL) was added dropwise to a stined solution of 2-[(aminooxy)methyl]-l-(2- methylpropyl)-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 123, 860 mg, 2.97 mmol) and triethylamine (1.24 mL, 8.92 mmol) in dichloromethane (20 mL) at 0 °C. After 1 hour, additional methanesulfonyl chloride (0.125 L in dichloromethane (5 mL)) and triethylamine (0.5 mL) were added. The reaction mixture was stined for an additional 30 minutes, then was concentrated under reduced pressure to afford a yellow foam. The foam was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% 1 M NH3 in methanol/dichloromethane) followed by crystallization from methanol/acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to yield 160 mg ofN-{[4-amino-l-(2-methylpropyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-2-yl]methoxy} methanesulfonamide hydrochloride as a white crystals, mp 211-
213 °C.
'H ΝMR (300 MHz, DMSO-d6) δ 13.6 (br s, IH), 10.4 (s, IH), 8.26 (br s, 2H), 5.18 (s, 2H), 4.28 (d, J= 7.7 Hz, 2H), 3.04 (s, 3H), 2.94 (br s, 2H), 2.79 (br s, 2H), 2.06 (m, IH), 1.80 (br s, 4H), 0.88 (d, J= 6.6 Hz, 6H); MS (APCI) m/z 368.2 (M + H)+;
Anal, calcd for C16H25Ν5O3S»HCl: C, 47.58; H, 6.49; N, 17.34. Found: C, 47.68; H, 6.51; N, 17.38.
Example 125 N-{[4-Amino-l-(2-methylpropyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-2- yljmethoxy} acetamide
Figure imgf000152_0001
A solution of acetyl chloride (0.232 mL, 3.27 mmol) in dichloromethane (10 mL) was added dropwise to a stined solution of 2-[(aminooxy)methyl]-l-(2-methylpropyl)- 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example
123, 860 mg, 2.97 mmol) and triethylamine (1.24 mL, 8.92 mmol) in dichloromethane (20 mL) at 0 °C. After 1 hour, additional acetyl chloride (0.232 mL) in dichloromethane (10 mL) and triethylamine (1.0 mL) were added. The reaction mixture was stined for an additional 30 minutes, then was concentrated under reduced pressure. The crade product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% 1 M NH3 in methanol/dichloromethane) followed by crystallization from acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to yield 257 mg of N-{[4-amino-l-(2-methylpropyl)-6,7,8,9- tetrahydro-lH-imidazo[4,5-c]quinolin-2-yl]methoxy}acetamide as pale yellow crystals, mp 187-188 °C.
1H ΝMR (300 MHz, DMSO-d6) δ 11.1 (br s, IH), 5.91 (br s, 2H), 4.99 (br s, 2H), 4.32 (d, J= 7.2 Hz, 2H), 2.93 (br s, 2H), 2.67 (br s, 2H), 2.02 (m, IH), 1.76 (m, 7H), 0.86 (d, = 6.7 Hz, 6H);
MS (APCI) m/z 332.2 (M + H)+;
Anal, calcd for Ci7H25Ν5O2: C, 61.61; H, 7.60; N, 21.13. Found: C, 61.52; H, 7.73; N,
21.38.
Examples 126-135
A reagent from the table below (1.1 equivalents, 0.11 mmol) was added to a test tube containing a solution of 2-[(aminooxy)methyl]-l-(2-methylpropyl)-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 123, 29 mg, 0.10 mmol) and NN-diisopropylethylamine (36 μL, 0.20 mmol) in chloroform (1 mL). The test tubes were capped and placed on a shaker at ambient temperature for 4 hours. Water (two drops) was added to each test tube and the volatiles were removed from the test tubes by vacuum centrifugation. The compounds were purified as described in Examples 105-122. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Examples 126-135
Figure imgf000154_0001
Example 136 2-[(Ammooxy)methyl]-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridin-4-amine
Figure imgf000155_0001
Part A Isobutylamine (15.6 mL, 157 mmol) was added dropwise to a 5 °C solution of 4- chloro-3-nitro[l,5]naphthyridine (15.0 g, 71.6 mmol) in dichloromethane (300 mL). The reaction was allowed to stir at room temperature for 4 hours, then was concentrated under reduced pressure to afford a residue that was treated with water (300 mL). The mixture was stined for 30 minutes, then a solid was isolated by filtration, rinsed with water (100 mL), and dried in a vacuum oven at 50 °C overnight to afford 17.25 g of N-(2- methylpropyl)-3-nitro[l,5]naphthyridin-4-amine as a yellow solid.
Part B
The general method described in Part B of Example 92 was used to convert N-(2- methylpropyl)-3-nitro[l,5]naphthyridin-4-amine (17.25 g, 70.0 mmol) into N4-^- methylpropyl)[l,5]naphthyridine-3,4-diamine, which was isolated as a thick, yellow oil and used directly in the next step without purification.
Part C The general method described in Part C of Example 92 was used to convert N4-^- methylρropyl)[l,5]naphthyridine-3,4-diamine (from Part B) into 2-chloro-N-{4-[(2- methylpropyl)amino][l,5]naphthyridin-3-yl}acetamide hydrochloride, which was isolated as a pale yellow solid that was used directly in the next step without purification.
Part D
To a solution of 2-chloro-N-{4-[(2-methylpropyl)amino][l,5]naphthyridin-3- yl}acetamide hydrochloride (from Part C, approximately 70 mmol) in 3:1 ethanol/water (280 mL) was added 6 M aqueous potassium carbonate (17.5 mL). The reaction mixture was stined at room temperature over the weekend. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (200 mL) and brine (100 mL). The aqueous layer was extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 19.5 g of 2-(chloromethyl)-l -(2-methylpropyl)- 1H- imidazo[4,5-c][l,5]naphthyridine, which contained a small amount of dichloromethane and was used without further purification in the next step.
Part E mCPBA (70% pure, 9.85 g, 40.0 mmol) was added to a solution of 2-
(chloromethyl)-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridine (5.49 g, 20.0 rnmol) in chloroform (80 mL). The reaction mixture was allowed to stir for 1.5 hours, then was diluted with dichloromethane (150 mL) and washed with saturated aqueous sodium bicarbonate (2 x 75 mL). The aqueous layers were combined and back-extracted with dichloromethane (2 x 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford a yellow semi-solid that was used immediately without purification in the next step.
Part F The material from Part E was dissolved in methanol (70 mL) and the solution was cooled to 0 °C. Concentrated ammonium hydroxide (6.7 mL) was added, followed by dropwise addition of benzenesulfonyl chloride (5.25 mL, 42.0 mmol). The reaction mixture was stined at 0 °C for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The crade product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 0-25 % CMA in chloroform) to afford 4.14 g of approximately 85% pure 2-(chloromethyl)-l-(2-methylpropyl)-lH-imidazo[4,5- c] [ 1 ,5]naphthyridin-4-amine, wliich was used in the next step without further purification. Part G
The general method described in Part H of Example 92 was used to convert the material from Part F (85% pure, 4.14 g, 14.3 mmol) into 2.81 g of 2-{[4-amino-l-(2- methylpropyl)- lH-imidazo[4,5-c] [1 ,5]naphthyridin-2-yl]methoxy} - lH-isoindole-1 ,3(2H)- dione.
Part Η
Anhydrous hydrazine (0.640 mL, 20.2 mmol) was added to a suspension of 2-{[4- amino- 1 -(2-methylpropyl)- lH-imidazo [4,5-c] [ 1 ,5]naphthyridin-2-yl]methoxy} - 1H- isoindole-l,3(2i:ϊ)-dione (2.81 g, 6.75 mmol) in ethanol (40 mL). Gradually, a solution formed from which a solid began to precipitate. The reaction mixture was stined overnight at room temperature, then was concentrated under reduced pressure. The residue was triturated with 1 M aqueous hydrochloric acid (50 mL). The mixture was sonicated and the solid was isolated by filtration. The filtrate was adjusted to pΗ 8 with solid sodium carbonate and extracted with dichloromethane (3 x 25 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to afford a yellow solid. The solid was triturated with methanol to afford 0.863 g of 2- [(aminooxy)methyl] - 1 -(2-methylpropyl)- lH-imidazo[4,5-c] [ 1 ,5]naphthyridin-4-amine as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (dd, J= 4.3, 1.6 Hz, IH), 7.91 (dd, J= 8.4, 1.6 Hz,
IH), 7.44 (dd, J= 8.4, 4.3 Hz, IH), 6.88 (br s, 2H), 6.35 (br s, 2H), 4.90 (s, 2H), 4.73 (d, J = 7.5 Hz, 2H), 2.37 (septet, J= 7.0 Hz, IH), 0.89 (d, J- 6.7 Hz, 6H); MS (APCI) m/z 287 (M+l)+.
Examples 136-148
A reagent from the table below (1.1 equivalents, 0.11 mmol) was added to a test tube containing a solution of 2-[(aminooxy)methyl]-l-(2-methylpropyl)-lH-imidazo[4,5- c][l,5]naphthyridin-4-amine (prepared as described in Example 136, 29 mg, 0.10 mmol) and N,N-diisopropylethylamine (35 μL, 0.20 mmol) in chloroform (1 mL). The test tubes were capped and placed on a shaker at ambient temperature for 4 hours. The solvent was removed from the test tubes by vacuum centrifugation. The compounds were purified as described in Examples 105-122. The table below shows the reagent used for each example, the structure of the resulting compound, and the observed accurate mass for the isolated trifluoroacetate salt.
Figure imgf000158_0001
Figure imgf000159_0001
Examples 149-167
Part A
A mixture of triethyl orthoformate (154 g, 1.04 mol) and Meldrum's acid (142 g, 0.983 mol) was heated to 55°C for 4 hours. After cooling to 50 °C, a solution of 3- bromoaniline (162.6 g, 0.945 mol) in ethanol (300 mL) was added such that the temperature of the reaction was maintained between 50-55 °C. After half of the 3- bromoaniline had been added, stirring became difficult due to the formation of solids, so more ethanol (1 L) was added to facilitate stirring. Upon complete addition, the reaction was cooled to room temperature, and the solids were collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless, and the product was dried at 65 °C under vacuum to afford 287 g of 5-[(3-bromophenylimino)methyl]-2,2- dimethyl-l,3-dioxane-4,6-dione as an off-white solid. 1H NMR (300 MHz, CDC13) δ 11.19 (brd, J= 12.8 Hz, IH), 8.60 (d, J= 14.0 Hz, IH), 7.44-7.38 (m, 2H), 7.30 (t, J= 8.0 Hz, IH), 7.18 (ddd, J= 8.0, 2.2, 0.9 Hz, IH), 1.75 (s,
6H).
Part B
7-Bromoquinolin-4-ol was prepared in accordance with the literature procedure (D. Dibyendu et al., J. Med. Chem., 41, 4918-4926 (1998)) or by thermolysis of 5-[(3- bromophenylimino)methyl]-2,2-dimethyl-l,3-dioxane-4,6-dione in DOWTHERM A heat transfer fluid and had the following spectral properties:
1H NMR (300 MHz, d6-DMSO) δ 11.70 (brs, IH), 8.00 (d, J= 8.7 Hz, IH), 7.92 (d, J= 7.5 Hz, IH), 7.74 (d, J= 1.9 Hz, IH), 7.44 (dd, J= 8.7, 1.9 Hz, IH), 6.05 (d, J= 7.5 Hz, IH). Part C
A stined suspension of 7-bromoquinolin-4-ol (162 g, 0.723 mol) in propionic acid
(1500 mL) was brought to 110 °C. Nitric acid (85 g of 70%) was added dropwise over 1 hour such that the temperature was maintained between 110-115 °C. After half of the nitric acid had been added, stirring became difficult due to the formation of solids and an additional 200 mL of propionic acid was added. Upon complete addition, the reaction was stined for 1 hour at 110°C, cooled to room temperature, and the solid was collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless (800 mL), and the product was dried at 60 °C under vacuum to afford 152 g of 7- bromo-3-nitro-quinolin-4-ol as a pale yellow solid.
1H NMR (300 MHz, d6-DMSO) δ 13.0 (brs, IH), 9.22 (s, IH), 8.15 (d, J= 8.4 Hz, IH),
7.90 (d, J= 1.6 Hz, IH), 7.66 (dd, J= 8.7, 1.9 Hz, IH).
Part D 7-Bromo-3-nitroquinolin-4-ol (42 g, 156 mmol) was suspended in POCl3 (130 mL) and brought to 102 °C under an atmosphere of N2. After 45 min, all of the solids had dissolved, so the reaction was cooled to room temperature. The resulting solids were collected by filtration, washed with H2O, and then partitioned with CH C12 (3 L) and 2M
Na2CO3 (500 mL). The organic layer was separated, washed with H2O (lx), dried over Na2SO , filtered, and concentrated under reduced pressure to afford 33.7 g of 7-bromo-4- chloro-3-nitroquinoline as a beige solid.
1H NMR (300 MHz, CDC13) δ 9.26 (s, IH), 8.41 (d, J= 1.8 Hz, IH), 8.30 (d, J= 9.0 Hz,
IH), 7.90 (dd, J= 8.9, 2.1 Hz, IH).
Part E
To a suspension of 7-bromo-4-chloro-3-nitroquinoline (25.0 g, 87.0 mmol) in DMF (70 mL) was added triethylamine (18.2 mL, 130 mmol). A solution of iso- butylamine (9.50 mL, 95.7 mmol) in DMF (20 mL) was added dropwise. The viscous reaction mixture was stined overnight at ambient temperature. Water (200 mL) was added and the mixture was stined for 1 hour. A solid was isolated by filtration, washed with water, and dried in a vacuum oven overnight to yield 26.1 g of 7-bromo-N-(2- methylpropyl)-3-nitroquinolin-4- amine as a yellow powder. Part F
A mixture of 7-bromo-N-(2-methylpropyl)-3-nitroquinolin-4-amine (25.1 g, 77.4 mmol) and 5% platinum on carbon (2.5 g), dichloroethane (160 mL), and ethanol (80 mL) was hydrogenated on a Pan apparatus at 30 psi (2.1 x 105 Pa) for 2 hours. The mixture was filtered through CELITE filter agent and the filtrate was concentrated under reduced pressure to yield 23.1 g of a brown oil.
Part G To a stined solution of the material from Part F (23.1 g) and triethylamine (16.4 mL, 118 mmol) in dichloromethane (300 mL) was added dropwise chloroacetyl chloride (6.9 mL, 86.3 mmol). The reaction mixture was allowed to stir at room temperature for 7 days, then was concentrated under reduced pressure. The resulting brown foam was partitioned between ethyl acetate (400 mL) and 1 : 1 saturated aqueous sodium bicarbonate/water (400 mL). The water layer was extracted with dichloromethane (2 x
200 mL). The organic layers were combined and concentrated under reduced pressure. The crade product was divided into three portions, wliich were purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with ethyl acetate in hexanes). The purified material was combined to yield 18.32 g of 7-bromo-2- (chloromethyl)-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinoline as a yellow solid.
Part Η
To a solution of 7-bromo-2-(chloromethyl)-l-(2-methylpropyl)-lH-imidazo[4,5- cjquinoline (13.9 g, 39.4 mmol) in chloroform (300 mL) at room temperature was added mCPBA (77% pure, 17.7 g, 78.8 mmol) over ten minutes. The reaction mixture was stined at room temperature for 3 hours, then concentrated ammomum hydroxide (150 mL) was added, followed by -toluenesulfonyl chloride (9.00 g, 47.3 mmol, added in portions over 10 minutes). The mixture was stined at room temperature for 1 hour, then was transfened to a separatory funnel. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The organic layers were combined, dried over magnesium sulfate, filtered through CELITE filter agent, and concentrated under reduced pressure. The crude product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with ethyl acetate in hexanes) to yield 7.69 g of 7-bromo-2-(chloromethyl)-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-4-amine as a yellow foam.
Part i
A solution of 7-bromo-2-(chloromethyl)-l-(2-methylpropyl)-lH-imidazo[4,5- c]quinolin-4-amine (7.65 g, 20.8 mmol) in DMF (20 mL) was added dropwise via addition funnel to a solution of N-hydroxyphthalimide (4.07 g, 25.0 mmol) and triethylamine (4.3 mL, 31.2 mmol) in DMF (20 mL). The addition funnel was rinsed with DMF (20 mL) and the rinse was added to the reaction solution, which was stined at room temperature. After 30 minutes, a precipitate formed. The viscous mixture was stined at room temperature overnight, then diethyl ether (150 mL) was added. The solid was isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 7.44 g of 2-{[4-amino-7- bromo- 1 -(2-methylpropyl)- lH-imidazo[4,5-c] quinolin-2-yl]methoxy} - lH-isoindole- l,3(2H)-dione, which contained some triethylamine hydrochloride. The filtrate was concentrated to yield 8.5 g of a brown oil, which was found to contain product and was combined with the material from above and used in the next step.
Part J
Anhydrous hydrazine (20 mL) was added to a stined suspension of the material from Part I (approximately 20.8 mmol) in ethanol (150 mL) at room temperature. The mixture became homogeneous after 2 minutes. After 30 minutes, a precipitate had formed. The mixture was stined for another 1.5 hours, then was filtered through CELITE filter agent. The filtrate -was concentrated under reduced pressure to afford crade 2-
[(aminooxy)methyl]-7-bromo-l-(2-methylpropyl)-lH-imidazo[4,5-c]quinolin-4-amine as a brown solid, which was used in the next step without purification.
Part K The material from Part I was dissolved in methanol (150 mL) and acetone (50 mL).
The solution was stined at room temperature for 3 hours, then was concentrated under reduced pressure to yield a brown solid. Dichloromethane (100 mL) was added and the mixture was stined for 30 minutes, then filtered. The filtrate was concentrated under reduced pressure and purified by chromatography three times on a HORIZON HPFC system (silica gel) to yield 4.11 g of acetone O-{[4-amino-7-bromo-l-(2-methylpropyl)- lH-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as a pale orange solid.
Part L
3-Bromo-5-(tert-butyldimethylsilanyloxymethyl)pyridine was prepared according to the published procedure (Zhang, N. et al, J Med. Chem., 45, 2832-2840 (2002)). Under a nitrogen atmosphere, a solution of 3-bromo-5-(tert- butyldimethylsilanyloxymethyl)pyridine (28.70 g, 94.94 mmol) and triisopropyl borate (26.3 mL, 114 mmol) in dry TΗF was cooled to -70 °C. /z-Butyllithium (45.6 mL, 114 mmol) was added dropwise over a period of 1.5 hours. The reaction was stined for an additional 30 minutes and then allowed to warm to -20 °C. Dilute aqueous ammomum chloride was added, and the mixture was allowed to warm to ambient temperature. The aqueous layer was separated and extracted with diethyl ether. The combined organic fractions were concentrated under reduced pressure, and methanol was added to the resulting oil. A solid fonned, which was stined with water for two days, isolated by filtration, and dried under reduced pressure to provide 18.19 g of 5-(tert- butyldimethylsilanyloxymethyl)pyridine-3-boronic acid as a white solid.
Part M <
The compounds in the table below can be prepared according to the following method. A solution of acetone O-{[4-amino-7-bromo-l-(2-methylpropyl)-lH- imidazo[4,5-c]quinolin-2-yl]methyl} oxime (prepared as described in Parts A-K above,
0.20 mmol) in 7:3 volume:volume (v:v) chloroform:methanol (2 mL) can be added to a test tube, and the solvent can be removed by vacuum centrifugation. The boronic acid (0.22 mmol) indicated in the table below and ra-propanol (3.2 mL) can be sequentially added, and the test tube can be purged with nitrogen. The reaction mixture can be sonicated until a solution forms. Palladium (TT) acetate (0.292 mL of a 0.018 M solution in toluene, 0.0053 mmol), 2M aqueous sodium carbonate solution (1.2 mL), deionized water (225 μL), and a solution of 0.15 M triphenylphosphine in n-propanol (106 μL, 0.0159 mmol) can be added sequentially. The test tube can be purged with nitrogen, capped, and then heated to 80 °C overnight in a sand bath. For Example 158, the solvent can be removed by vacuum centrifugation, and glacial acetic acid (1 mL), tetrahydrofuran (1 mL), and deionized water (1 mL) can be added to the test tube. The reaction can be heated overnight at 60 °C. The solvent can be removed from the test tubes by vacuum centrifugation.
The contents of each test tube can be passed through a Waters Oasis Sample Extractions Cartridge MCX (6 cc) according to the following procedure. Hydrochloric acid (3 mL of 1 N) can be added to adjust each example to pH 5-7, and the resulting solution can be passed through the cartridge optionally using light nitrogen pressure. The cartridge can be washed with methanol (5 mL) optionally using light nitrogen pressure and transferred to a clean test tube. A solution of 1% ammonia in methanol (2 x 5 mL) can be then passed through the cartridge optionally using light nitrogen pressure, and the basic solution can be collected and concentrated.
The residue in each test tube can be dissolved in methanol (1 mL) and glacial acetic acid (1 mL). To each solution can be added a solution of sodium cyanoborohydride in tetrahydrofuran (1 M, 300-5 OO μL, 0.3-0.5 mmol). The test tubes can be capped and placed on a shaker at ambient temperature overnight. The solvent can be removed from the test tubes by vacuum centrifugation. The compounds can be purified as described in
Examples 105-122. The table below shows the boronic acid that can be used for each example and the structure of the resulting compound.
Examples 149-167
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Exemplary Compounds
Certain exemplary compounds, including some of those described above in the Examples, have the following Formulas (IIIc, IVc, Va, and Via) and the following Y' and Ri substituents, wherein each line of the table is matched with Formula c, IVc, Va, or Via to represent a specific embodiment of the invention.
Figure imgf000166_0002
HIc TVc
Figure imgf000167_0001
Va Via
Figure imgf000167_0002
CYTOKINE INDUCTION IN HUMAN CELLS Compounds of the invention have been found to induce cytokine biosynthesis when tested using the method described below.
An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon (α) and tumor necrosis factor (α) (IFN-α and TNF-α, 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). Blood Cell Preparation for Culture
Whole blood from healthy human donors is collected by venipuncture into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using HISTOPAQUE-1077. Blood is diluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank's Balanced Salts Solution
(HBSS). The PBMC layer is collected and washed twice with DPBS or HBSS and resuspended at 4 x 106 cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The 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 μM.
Incubation
The solution of test compound is added at 60 μM to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells. The PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (30-0.014 μM). The final concentration of PBMC suspension is 2 x 106 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
Separation
Following incubation the plates are centrifuged for 10 minutes at 1000 rpm (approximately 200 x g) at 4°C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transfened to sterile polypropylene tubes. Samples are maintained at -30 to -70°C until analysis. The samples are analyzed for interferon (α) by ELISA and for tumor necrosis factor (α) by ELISA or IGEN Assay. Interferon (α) and Tumor Necrosis Factor (ex) Analysis by ELISA
Interferon (α) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL. Tumor necrosis factor (α) (TNF) concentration is determined using ELISA kits available from Biosource Intemational, Camarillo, CA. Alternately, the TNF concentration can be determined by ORIGEN M-Series
Figure imgf000169_0001
and read on an IGEN M-8 analyzer from IGEN Intemational, Gaithersburg, MD. The immunoassay uses a human TNF capture and detection antibody pair from Biosource International, Camarillo, CA. Results are expressed in pg/mL.
Certain compounds of the invention may modulate cytokine biosynthesis by inhibiting production of tumor necrosis factor α (TNF-α) when tested using the method described below.
TNF-α INHIBITION IN MOUSE CELLS The mouse macrophage cell line Raw 264.7 is used to assess the ability of compounds to inhibit tumor necrosis factor-α (TNF-α) production upon stimulation by lipopolysaccharide (LPS).
Single Concentration Assay: Blood Cell Preparation for Culture
Raw cells (ATCC) are harvested by gentle scraping and then counted. The cell suspension is brought to 3 x 105 cells/mL in RPMI with 10 % fetal bovine serum (FBS). Cell suspension (100 μL) is added to 96-well flat bottom sterile tissues culture plates
(Becton Dickinson Labware, Lincoln Park, TSTJ). The final concentration of cells is 3 x 104 cells/well. The plates are incubated for 3 hours. Prior to the addition of test compound the medium is replaced with colorless RPMI medium with 3 % FBS. Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. Compounds are tested at 5μM. LPS (Lipopolysaccaride from Salmonella typhimurium, Sigma-Aldrich) is diluted with colorless RPMI to the EC70 concentration as measured by a dose response assay.
Incubation
A solution of test compound (lμl) is added to each well. The plates are mixed on a microtiter plate shaker for 1 minute and then placed in an incubator. Twenty minutes later the solution of LPS (1 μL, EC 0 concentration ~ 10 ng/ml) is added and the plates are mixed for 1 minute on a shaker. The plates are incubated for 18 to 24 hours at 37 °C in a 5 % carbon dioxide atmosphere.
TNF-α Analysis
Following the incubation the supernatant is removed with a pipet. TNF-α concentration is determined by ELISA using a mouse TNF- α kit (from Biosource
International, Camarillo, CA). Results are expressed in pg/mL. TNF-α expression upon
LPS stimulation alone is considered a 100% response.
Dose Response Assay:
Blood Cell Preparation for Culture
Raw cells (ATCC) are harvested by gentle scraping and then counted. The cell suspension is brought to 4 x 105 cells/mL in RPMI with 10 % FBS. Cell suspension (250 μL) is added to 48-well flat bottom sterile tissues culture plates (Costar, Cambridge, MA).
The final concentration of cells is 1 x 105 cells/well. The plates are incubated for 3 hours.
Prior to the addition of test compound the medium is replaced with colorless RPMI medium with 3 % FBS. Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. Compounds are tested at 0.03, 0.1, 0.3, 1, 3, 5 and 10 μM. LPS (Lipopolysaccaride from Salmonella typhimurium, Sigma-Aldrich) is diluted with colorless RPMI to the EC 0 concentration as measured by dose response assay.
Incubation
A solution of test compound (200 μl) is added to each well. The plates are mixed on a microtiter plate shaker for 1 minute and then placed in an incubator. Twenty minutes later the solution of LPS (200 μL, EC70 concentration - 10 ng/ml) is added and the plates are mixed for 1 minute on a shaker. The plates are incubated for 18 to 24 hours at 37 °C in a 5 % carbon dioxide atmosphere.
TNF-α Analysis
Following the incubation the supernatant is removed with a pipet. TNF-α concentration is determined by ELISA using a mouse TNF- α kit (from Biosource Intemational, Camarillo, CA). Results are expressed in pg/mL. TNF-α expression upon LPS stimulation alone is considered a 100% response.
The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.
-17O-

Claims

WHAT IS CLAIMED IS:
1. A compound of the Formula I:
Figure imgf000172_0001
I wherein:
X is Cι_ιo alkylene or C2_ιo alkenylene;
RA and RB are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R9)2; or when taken together, RA and RB form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R'" groups; or when taken together, RA and RB form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O)2-, -S(O)2-N(R8)-,
Figure imgf000173_0001
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-;
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000173_0002
-C(O)-C(O)-, -C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R and R2a are 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,
-S(O)0.2-aryl,
-NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
-C(O)-O-alkyl, -C(O)-N(R8)2,
-N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and
-C(O)-alkyl; or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- CfF -N- S(O)2 and ;
R' is hydrogen or a non-interfering substituent; R'" is a non-interfering substituent; R6 is selected from the group consisting of -O and =S; R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, Ci-10 alkyl, C2-ι0 alkenyl, Ci-io alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; and Rio is C .8 alkylene; or a pharmaceutically acceptable salt thereof.
2. A compound of the Formula H:
Figure imgf000175_0001
π wherein:
X is Ci-io alkylene or C2-ι0 alkenylene;
RAI and RBI are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and
-N(R9)2; or when taken together, RAI and RBI form a fused aryl ring or heteroaryl ring containing one heteroatom selected from the group consisting of N and S, wherein the aryl or heteroaryl ring is unsubstituted or substituted by one or more R groups, or substituted by one R3 group, or substituted by one R3 group and one R group; or when taken together, RAI and RBI form a fused 5 to 7 membered saturated ring, optionally containing one heteroatom selected from the group consisting of N and S, and unsubstituted or substituted by one or more R groups; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2;
R is selected from the group consisting of: -Z-R4, -Z-X'-Rt,
Figure imgf000176_0001
-Z-X'-Y-X'-Y-R^ and
-Z-X'-R5; Y is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
-S(O)2-, -S(O)2-N(R8)-,
Figure imgf000176_0002
-C(O)-O-, -C(O)-N(R8)-, -C(S)-N(R8)-, -C(O)-N(R8)-S(O)2-, -C(O)-N(R8)-C(O)-, -C(S)-N(R8)-C(O)-,
Figure imgf000177_0001
-C(O)-C(O)-,
-C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; Ri is selected from the group consisting of: -R4,
-X-R4,
-X'-Y-R4,
-X'-Y-X'-Y-R^
-X'-R5, -X"-O-NRla-Y'-Rib, and
-X"-O-N=C(Rι')(Rι"); Ria, Ri , Ri', Ri", R2, and R2a are 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, aikoxy, dialkylamino,
-S(O)o-2-alkyl,
-S(O)0-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl,
-C(O)-N(R8)2,
-N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and
-C(O)-alkyl; or Ria and Rib and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of:
Figure imgf000178_0001
or Ri' and Ri" can join together to form a ring system selected from the group consisting of: R11 ~ A'
-R
11 wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000179_0001
wherein the total number of atoms in the nng is 4 to 9;
Ro and d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N( .c))2; or Rς and Ra can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrapted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrapted by one or more -O- groups; Y is selected from the group consisting of:
-S(O)o-2-, -S(O)2-N(R8)-,
Figure imgf000179_0002
-C(R6)-O-,
-O-C(R6)-,
-O-C(O)-O-, -N(R8)-Q-,
-C(R6)-N(R8)-,
-O-C(R6)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000179_0003
Figure imgf000180_0001
Z is a bond or -O-;
R4 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 ;
R5 is selected from the group consisting of:
— N IN
Figure imgf000180_0002
R6 is selected from the group consisting of =O and =S; R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, Cι-10 alkyl, C2-10 alkenyl,
Cι-10 alkoxy-Ci-io alkylenyl, and aryl-Ci.io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene;
Rn is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
R12 is selected from the group consisting of a bond, Cι-5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl which may be optionally intenupted by one or more -O- groups;
A is selected from the group consisting of -CH2-, -O-, -C(O)-, -S(O)o-2-, and
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R_ι)-, and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
3. A compound of the Formula HI:
Figure imgf000181_0001
m wherein:
X is Cι-10 alkylene or C2-10 alkenylene; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
-S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000182_0001
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-:
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000182_0002
-C(O)-C(O)-,
-C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R2 and R a are 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,
-S(O)0-2-aryl,
-NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
-C(O)-O-alkyl, -C(O)-N(R8)2,
-N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and
-C(O)-alkyl; R8 is selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, Ci-io alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
Rio is C3-8 alkylene; n is an integer from 0 to 4; R'" is a non-interfering substituent; and R' is hydrogen or a non-interfering substituent; or a pharmaceutically acceptable salt thereof.
4. A compound of the Formula a:
Figure imgf000184_0001
wherein: X is Ci-io alkylene or C2-1o alkenylene;
Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000184_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000184_0003
-C(O)-C(O)-,
-C(O)-C(O)-O-, and -C(=NH)-N(R8)-; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; Ri is selected from the group consisting of:
-R4, -X'-E^,
-X'-Y-R^ -X'-Y-X'-Y-R^ -X*-R5,
-X"-O-NRla-Y'-Rib, and -X"-O-N=C(Rι')(Rι");
Ria, Rib, Ri', Ri", R2, and R2a are 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)o-2-alkyl,
-S(O)o-2-aryl,
-NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
-C(O)-O-alkyl,
-C(O)-N(R8)2, -N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and
-C(O)-alkyl; or Ria and Rib and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R6) -N- S(0)2 V and . or Ri' and Ri" can join together to form a ring system selected from the group consisting of: R11 ^ A"
-R 11 wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000187_0001
wherein the total number of atoms in the ring is 4 to 9;
Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R )2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
R3 is selected from the group consisting of: -Z-R4, -Z-X'-R4,
Figure imgf000187_0002
-Z-X'-R5; n is an integer from 0 to 4; m is 0 or 1 ; with the proviso that when m is 1 , then n is 0 or 1 ; X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(R13)-alkylene- or-CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrapted by one or more -O- groups;
Y is selected from the group consisting of: -S(O)o-2-, -S(O)2-N(R8)-, -C(R6)-, -C(R6)-O-,
-O-C(R6)-, -O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-, -O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000188_0001
Z is a bond or -O-;
Rj 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;
R5 is selected from the group consisting of:
Figure imgf000189_0001
R6 is selected from the group consisting of =O and -S; R7 is C2_7 alkylene;
R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2_ιo alkenyl, CLIO alkoxy-Cno alkylenyl, and aryl-Ci-io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene;
Rii is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom; Ri2 is selected from the group consisting of a bond, Cι-5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
Rι is selected from the group consisting of hydrogen and alkyl which maybe optionally interrapted by one or more -O- groups; A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o-2-, and
-N(R4)-;
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-; Q is selected from the group consisting of a bond, -C(Re)-, -C(R6)-C(Rδ)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-; V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and
-S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
5. A compound of the Formula Ala:
Figure imgf000190_0001
wherein: X is CLIO alkylene or C2-ιo alkenylene;
Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-, -S(O)2-,
-S(O)2-N(R8)-,
Figure imgf000190_0002
-C(O)-O-,
-C(O)-N(R8)-, -C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000190_0003
-C(O)-C(O)-,
-C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R2 and R2a are 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, -S(O)o-2-aryl, -NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
-C(O)-O-alkyl, -C(0)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(0)-alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; Ri is selected from the group consisting of: -R4,
-X-R4,
-X'-Y-R4,
-X'-Y-X'-Y-R^
-X'-R5, -X"-O-NH-Y'-Rι', and
-X"-O-N=C(Rι')(Rι"); R3 is selected from the group consisting of: -Z-R4, -Z-X'-R4,
Figure imgf000192_0001
-Z-X'-Y-X'-Y-R^ and -Z-X-R5; n is an integer from 0 to 4; m is 0 or 1 ; with the proviso that when m is 1 , then n is 0 or 1 ; X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrapted by one or more -O- groups; X" is -CH(Rι3)-alkylene- or -CH(R13)-alkenylene-; Y is selected from the group consisting of: -S(O)o-2-,
-S(O)2-N(R8)-, -C(R6)-, -C(R6)-O-, -O-C(R6)-, -O-C(O)-O-,
-N(R8)-Q-, -C(R6)-N(R8)-, -O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000193_0001
Z is a bond or -O-;
R4 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;
R5 is selected from the group consisting of:
Figure imgf000194_0001
Ri', and Ri" are independently the same as R2, or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Figure imgf000194_0002
wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000194_0003
wherein the total number of atoms in the ring is 4 to 9;
Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and
Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
R6 is selected from the group consisting of =O and =S;
R is C2-7 alkylene; R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2-ιo alkenyl,
CLIO alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
Rπ is C1-6 alkylene or C -6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom; R12 is selected from the group consisting of a bond, C1-5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
R13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrapted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o-2-, and -N(R4)-;
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O) -; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
6. A compound of the Formula TV:
Figure imgf000195_0001
rv wherein:
X is CLIO alkylene or C2-ι0 alkenylene; Y' is selected from the group consisting of: a bond, -C(O)-, -C(S)-,
-S(O)2-, -S(O)2-N(R8)-,
Figure imgf000196_0001
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-;
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000196_0002
-C(O)-C(O)-, -C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; n is an integer from 0 to 4;
R2 and R2a are 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, -S(O)o-2-aryl, -NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy;
-C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl;
R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2-10 alkenyl, CLIO alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
R is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene; and R' is hydrogen or a non-interfering substituent; or a pharmaceutically acceptable salt thereof.
7. A compound of the Formula (IVa):
Figure imgf000198_0001
IVa : X is CLIO alkylene or C2-ιo alkenylene;
Y' is ; selected from the group consisting of: a bond,
-C(O)-,
-C(S)-,
-S(O)2-,
-S(O)2-N(R8)-,
- S(0)2— N / _ Rιo
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000199_0001
-C(O)-C(O)-,
-C(O)-C(O)-O-, and
-C(=NTΪ)-N(R8)-; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
-N(R9)2; Ri is selected from the group consisting of: -R4,
-X-R4,
-X'-Y-R^
-X'-Y-X'-Y-R^
-X'-R5, -X"-O-NRιa-Y'-Rib, and
-X"-O-N=C(Rι')(R!"); Rla, R^, Ri', R^', R2, and R2a are 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,
-S(0)o-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl,
-C(O)-N(R8)2,
-N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and
-C(O)-alkyl; or Ria and Rib and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of:
Figure imgf000201_0001
or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Λ~ Rι
^ ι 1 wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000201_0002
wherein the total number of atoms in the ring is 4 to 9;
Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms; n is an integer from 0 to 4;
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrapted by one or more -O- groups; X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrapted by one or more -O- groups; Y is selected from the group consisting of: -S(O)o-2-, -S(O)2-N(R8)-, -C(R6)-,
-C(R6)-O-, -O-C(R6)-, -O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-,
-O-C(R6)-N(R8)-, -C(R6)-N(OR9)-
Figure imgf000202_0001
R4 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 ;
R5 is selected from the group consisting of:
Figure imgf000202_0002
Rδ is selected from the group consisting of =O and =S;
R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2-ιo alkenyl, CLIO alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene;
Rn is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
Rι2 is selected from the group consisting of a bond, Cι-5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrapted by one or more -O- groups;
A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o-2-, and -N(R4)-;
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R4)-, and -CH2-; Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C^-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
8. A compound of the Fomiula TVa:
Figure imgf000203_0001
IVa wherein:
X is CLIO alkylene or C2-10 alkenylene; Y' is selected from the group consisting of: a bond, -C(O)-,
-C(S)-,
-S(O)2-,
-S(O)2-N(R8)-,
- S(0)2- N V_ Rιo
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000204_0001
-C(O)-C(O)-, -C(O)-C(O)-O-, and -C(=NH)-N(R8)-;
R2 and R2a are 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,
-S(O)0-2-aryl,
-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy; -C(O)-O-alkyl,
-C(O)-N(R8)2,
-N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and
-C(O)-alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and
-N(R9)2; n is an integer from 0 to 4; Ri is selected from the group consisting of: -RA,
-X'-RA,
-X'-Y-RA,
-X'-Y-X'-Y-R4,
-X'-R5, -X"-O-NH-Y'-Rι', and
-X"-O-N-C(Rι')(Rι"); X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrapted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrapted by one or more -O- groups;
X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-; Y is selected from the group consisting of: -S(O)0-2-, -S(O)2-N(R8)-, -C(R6)-,
-C(R6)-O-, -O-C(R6)-, -O-C(O)-O-, -N(R8)-Q-, -C(R6)-N(R8)-,
-O-C(R6)-N(R8)-, -C(R6)-N(OR9)-,
Figure imgf000206_0001
Figure imgf000207_0001
R4 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;
R5 is selected from the group consisting of:
Figure imgf000207_0002
Ri' and Ri" are independently R2, or Ri' and Ri" can join together to form a ring system selected from the group consisting of: R11 ^ A'
/ -R 1 wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000208_0001
wherein the total number of atoms in the ring is 4 to 9;
Rc and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
R6 is selected from the group consisting of =O and =S;
R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2-1o alkenyl, CLIO alkoxy-Ci.io alkylenyl, and aryl-Ci-io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene;
Rn is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom; R12 is selected from the group consisting of a bond, CL5 alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl which maybe optionally interrapted by one or more -O- groups; A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)o-2-, and
A' is selected from the group consisting of -O-, -S(O)o-2-, -N -Q-R^-, and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-; V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and
-S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
9. A compound of the Formula V:
Figure imgf000209_0001
wherein:
X is CLIO alkylene or C2-ιo alkenylene; Y' is selected from the group consisting of: a bond,
-C(O)-, -C(S)-, -S(O)2-, -S(O)2-N(R8)-,
Figure imgf000209_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000209_0003
-C(O)-C(O)-, -C(O)-C(O)-O-, and -C(=NH)-N(R8>; R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and -N(R9)2;
Ri is selected from the group consisting of:
-R4,
-X'-R4,
Figure imgf000210_0001
-X'-Y-X'-Y-R-t,
-X*-R5,
-X"-O-NRia-Y'-Rib, and
-X"-O-N=C(Rι*)(Rι"); Ria, Rib, Ri', Ri", R-, and R2a are 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)o-2-alkyl,
-S(O)o-2-aryl, -NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and -C(O)-alkyl; or Ria and Rib and/or R2 and R2a together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R6) -N- S(0)2 R7 and R? ; or Ri' and Ri" can join together to form a ring system selected from the group consisting of:
Figure imgf000212_0001
wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000212_0002
wherein the total number of atoms in the ring is 4 to 9; Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
R3 is selected from the group consisting of: -Z-R4,
-Z-X'-R4, -Z-X'-Y-R4, -Z-X'-Y-X'-Y-R4, and -Z-X'-R5; p is an integer from 0 to 3; m is 0 or 1 , with the proviso that when m is 1 , p is 0 or 1 ; X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrapted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrapted by one or more -O- groups;
X" is -CH(Rι3)-alkylene- or -CH(Rι3)-alkenylene-, wherein the alkylene and alkenylene are optionally interrapted by one or more -O- groups; Y is selected from the group consisting of:
Figure imgf000212_0003
-S(O)2-N(R8)-,
-C(R6)-, -C(R6)-O-, -O-C(R6)-,
-O-C(O)-O-,
-N(R8)-Q-,
-C(R6)-N(R8)-,
-O-C(R6)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000213_0001
Z is a bond or -O-;
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, 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;
R5 is selected from the group consisting of: - -N
Figure imgf000214_0001
R6 is selected from the group consisting of =O and =S; R7 is C2-7 alkylene;
R8 is selected from the group consisting of hydrogen, Cno alkyl, C2-ιo alkenyl, CLIO alkoxy-Ci-io alkylenyl, and aryl-Ci-io alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene;
R11 is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom; R12 is selected from the group consisting of a bond, CLS alkylene, and
C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl wliich may be optionally interrupted by one or more -O- groups; A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)0-2~, and
-N(R4)-;
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R )-, and -CH2-; Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-; V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and
-S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
10. A compound of the Formula VI:
Figure imgf000215_0001
VI wherein: X is CLIO alkylene or C2-1o alkenylene;
RA2 and RB2 are each independently selected from the group consisting of: hydrogen, halogen, alkyl, alkenyl, alkoxy, alkylthio, and -N(R9)2; Y' is selected from the group consisting of: a bond,
-C(O)-, -C(S)-, -S(O)2-, -S(O)2-N(R8)-,
Figure imgf000215_0002
-C(O)-O-,
-C(O)-N(R8)-,
-C(S)-N(R8)-,
-C(O)-N(R8)-S(O)2-,
-C(O)-N(R8)-C(O)-,
-C(S)-N(R8)-C(O)-,
Figure imgf000216_0001
-C(O)-C(O)-, -C(O)-C(O)-O-, and
-C(=NH)-N(R8)-; Ri is selected from the group consisting of:
-R-4, -X'-R4, -X'-Y-RA, -X'-Y-X'-Y-RA, -X'-R5,
-X"-O-NRia-Y'-Rib, and -X"-O-N=C(Rι')(Rι"); Ria, Rib, Ri', Ri", R2, and R2a are independently selected from the group consisting of: hydrogen, alkyl, aikenyl, 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)o-2-alkyl,
-S(O)o-2-aryl, -NH-S(O)2-alkyl,
-NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy,
-C(O)-O-alkyl,
-C(O)-N(R8)2,
-N(R8)-C(O)-alkyl,
-O-(CO)-alkyl, and -C(O)-alkyl; or Ria and Rib and/or R2 and R2 together with the nitrogen atom and Y' to which they are bonded can join to form a ring selected from the group consisting of: -N- C(R6) -N- S(0)2
or Ri' and Ri" can join together to form a ring system selected from the group consisting of: ' R11 " A'
-R
11 wherein the total number of atoms in the ring is 4 to 9, and
Figure imgf000218_0001
wherein the total number of atoms in the ring is 4 to 9;
Re and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R )2; or Re and Rd can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrapted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups;
X" is -CH(Rι3)-alkylene- or -CH(Rι )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more -O- groups;
Y is selected from the group consisting of:
Figure imgf000218_0002
-S(O)2-N(R8)-,
-C(R6)-,
-C(R6)-O-,
-O-C(R6)-,
-O-C(O)-O-, -N(R8)-Q-,
-C(Ro-)-N(R8)-,
-O-C(Rs)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000218_0003
Figure imgf000219_0001
R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, 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;
R5 is selected from the group consisting of:
Figure imgf000219_0002
R6 is selected from the group consisting of =O and =S;
R7 is C2-7 alkylene; R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2-10 alkenyl,
CLIO alkoxy-Ci-io alkylenyl, and aryl-Cno alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl;
Rio is C3-8 alkylene; Rπ is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
R12 is selected from the group consisting of a bond, C1-5 alkylene, and C2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrapted by one or more -O- groups;
A is selected from the group consisting of -CH2-, -O-, -C(O)-, -S(O)o-2-, and
A' is selected from the group consisting of -O-, -S(O)o-2-,
Figure imgf000220_0001
and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(Rs)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R )-, -N(R8)-C(R6)-, and -S(O)2-; W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; or a pharmaceutically acceptable salt thereof.
11. The compound or salt of claim 9 wherein p is 0.
12. The compound or salt of any one of claims 4, 5, 9, or 11 wherein m is 0.
13. The compound or salt of any one of claims 3 through 8, or claim 12 as dependent on any one of claims 4 or 5, wherein n is 0.
14. The compound or salt of any one of claims 4 or 5 or claim 13 as dependent on any one of claims 4, 5, or 12 wherein m and n are 0.
15. The compound or salt of claim 9 or claim 12 as dependent on any one of claims 9 or 11 wherein p and m are 0.
16. The compound or salt of claim 10 wherein RA2 and RB2 are each methyl.
17. The compound or salt of any one of claims 1, 3, or 6, or claim 13 as dependent on any one of claims 3 or 6, wherein R' is selected from the group consisting of: -RA,
-X'-RA,
-X'-Y-RA,
-X'-Y-X'-Y-RA,
-X'-R5, -X"-O-NH-Y'-Rι', and
-X"-O-N=C(Rι')(Rι"); wherein:
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrapted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrapted by one or more -O- groups;
X" is -CH(Rι3)alkylene or-CH(Rι3)alkenylene;
Y is selected from the group consisting of:
Figure imgf000221_0001
-S(O)2-N(R8)-,
-C(R6)-,
-C(R6)-O-,
-O-C(R6)-,
-O-C(O)-O-, -N(R8)-Q-,
-C(R6)-N(R8)-,
-O-C(R6)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000221_0002
Figure imgf000222_0001
R4 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;
R5 is selected from the group consisting of
-N
Figure imgf000222_0002
Ri' and Ri" are independently R2, or Ri' and Ri" can join together to form a ring system selected from the group consisting of
Figure imgf000223_0001
wherein the total number of atoms in the ring'is 4 to 9, and
Figure imgf000223_0002
wherein the total number of atoms in the ring is 4 to 9; Re and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and -N(R9)2; or Re and Rd can join to fonn a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four hetero atoms;
R6 is selected from the group consisting of =O and =S; R7 is C _7 alkylene;
R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2-ιo alkenyl, CLIO alkoxy-Ci-io alkylenyl, and aryl-Cι-10 alkylenyl;
R is selected from the group consisting of hydrogen and alkyl; R10 is C3-8 alkylene;
R11 is Cι-6 alkylene or C2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrapted by one heteroatom; RJ is selected from the group consisting of a bond, C1-5 alkylene, and
C2_5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;
Rι3 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more -O- groups; A is selected from the group consisting of-CH2-, -O-, -C(O)-, -S(O)0-2-, and
-N(R4)-;
A' is selected from the group consisting of -O-, -S(O)o-2-, -N(-Q-R- -. and -CH2-;
Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-; V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and
-S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7.
18. The compound or salt of claim 1, claim 3, or claim 17 as dependent on any one of claims 1 or 3 wherein: R'" is R or R3 when n is 1 , R or one R and one R3 when n is 2, or R when n is 3 to
4;
R is selected from the group consisting of: halogen, hydroxy, alkyl, alkenyl, haloalkyl, aikoxy, alkylthio, and -N(R9)2;
R3 is selected from the group consisting of:
-Z-R4,
-Z-X'-R4, -Z-X'-Y-R^ -Z-X*-Y-X'-Y-R4, and
-Z-X'-R5; n is 0 to 4; Z is a bond or -O-;
X' is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrapted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrapted by one or more -O- groups; Y is selected from the group consisting of: -S(O)o-2-, -S(O)2-N(R8)-,
-C(R6)-, -C(R6)-O-,
-O-C(R6)-,
-O-C(O)-O-,
-N(R8)-Q-,
-C(R6)-N(R8)-,
-O-C(R6)-N(R8)-,
-C(R6)-N(OR9)-,
Figure imgf000225_0001
R4 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 ;
R5 is selected from the group consisting of
Figure imgf000226_0001
R6 is selected from the group consisting of =O and =S; R7 is C2_7 alkylene;
R8 is selected from the group consisting of hydrogen, CLIO alkyl, C2_ιo alkenyl, CLIO alkoxy-Cι-10 alkylenyl, and aryl-Cι-10 alkylenyl;
R9 is selected from the group consisting of hydrogen and alkyl; Rio is C3-8 alkylene;
A is selected from the group consisting of -CH2-, -O-, -C(O)-, -S(O)o-2-, and -N(R4)-; Q is selected from the group consisting of a bond, -C(R6)-, -C(R6)-C(Re)-, -S(O)2-,
-C(R6)-N(R8)-W-, -S(O)2-N(R8)-, -C(R6)-O-, and -C(R6)-N(OR9)-;
V is selected from the group consisting of -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-;
W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7.
19. The compound or salt of any one of claims 2, 4, 5, 7 through 12, or 14 through 16, or claim 13 as dependent on any one of claims 4, 5, 7, 8, or 12, wherein Ri is selected from the group consisting of alkyl, arylalkylenyl, aryloxyalkylenyl, hydroxyalkyl, alkylsulfonylalkylenyl, -X'-Y-R^ and -X'-R5; wherein X' is alkylene; Y is -N(R8)-C(O)-,
-N(R8)-S(O)2-, -N(R8)-S(O)2-N(R8)-, -N(R8)-C(O)-N(R8)-, -N(R8)-C(O)-N(R8)-C(O)-,
Figure imgf000226_0002
; Rφ is hydrogen, alkyl, alkenyl, aryl, or heteroaryl, wherein alkyl and alkenyl are optionally substituted by aryl or aryloxy and wherein aryl is optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, cyano, haloalkyl, and halogen; and R5 is
Figure imgf000226_0003
20. The compound or salt of claim 19 wherein R] is 2-methylpropyl, 2-hydroxy-2- methylpropyl, or -X'-Y-Ri; X' is ethylene, propylene, or butylene; Y is -NH-C(O)-, -NH-S(O)2-, -NH-S(O)2-N(R8)-, -NH-C(O)-N(R8)-, -NH-C(O)-NH-C(O)-, or
— NH- C(O)-N ; and R8 is hydrogen or methyl.
21. The compound or salt of any one of claims 1 through 20 wherein X is Ci_4 alkylene.
22. The compound or salt of claim 21 wherein X is methylene.
23. The compound or salt of any one of claims 1 through 22 wherein Y' is selected from the group consisting of a bond, -C(O)-, -C(O)-O-, -S(O)2-, -S(O)2-N(R8 , -C(O)-N(R8)-, -C(S)-N(R8)-, -C(O)-N(R8)-C(O)-, and
Figure imgf000227_0001
24. The compound or salt of claim 23 wherein Y' is selected from the group consisting of -C(O)-, -S(O)2-, and -C(O)-N(R8)-.
25. The compound or salt of any one of claims 1 through 24 wherein R2 and R2a are 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)o-2-alkyl, -S(O)o-2-aryl,-NH-S(O)2-alkyl, -NH-S(O)2-aryl, haloalkoxy, halogen, cyano, nitro, aryl, heteroaryl, heterocyclyl, aryloxy, arylalkyleneoxy, -C(O)-O-alkyl, -C(O)-N(R8)2, -N(R8)-C(O)-alkyl, -O-(CO)-alkyl, and -C(O)-alkyl.
26. The compound or salt of any one of claims 1 through 25 wherein R2a is hydrogen.
27. The compound or salt of any one of claims 1 through 25 wherein R2 and R2a are independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, wherein the alkyl, alkenyl, aryl, and heteroaryl are each optionally substituted with one or more substitutents selected from the group consisting of CLIO alkyl, aryl, heteroaryl, CLIO alkoxy, -O-C(O)-CLIO alkyl, -C(O)-O-CLIO alkyl, halogen, and cyano.
28. The compound or salt of any one of claims 1 tlirough 27 wherein R is alkyl or substituted alkyl, and R2a is hydrogen.
29. The compound or salt of claim 28 wherein R2 is methyl or cyclopropyl, and R a is hydrogen.
30. The compound or salt of any one of claims 1 through 27 wherein R2 is alkenyl or substituted alkenyl, and R2a is hydrogen.
31. The compound or salt of any one of claims 1 through 26 wherein Rj is aryl, arylalkylenyl, substituted aryl, or substituted arylalkylenyl, and R2a is hydrogen.
32. The compound or salt of any one of claims 1 through 26 wherein R2 is heteroaryl, heteroarylalkylenyl, substituted heteroaryl, or substituted heteroarylalkylenyl, and R2a is hydrogen.
33. The compound or salt of any one of claims 1 through 26 wherein R2 is heterocyclyl, heterocyclylalkylenyl, substituted heterocyclyl, or substituted heterocyclylalkylenyl, and R2a is hydrogen.
34. The compound or salt of any one of claims 1 through 26 wherein R2 is selected from the group consisting of methyl, (ethoxycarbonyl)methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-(ethoxycarbonyl)cyclopropylmethyl, propyl, butyl, 2-methylpropyl, tert-butyl, 3 -methylbutyl, 2,2-dimethylpropyl, cyclopentyl, 2-cyclopentylethyl, furyl, fur-3- ylmethyl, furfuryl, furfurylmethyl, cyclohexyl, tetrahydrofuranyl, tetrahydrofuran-3- ylmethyl, 2-(methylthio)ethyl, 3-(methylthio)propyl, phenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 4- (dimethylamino)phenyl, 3-hydroxy-4-methoxyphenyl, 4-acetamidophenyl, 4- (methoxycarbonyl)phenyl, 4-(trifluoromethyl)phenyl, biphenyl, benzyl, 2-methylbenzyl, 3- methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2- chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4- cyanobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4- dimethylaminobenzyl, 3-hydroxy-4-methoxybenzyl, 4-acetamidobenzyl, 4- (methoxycarbonyl)benzyl, 4-(trifluoromethyl)benzyl, 1-phenylethyl, 2-phenylethyl, 2- phenylpropyl, 3-phenylpropyl, 2-phenylethenyl, phenoxymethyl, 2-pyridyl, 3 -pyridyl, 4- pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethy, l-methylpyrrol-2-yl, 1- methylpynol-2 -ylmethyl, l-methylimidazol-2-yl, l-methylimidazol-2-ylmethyl, 1- methylimidazol-4-yl, l-methylimidazol-4-ylmethyl, 3-cyclohexen-l-yl, 3-cyclohexen-l- ylmethyl, 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-2-yhnethyl, 1- methylpiperidin-4-yl, l-acetylpiperidin-4-yl, l-benzylpiperidin-4-yl, 2-thienyl, 3-thienyl, thien-2 -ylmethyl, thiazol-2-yl, thiazol-2-ylmethyl, 5-isoxazolyl, 5-isoxazolylmethyl, quinolin-2-yl, quinolin-2-ylmethyl, pynolidinyl, 3,4-dichlorophenyl, α-methylbenzyl, methoxymethyl, trifluoromethyl, and 2,2,2-trifluoroethyl; and R2a is hydrogen.
35. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of claims 1 through 34 in combination with a pharmaceutically acceptable carrier.
36. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of any one of claims 1 through 34 to the animal.
37. 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 claims 1 tlirough 34 to the animal.
38. 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 claims 1 through 34 to the animal.
PCT/US2004/038033 2003-11-14 2004-11-12 Hydroxylamine substituted imidazo ring compounds WO2005048945A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP04810969A EP1682544A4 (en) 2003-11-14 2004-11-12 Hydroxylamine substituted imidazo ring compounds
AU2004291122A AU2004291122A1 (en) 2003-11-14 2004-11-12 Hydroxylamine substituted imidazo ring compounds
JP2006539957A JP2007511535A (en) 2003-11-14 2004-11-12 Hydroxylamine substituted imidazo ring compounds
US10/595,790 US8598192B2 (en) 2003-11-14 2004-11-12 Hydroxylamine substituted imidazoquinolines
CA002545825A CA2545825A1 (en) 2003-11-14 2004-11-12 Hydroxylamine substituted imidazo ring compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52021503P 2003-11-14 2003-11-14
US60/520,215 2003-11-14

Publications (2)

Publication Number Publication Date
WO2005048945A2 true WO2005048945A2 (en) 2005-06-02
WO2005048945A3 WO2005048945A3 (en) 2006-03-23

Family

ID=34619446

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/038033 WO2005048945A2 (en) 2003-11-14 2004-11-12 Hydroxylamine substituted imidazo ring compounds

Country Status (7)

Country Link
US (1) US8598192B2 (en)
EP (1) EP1682544A4 (en)
JP (1) JP2007511535A (en)
CN (1) CN1906192A (en)
AU (1) AU2004291122A1 (en)
CA (1) CA2545825A1 (en)
WO (1) WO2005048945A2 (en)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006080043A2 (en) * 2005-01-27 2006-08-03 Alma Mater Studiorum- Universita' Di Bologna Organic compounds useful for the treatment of alzheimer's disease, their use and method of preparation
WO2006086634A2 (en) * 2005-02-11 2006-08-17 Coley Pharmaceutical Group, Inc. Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
EP1685129A4 (en) * 2003-11-14 2008-10-22 3M Innovative Properties Co Oxime substituted imidazo ring compounds
WO2009118296A2 (en) * 2008-03-24 2009-10-01 4Sc Ag Novel substituted imidazoquinolines
US7879849B2 (en) 2003-10-03 2011-02-01 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
US7906506B2 (en) 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
US7915281B2 (en) 2004-06-18 2011-03-29 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method
US7923429B2 (en) 2003-09-05 2011-04-12 3M Innovative Properties Company Treatment for CD5+ B cell lymphoma
US7943609B2 (en) 2004-12-30 2011-05-17 3M Innovative Proprerties Company Chiral fused [1,2]imidazo[4,5-C] ring compounds
US7943610B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company Pyrazolopyridine-1,4-diamines and analogs thereof
US7943636B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company 1-substituted pyrazolo (3,4-C) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
US8034938B2 (en) 2004-12-30 2011-10-11 3M Innovative Properties Company Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds
EP2394650A1 (en) 2004-12-30 2011-12-14 3M Innovative Properties Co. Use of resiquimod for the treatment of cutaneous metastases
CN103435524A (en) * 2006-03-17 2013-12-11 约翰斯·霍普金斯大学医学院 N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
WO2014107663A2 (en) 2013-01-07 2014-07-10 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cutaneous t cell lymphoma
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US8951528B2 (en) 2006-02-22 2015-02-10 3M Innovative Properties Company Immune response modifier conjugates
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
EP3153180A1 (en) 2011-06-03 2017-04-12 3M Innovative Properties Company Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom
US9932303B2 (en) 2014-01-17 2018-04-03 Cardioxyl Pharmaceuticals, Inc. N-hydroxymethanesulfonamide nitroxyl donors
US9962453B2 (en) 2013-12-02 2018-05-08 Altimmune Uk Limited Immunogenic compound
US10144735B2 (en) 2006-12-22 2018-12-04 3M Innovative Properties Company Immune response modifier compositions and methods
WO2019166946A1 (en) 2018-02-28 2019-09-06 Pfizer Inc. Il-15 variants and uses thereof
WO2019224716A2 (en) 2018-05-23 2019-11-28 Pfizer Inc. Antibodies specific for gucy2c and uses thereof
WO2019224715A1 (en) 2018-05-23 2019-11-28 Pfizer Inc. Antibodies specific for cd3 and uses thereof
WO2020128893A1 (en) 2018-12-21 2020-06-25 Pfizer Inc. Combination treatments of cancer comprising a tlr agonist
WO2021124073A1 (en) 2019-12-17 2021-06-24 Pfizer Inc. Antibodies specific for cd47, pd-l1, and uses thereof
WO2022013775A1 (en) 2020-07-17 2022-01-20 Pfizer Inc. Therapeutic antibodies and their uses

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040265351A1 (en) 2003-04-10 2004-12-30 Miller Richard L. Methods and compositions for enhancing immune response
AR045260A1 (en) 2003-08-12 2005-10-19 3M Innovative Properties Co COMPOUNDS CONTAINING IMIDAZO-OXIMA REPLACED
MXPA06002199A (en) 2003-08-27 2006-05-22 3M Innovative Properties Co Aryloxy and arylalkyleneoxy substituted imidazoquinolines.
WO2005079195A2 (en) 2003-10-03 2005-09-01 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
CA2547020C (en) 2003-11-25 2014-03-25 3M Innovative Properties Company 1h-imidazo[4,5-c]pyridine-4-amine derivatives as immune response modifier
WO2005066170A1 (en) 2003-12-29 2005-07-21 3M Innovative Properties Company Arylalkenyl and arylalkynyl substituted imidazoquinolines
JP2007517044A (en) 2003-12-30 2007-06-28 スリーエム イノベイティブ プロパティズ カンパニー Imidazoquinolinyl, imidazopyridinyl, and imidazonaphthyridinylsulfonamide
WO2005094531A2 (en) 2004-03-24 2005-10-13 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
US8017779B2 (en) 2004-06-15 2011-09-13 3M Innovative Properties Company Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
US8541438B2 (en) * 2004-06-18 2013-09-24 3M Innovative Properties Company Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
WO2006038923A2 (en) 2004-06-18 2006-04-13 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
US8026366B2 (en) 2004-06-18 2011-09-27 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
US8378102B2 (en) 2005-02-09 2013-02-19 3M Innovative Properties Company Oxime and hydroxylamine substituted thiazolo[4,5-c] ring compounds and methods
WO2006086449A2 (en) * 2005-02-09 2006-08-17 Coley Pharmaceutical Group, Inc. Alkyloxy substituted thiazoloquinolines and thiazolonaphthyridines
US8658666B2 (en) 2005-02-11 2014-02-25 3M Innovative Properties Company Substituted imidazoquinolines and imidazonaphthyridines
EP1851224A2 (en) * 2005-02-23 2007-11-07 3M Innovative Properties Company Hydroxyalkyl substituted imidazoquinolines
CA2598437A1 (en) * 2005-02-23 2006-08-31 Coley Pharmaceutical Group, Inc. Method of preferentially inducing the biosynthesis of interferon
WO2006091567A2 (en) * 2005-02-23 2006-08-31 Coley Pharmaceutical Group, Inc. Hydroxyalkyl substituted imidazoquinoline compounds and methods
EP1922317A4 (en) 2005-09-09 2009-04-15 Coley Pharm Group Inc Amide and carbamate derivatives of n-{2-ý4-amino-2- (ethoxymethyl)-1h-imidazoý4,5-c¨quinolin-1-yl¨-1,1-dimethylethyl}methanesulfonamide and methods
ZA200803029B (en) 2005-09-09 2009-02-25 Coley Pharm Group Inc Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods
US8088790B2 (en) 2005-11-04 2012-01-03 3M Innovative Properties Company Hydroxy and alkoxy substituted 1H-imidazoquinolines and methods
US8329721B2 (en) 2006-03-15 2012-12-11 3M Innovative Properties Company Hydroxy and alkoxy substituted 1H-imidazonaphthyridines and methods
WO2008030511A2 (en) * 2006-09-06 2008-03-13 Coley Pharmaceuticial Group, Inc. Substituted 3,4,6,7-tetrahydro-5h, 1,2a,4a,8-tetraazacyclopenta[cd]phenalenes
US10047066B2 (en) * 2007-11-30 2018-08-14 Newlink Genetics Corporation IDO inhibitors
PT2411521E (en) 2009-03-25 2015-04-21 Univ Texas Compositions for stimulation of mammalian innate immune resistance to pathogens
JP2013512859A (en) * 2009-12-03 2013-04-18 大日本住友製薬株式会社 Imidazoquinoline acting through a toll-like receptor (TLR)
WO2011086053A1 (en) * 2010-01-12 2011-07-21 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof
MX359517B (en) 2010-08-17 2018-10-01 3M Innovative Properties Company Star Lipidated immune response modifier compound compositions, formulations, and methods.
US9475804B2 (en) 2011-06-03 2016-10-25 3M Innovative Properties Company Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom
CN102516244B (en) * 2011-12-02 2013-08-28 山东大学 Hexa-atomic aromatic heterocyclic imidazole mercapto-acetamide derivative, and preparation method and application thereof
PT106142B (en) 2012-02-10 2014-07-18 Hovione Farmaci Ncia S A PROCESS FOR THE PREPARATION OF TIOTROPE BROMIDE
US10286065B2 (en) 2014-09-19 2019-05-14 Board Of Regents, The University Of Texas System Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds
WO2016057931A1 (en) 2014-10-10 2016-04-14 The Research Foundation For The State University Of New York Trifluoromethoxylation of arenes via intramolecular trifluoromethoxy group migration
MA41614A (en) * 2015-02-25 2018-01-02 Alios Biopharma Inc ANTIVIRAL COMPOUNDS
EP3350178B1 (en) * 2015-09-14 2021-10-20 Pfizer Inc. Novel imidazo [4,5-c]quinoline and imidazo [4,5-c][1,5]naphthyridine derivatives as lrrk2 inhibitors
CA3086439A1 (en) 2017-12-20 2019-06-27 3M Innovative Properties Company Amide substitued imidazo[4,5-c]quinoline compounds with a branched chain linking group for use as an immune response modifier

Family Cites Families (298)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3314941A (en) 1964-06-23 1967-04-18 American Cyanamid Co Novel substituted pyridodiazepins
DE1645976A1 (en) 1966-06-18 1971-01-21 Ajinomoto Kk Process for the preparation of adenosine and 2 ', 3'-O-isopropylidene adenosine
ZA704419B (en) 1969-07-21 1971-04-28 Ici Australia Ltd Injectable aqueous solutions of tetramisole
US3692907A (en) 1970-10-27 1972-09-19 Richardson Merrell Inc Treating viral infections with bis-basic ethers and thioethers of fluorenone and fluorene and pharmaceutical compositons of the same
US3917624A (en) 1972-09-27 1975-11-04 Pfizer Process for producing 2-amino-nicotinonitrile intermediates
US4006237A (en) * 1973-10-11 1977-02-01 Beecham Group Limited Tetrahydrocarbostyril derivatives for the prophylaxis of asthma, hayfever and rhinitis
US3891660A (en) 1974-02-07 1975-06-24 Squibb & Sons Inc Derivatives of 1H-imidazo{8 4,5-c{9 pyridine-7-carboxylic acids and esters
US3899508A (en) 1974-04-12 1975-08-12 Lilly Co Eli 5-(2-Aminophenyl)pyrazole-3-carboxylic acids and esters thereof
DE2423389A1 (en) 1974-05-14 1975-12-04 Hoechst Ag PSYCHOTROPIC MEDICINAL PRODUCTS AND THE METHOD OF MANUFACTURING THEREOF
US4381344A (en) * 1980-04-25 1983-04-26 Burroughs Wellcome Co. Process for producing deoxyribosides using bacterial phosphorylase
DE3204126A1 (en) 1982-02-06 1983-08-11 Bayer Ag, 5090 Leverkusen PYRAZOLOXAZINE, -THIAZINE, -CHINOLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT
US4758574A (en) 1982-05-03 1988-07-19 Eli Lilly And Company 2-phenylimidazio (4,5-c) pyridines
US4563525A (en) * 1983-05-31 1986-01-07 Ici Americas Inc. Process for preparing pyrazolopyridine compounds
IL73534A (en) 1983-11-18 1990-12-23 Riker Laboratories Inc 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds
ZA848968B (en) 1983-11-18 1986-06-25 Riker Laboratories Inc 1h-imidazo(4,5-c)quinolines and 1h-imidazo(4,5-c)quinolin-4-amines
CA1271477A (en) 1983-11-18 1990-07-10 John F. Gerster 1h-imidazo[4,5-c]quinolin-4-amines
JPS61112075A (en) 1984-11-05 1986-05-30 Shionogi & Co Ltd Thienylpyrazoloquinoline derivative
US4593821A (en) 1985-04-25 1986-06-10 Laros Equipment Company, Inc. Belt separator for blow molding parts
US4668686A (en) * 1985-04-25 1987-05-26 Bristol-Myers Company Imidazoquinoline antithrombrogenic cardiotonic agents
US4698346A (en) 1985-05-08 1987-10-06 Usv Pharmaceutical Corporation Thiazolo[5,4-h]quinoline compounds useful as anti-allergy agents
US4826830A (en) * 1985-07-31 1989-05-02 Jui Han Topical application of glyciphosphoramide
CA1306260C (en) 1985-10-18 1992-08-11 Shionogi & Co., Ltd. Condensed imidazopyridine derivatives
HU197019B (en) * 1985-11-12 1989-02-28 Egyt Gyogyszervegyeszeti Gyar Process for producing thiqzolo (4,5-c) quinoline derivatives and pharmaceuticals comprising same
US4837378A (en) 1986-01-15 1989-06-06 Curatek Pharmaceuticals, Inc. Topical metronidazole formulations and therapeutic uses thereof
US4775674A (en) 1986-05-23 1988-10-04 Bristol-Myers Company Imidazoquinolinylether derivatives useful as phosphodiesterase and blood aggregation inhibitors
CA1287061C (en) * 1986-06-27 1991-07-30 Roche Holding Ltd. Pyridine ethanolamine derivatives
US5500228A (en) * 1987-05-26 1996-03-19 American Cyanamid Company Phase separation-microencapsulated pharmaceuticals compositions useful for alleviating dental disease
US4880779A (en) 1987-07-31 1989-11-14 Research Corporation Technologies, Inc. Method of prevention or treatment of AIDS by inhibition of human immunodeficiency virus
US4774339A (en) 1987-08-10 1988-09-27 Molecular Probes, Inc. Chemically reactive dipyrrometheneboron difluoride dyes
US5536743A (en) 1988-01-15 1996-07-16 Curatek Pharmaceuticals Limited Partnership Intravaginal treatment of vaginal infections with buffered metronidazole compositions
US5225183A (en) 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
US5736553A (en) * 1988-12-15 1998-04-07 Riker Laboratories, Inc. Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo 4,5-C!quinolin-4-amine
US5238944A (en) 1988-12-15 1993-08-24 Riker Laboratories, Inc. Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
DK0385630T3 (en) 1989-02-27 1997-05-12 Riker Laboratories Inc 1H-imidazo (4,5-c) quinoline-4-amines as antivirals
US5756747A (en) 1989-02-27 1998-05-26 Riker Laboratories, Inc. 1H-imidazo 4,5-c!quinolin-4-amines
US5457183A (en) * 1989-03-06 1995-10-10 Board Of Regents, The University Of Texas System Hydroxylated texaphyrins
US5037986A (en) 1989-03-23 1991-08-06 Minnesota Mining And Manufacturing Company Olefinic 1H-imidazo[4,5-c]quinolin-4-amines
US4929624A (en) 1989-03-23 1990-05-29 Minnesota Mining And Manufacturing Company Olefinic 1H-imidazo(4,5-c)quinolin-4-amines
NZ232740A (en) 1989-04-20 1992-06-25 Riker Laboratories Inc Solution for parenteral administration comprising a 1h-imidazo(4,5-c) quinolin-4-amine derivative, an acid and a tonicity adjuster
US4988815A (en) 1989-10-26 1991-01-29 Riker Laboratories, Inc. 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines
US5750134A (en) * 1989-11-03 1998-05-12 Riker Laboratories, Inc. Bioadhesive composition and patch
EP0507863A4 (en) * 1989-12-28 1993-07-07 Virginia Commonwealth University Sigma receptor ligands and the use thereof
US5274113A (en) 1991-11-01 1993-12-28 Molecular Probes, Inc. Long wavelength chemically reactive dipyrrometheneboron difluoride dyes and conjugates
AU649673B2 (en) 1990-04-30 1994-06-02 Isis Pharmaceuticals, Inc. Oligonucleotide modulation of arachidonic acid metabolism
AU653524B2 (en) 1990-06-08 1994-10-06 Roussel-Uclaf New imidazole derivatives, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them
CA2093132C (en) 1990-10-05 2002-02-26 John F. Gerster Process for the preparation of imidazo[4,5-c]quinolin-4-amines
MX9203481A (en) 1990-10-18 1992-07-01 Minnesota Mining & Mfg FORMULATIONS.
US5248782A (en) 1990-12-18 1993-09-28 Molecular Probes, Inc. Long wavelength heteroaryl-substituted dipyrrometheneboron difluoride dyes
US5389640A (en) 1991-03-01 1995-02-14 Minnesota Mining And Manufacturing Company 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines
US5175296A (en) 1991-03-01 1992-12-29 Minnesota Mining And Manufacturing Company Imidazo[4,5-c]quinolin-4-amines and processes for their preparation
US5342784A (en) 1991-04-12 1994-08-30 Mitsubishi Paper Mills Limited Electrophotographic lithographic printing plate
JPH04327587A (en) 1991-04-26 1992-11-17 Asahi Chem Ind Co Ltd 6'-c-alkyl-3-deazaneplanocin a derivative, its production and use
US5187288A (en) * 1991-05-22 1993-02-16 Molecular Probes, Inc. Ethenyl-substituted dipyrrometheneboron difluoride dyes and their synthesis
US5268376A (en) 1991-09-04 1993-12-07 Minnesota Mining And Manufacturing Company 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines
TW300219B (en) 1991-09-14 1997-03-11 Hoechst Ag
PH31245A (en) 1991-10-30 1998-06-18 Janssen Pharmaceutica Nv 1,3-Dihydro-2H-imidazoÄ4,5-BÜ-quinolin-2-one derivatives.
US5266575A (en) 1991-11-06 1993-11-30 Minnesota Mining And Manufacturing Company 2-ethyl 1H-imidazo[4,5-ciquinolin-4-amines
US5378848A (en) 1992-02-12 1995-01-03 Shionogi & Co., Ltd. Condensed imidazopyridine derivatives
IL105325A (en) 1992-04-16 1996-11-14 Minnesota Mining & Mfg Immunogen/vaccine adjuvant composition
DK0641192T3 (en) 1992-05-18 1998-03-02 Minnesota Mining & Mfg Transmucosal drug delivery device
US5352680A (en) 1992-07-15 1994-10-04 Regents Of The University Of Minnesota Delta opioid receptor antagonists to block opioid agonist tolerance and dependence
US6608201B2 (en) 1992-08-28 2003-08-19 3M Innovative Properties Company Process for preparing 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines
US5395937A (en) 1993-01-29 1995-03-07 Minnesota Mining And Manufacturing Company Process for preparing quinoline amines
ES2122261T3 (en) 1993-03-17 1998-12-16 Minnesota Mining & Mfg AEROSOL FORMULATION CONTAINING A DISPERSION ADJUVANT DERIVED FROM AN ESTER, AMIDA OR MERCAPTOESTER.
DE4309969A1 (en) 1993-03-26 1994-09-29 Bayer Ag Substituted hetero-fused imidazoles
DE69314318T2 (en) 1993-04-27 1998-04-09 Agfa Gevaert Nv Method for inserting a water-soluble compound into a hydrophilic layer
US5648516A (en) * 1994-07-20 1997-07-15 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines
US5352784A (en) 1993-07-15 1994-10-04 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines
DE69425661T2 (en) 1993-07-15 2001-04-19 Minnesota Mining & Mfg IMIDAZO [4,5-c] PYRIDINE-4-AMINE
CA2131680C (en) 1993-09-17 2006-11-07 Gerhard Stucky Process for preparing imidazopyridine derivatives
US5837809A (en) 1995-08-11 1998-11-17 Oregon Health Sciences University Mammalian opioid receptor ligand and uses
JPH07163368A (en) * 1993-12-15 1995-06-27 Hayashibara Biochem Lab Inc Recombinant dna and transformant containing the same recombinant dna
TW530047B (en) 1994-06-08 2003-05-01 Pfizer Corticotropin releasing factor antagonists
US6207646B1 (en) * 1994-07-15 2001-03-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US6239116B1 (en) * 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
EP0772619B2 (en) * 1994-07-15 2010-12-08 The University of Iowa Research Foundation Immunomodulatory oligonucleotides
US5612377A (en) * 1994-08-04 1997-03-18 Minnesota Mining And Manufacturing Company Method of inhibiting leukotriene biosynthesis
US5644063A (en) 1994-09-08 1997-07-01 Minnesota Mining And Manufacturing Company Imidazo[4,5-c]pyridin-4-amine intermediates
GB9420168D0 (en) 1994-10-06 1994-11-23 Boots Co Plc Therapeutic agents
US5571819A (en) 1994-11-22 1996-11-05 Sabb; Annmarie L. Imidazopyridines as muscarinic agents
US5482936A (en) 1995-01-12 1996-01-09 Minnesota Mining And Manufacturing Company Imidazo[4,5-C]quinoline amines
US6071949A (en) 1995-03-14 2000-06-06 The United States Of America As Represented By The Department Of Health And Human Services Use of lipoxygenase inhibitors as anti-cancer therapeutic and intervention agents
US5585612A (en) 1995-03-20 1996-12-17 Harp Enterprises, Inc. Method and apparatus for voting
FR2732605B1 (en) 1995-04-07 1997-05-16 Pasteur Merieux Serums Vacc COMPOSITION FOR INDUCING MUCOSAL IMMUNE RESPONSE
US5766789A (en) 1995-09-29 1998-06-16 Energetics Systems Corporation Electrical energy devices
ES2200039T3 (en) 1995-12-08 2004-03-01 Pfizer Inc. HETEROCICLIC DERIVATIVES REPLACED AS CRF ANTAGONISTS.
US5939047A (en) 1996-04-16 1999-08-17 Jernberg; Gary R. Local delivery of chemotherapeutic agents for treatment of periodontal disease
US5861268A (en) * 1996-05-23 1999-01-19 Biomide Investment Limited Partnership Method for induction of tumor cell apoptosis with chemical inhibitors targeted to 12-lipoxygenase
US5741908A (en) 1996-06-21 1998-04-21 Minnesota Mining And Manufacturing Company Process for reparing imidazoquinolinamines
US5693811A (en) 1996-06-21 1997-12-02 Minnesota Mining And Manufacturing Company Process for preparing tetrahdroimidazoquinolinamines
CA2230808C (en) * 1996-07-03 2006-08-15 Japan Energy Corporation A novel purine derivative
US6387938B1 (en) * 1996-07-05 2002-05-14 Mochida Pharmaceutical Co., Ltd. Benzimidazole derivatives
KR100518903B1 (en) * 1996-10-25 2005-10-06 미네소타 마이닝 앤드 매뉴팩춰링 캄파니 Immune response modifier compounds for treatment of the th2 mediated and related diseases
US5939090A (en) * 1996-12-03 1999-08-17 3M Innovative Properties Company Gel formulations for topical drug delivery
JP4101302B2 (en) 1997-01-09 2008-06-18 テルモ株式会社 Novel amide derivatives and synthetic intermediates
US6406705B1 (en) 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
US6426334B1 (en) 1997-04-30 2002-07-30 Hybridon, Inc. Oligonucleotide mediated specific cytokine induction and reduction of tumor growth in a mammal
US6303347B1 (en) 1997-05-08 2001-10-16 Corixa Corporation Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors
US6113918A (en) 1997-05-08 2000-09-05 Ribi Immunochem Research, Inc. Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
CA2301575C (en) * 1997-05-20 2003-12-23 Ottawa Civic Hospital Loeb Research Institute Vectors and methods for immunization or therapeutic protocols
US6123957A (en) 1997-07-16 2000-09-26 Jernberg; Gary R. Delivery of agents and method for regeneration of periodontal tissues
US6077349A (en) 1997-08-20 2000-06-20 Sony Corporation Method and apparatus for manufacturing disc-shaped recording medium
US6309623B1 (en) 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
EP1035123B1 (en) 1997-11-28 2003-08-20 Sumitomo Pharmaceuticals Company, Limited Novel heterocyclic compounds
US6121323A (en) 1997-12-03 2000-09-19 3M Innovative Properties Company Bishydroxyureas
UA67760C2 (en) 1997-12-11 2004-07-15 Міннесота Майнінг Енд Мануфакчурінг Компані Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines
TW572758B (en) * 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
US6114058A (en) 1998-05-26 2000-09-05 Siemens Westinghouse Power Corporation Iron aluminide alloy container for solid oxide fuel cells
US6110929A (en) * 1998-07-28 2000-08-29 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
JP2000119271A (en) 1998-08-12 2000-04-25 Hokuriku Seiyaku Co Ltd 1h-imidazopyridine derivative
US5962636A (en) 1998-08-12 1999-10-05 Amgen Canada Inc. Peptides capable of modulating inflammatory heart disease
US6518280B2 (en) * 1998-12-11 2003-02-11 3M Innovative Properties Company Imidazonaphthyridines
SK287112B6 (en) 1999-01-08 2009-12-07 3M Innovative Properties Company Use of immune response modifiying compound for cervical dysplasias treatment
US20020058674A1 (en) 1999-01-08 2002-05-16 Hedenstrom John C. Systems and methods for treating a mucosal surface
US6486168B1 (en) 1999-01-08 2002-11-26 3M Innovative Properties Company Formulations and methods for treatment of mucosal associated conditions with an immune response modifier
EP1495758A3 (en) 1999-01-08 2005-04-13 3M Innovative Properties Company Formulations and methods for treatment of mucosal associated conditions with an immune response modifier
US6558951B1 (en) 1999-02-11 2003-05-06 3M Innovative Properties Company Maturation of dendritic cells with immune response modifying compounds
US6294271B1 (en) 1999-02-12 2001-09-25 Shin-Etsu Chemical Co., Ltd. Flip-chip type semiconductor device sealing material and flip-chip type semiconductor device
JP2000247884A (en) 1999-03-01 2000-09-12 Sumitomo Pharmaceut Co Ltd Arachidonic acid-induced skin disease-treating agent
US6582957B1 (en) 1999-04-12 2003-06-24 Lexicon Genetics Incorporated Lipoxygenase proteins and polynucleotides encoding the same
US6331539B1 (en) * 1999-06-10 2001-12-18 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6573273B1 (en) 1999-06-10 2003-06-03 3M Innovative Properties Company Urea substituted imidazoquinolines
US6541485B1 (en) 1999-06-10 2003-04-01 3M Innovative Properties Company Urea substituted imidazoquinolines
US6451810B1 (en) 1999-06-10 2002-09-17 3M Innovative Properties Company Amide substituted imidazoquinolines
US6756382B2 (en) * 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
US6315985B1 (en) 1999-06-18 2001-11-13 3M Innovative Properties Company C-17/21 OH 20-ketosteroid solution aerosol products with enhanced chemical stability
DE60017259T2 (en) 1999-08-13 2005-12-08 Hybridon, Inc., Cambridge Modulation of CPG oligonucleotide-mediated immune stimulation by positional modification of nucleosides
US6432989B1 (en) 1999-08-27 2002-08-13 Pfizer Inc Use of CRF antagonists to treat circadian rhythm disorders
IL139197A0 (en) 1999-10-29 2001-11-25 Pfizer Prod Inc Use of corticotropin releasing factor antagonists and related compositions
PT1666028E (en) * 1999-10-29 2010-06-15 Novartis Ag Dry powder compositions having improved dispersivity
US6916925B1 (en) 1999-11-05 2005-07-12 3M Innovative Properties Co. Dye labeled imidazoquinoline compounds
US6376669B1 (en) 1999-11-05 2002-04-23 3M Innovative Properties Company Dye labeled imidazoquinoline compounds
US6313156B1 (en) 1999-12-23 2001-11-06 Icos Corporation Thiazole compounds as cyclic-AMP-specific phosphodiesterase inhibitors
US20040023870A1 (en) * 2000-01-21 2004-02-05 Douglas Dedera Methods of therapy and diagnosis using targeting of cells that express toll-like receptor proteins
GB0001704D0 (en) * 2000-01-25 2000-03-15 Glaxo Group Ltd Protein
US20040054182A1 (en) 2000-02-09 2004-03-18 Hideo Kato 1h-imidazopyridine derivatives
AU2001245823A1 (en) 2000-03-17 2001-10-03 Corixa Corporation Novel amphipathic aldehydes and their use as adjuvants and immunoeffectors
US20010046968A1 (en) 2000-03-23 2001-11-29 Zagon Ian S. Opioid growth factor modulates angiogenesis
BR0109643A (en) * 2000-03-30 2003-04-22 Shionogi & Co Synthetic process and crystal form of condensed imidazopyridine derivatives
US6894060B2 (en) 2000-03-30 2005-05-17 3M Innovative Properties Company Method for the treatment of dermal lesions caused by envenomation
DE10020465A1 (en) 2000-04-26 2001-11-08 Osram Opto Semiconductors Gmbh Radiation-emitting semiconductor component with luminescence conversion element
AU2001264753A1 (en) 2000-05-19 2001-12-03 Millennium Pharmaceuticals, Inc. 46638, a putative family member of human lipoxygenase
DE10029580C1 (en) * 2000-06-15 2002-01-10 Ferton Holding Sa Device for removing body stones with an intracorporeal lithotripter
US6387383B1 (en) * 2000-08-03 2002-05-14 Dow Pharmaceutical Sciences Topical low-viscosity gel composition
US6900016B1 (en) 2000-09-08 2005-05-31 Applera Corporation Polymorphisms in known genes associated with inflammatory autoimmune disease, methods of detection and uses thereof
US6943240B2 (en) 2000-09-15 2005-09-13 Coley Pharmaceuticals Gmbh Nucleic acids for high throughput screening of CpG-based immuno-agonist/antagonist
US20020055517A1 (en) 2000-09-15 2002-05-09 3M Innovative Properties Company Methods for delaying recurrence of herpes virus symptoms
GB0023008D0 (en) * 2000-09-20 2000-11-01 Glaxo Group Ltd Improvements in vaccination
CZ20031587A3 (en) * 2000-12-07 2004-01-14 Aoyama Seisakusho Co., Ltd. Method for baking steel parts of a product
US6525064B1 (en) * 2000-12-08 2003-02-25 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6660735B2 (en) 2000-12-08 2003-12-09 3M Innovative Properties Company Urea substituted imidazoquinoline ethers
US6677347B2 (en) * 2000-12-08 2004-01-13 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US6660747B2 (en) 2000-12-08 2003-12-09 3M Innovative Properties Company Amido ether substituted imidazoquinolines
US6664264B2 (en) 2000-12-08 2003-12-16 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6677348B2 (en) 2000-12-08 2004-01-13 3M Innovative Properties Company Aryl ether substituted imidazoquinolines
US6545017B1 (en) * 2000-12-08 2003-04-08 3M Innovative Properties Company Urea substituted imidazopyridines
US6545016B1 (en) * 2000-12-08 2003-04-08 3M Innovative Properties Company Amide substituted imidazopyridines
UA74593C2 (en) 2000-12-08 2006-01-16 3M Innovative Properties Co Substituted imidazopyridines
UA74852C2 (en) 2000-12-08 2006-02-15 3M Innovative Properties Co Urea-substituted imidazoquinoline ethers
US6667312B2 (en) 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6664265B2 (en) 2000-12-08 2003-12-16 3M Innovative Properties Company Amido ether substituted imidazoquinolines
EP1360486A2 (en) * 2000-12-08 2003-11-12 3M Innovative Properties Company Screening method for identifying compounds that selectively induce interferon alpha
US20020107262A1 (en) 2000-12-08 2002-08-08 3M Innovative Properties Company Substituted imidazopyridines
US6664260B2 (en) * 2000-12-08 2003-12-16 3M Innovative Properties Company Heterocyclic ether substituted imidazoquinolines
US20020182274A1 (en) * 2001-03-21 2002-12-05 Kung-Ming Lu Methods for inhibiting cancer growth, reducing infection and promoting general health with a fermented soy extract
CN1250548C (en) 2001-04-17 2006-04-12 大日本住友制药株式会社 Novel adenine derivatives
DE60141773D1 (en) * 2001-04-20 2010-05-20 Inst Systems Biology GREAT SIMILAR RECEPTOR 5-LIGANDS AND USE PROCESS
US20020193729A1 (en) 2001-04-20 2002-12-19 Cormier Michel J.N. Microprojection array immunization patch and method
US6627639B2 (en) 2001-04-26 2003-09-30 Wyeth Uses for indoletetrahydropyridine derivatives of 2,3-dihydro-7H-[1,4]dioxino-[2,3-e]indole
US7226928B2 (en) 2001-06-15 2007-06-05 3M Innovative Properties Company Methods for the treatment of periodontal disease
US6756399B2 (en) * 2001-06-29 2004-06-29 The United States Of America As Represented By The Department Of Health And Human Services Use of lipoxygenase inhibitors and PPAR ligands as anti-cancer therapeutic and intervention agents
MXPA04000449A (en) 2001-07-16 2004-03-18 Shionogi & Co Process for preparation of amidine derivatives.
US20030133913A1 (en) 2001-08-30 2003-07-17 3M Innovative Properties Company Methods of maturing plasmacytoid dendritic cells using immune response modifier molecules
WO2003030902A1 (en) 2001-10-09 2003-04-17 Tularik Inc. Imidazole derivates as anti-inflammatory agents
AU2002360278A1 (en) 2001-10-12 2003-11-11 Coley Pharmaceutical Gmbh Methods and products for enhancing immune responses using imidazoquinoline compounds
DE60230340D1 (en) 2001-11-16 2009-01-22 3M Innovative Properties Co N-Ä4- (4-amino-2-ethyl-1H-imidazoÄ4,5-quinolin-1-yl) -butyl-methanesulfonamide, pharmaceutical composition containing the same and their use
WO2003045494A2 (en) * 2001-11-17 2003-06-05 Martinez-Colon Maria Imiquimod therapies
DE60234376D1 (en) 2001-11-27 2009-12-24 Anadys Pharmaceuticals Inc 3-BETA-D-RIBOFURANOSYLTHIAZOLO (4,5-DELTA) PYRIDIMINE NUCLEOSIDE AND ITS USE
KR100962751B1 (en) 2001-11-29 2010-06-09 쓰리엠 이노베이티브 프로퍼티즈 컴파니 Pharmaceutical Formulations Comprising an Immune Response Modifier
US6677349B1 (en) 2001-12-21 2004-01-13 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6775514B2 (en) 2002-01-11 2004-08-10 Xerox Corporation Substrate size monitoring system for use in copier/printers
US6525028B1 (en) * 2002-02-04 2003-02-25 Corixa Corporation Immunoeffector compounds
US20050281813A1 (en) 2002-02-14 2005-12-22 Nuvelo, Inc. Methods of therapy and diagnosis using targeting of cells that express toll-like receptor proteins
BR0307788A (en) * 2002-02-22 2006-04-04 3M Innovative Properties Co reduction method and treatment of uv-b-induced immunosuppression
US20030185835A1 (en) 2002-03-19 2003-10-02 Braun Ralph P. Adjuvant for vaccines
NZ573064A (en) 2002-04-04 2011-02-25 Coley Pharm Gmbh Immunostimulatory G,U-containing oligoribonucleotides
CN100544715C (en) 2002-04-30 2009-09-30 尤尼根制药公司 As there not being the compositions that replaces B lopps flavone and flavane mixture comprising of therapeutic agent
GB0211649D0 (en) 2002-05-21 2002-07-03 Novartis Ag Organic compounds
US6743920B2 (en) 2002-05-29 2004-06-01 3M Innovative Properties Company Process for imidazo[4,5-c]pyridin-4-amines
MXPA04012199A (en) * 2002-06-07 2005-02-25 3M Innovative Properties Co Ether substituted imidazopyridines.
DK1543002T3 (en) 2002-07-23 2006-12-27 Teva Gyogyszergyar Zartkoeruee Preparation of 1H-imidazo (4,5-c) quinoline-4-amines via 1H-imidazo (4,5-c) quinoline-4-phthalimide intermediates
CA2493158A1 (en) 2002-07-26 2004-02-05 Biogal Gyogyszergyar Rt. Preparation of 1h-imidazo [4,5-c] quinolin-4-amines via novel 1h-imidazo [4,5-c] quinolin-4-cyano and 1h-imidazo [4,5-c] quinolin-4-carboxamide intermediates
MXPA05001647A (en) 2002-08-15 2005-04-19 3M Innovative Properties Co Immunostimulatory compositions and methods of stimulating an immune response.
EP1542688A4 (en) 2002-09-26 2010-06-02 3M Innovative Properties Co 1h-imidazo dimers
JP2006512313A (en) 2002-10-31 2006-04-13 アムジェン インコーポレイテッド Anti-inflammatory agent
US20040166137A1 (en) 2002-11-08 2004-08-26 Lackey John William Hetero-substituted benzimidazole compounds and antiviral uses thereof
AU2003287324A1 (en) 2002-12-11 2004-06-30 3M Innovative Properties Company Gene expression systems and recombinant cell lines
AU2003287316A1 (en) 2002-12-11 2004-06-30 3M Innovative Properties Company Assays relating to toll-like receptor activity
CA2510375A1 (en) 2002-12-20 2004-07-15 3M Innovative Properties Company Aryl / hetaryl substituted imidazoquinolines
AU2003300184B8 (en) 2002-12-30 2009-12-03 3M Innovative Properties Company Immunostimulatory combinations
EP1592302A4 (en) 2003-02-13 2007-04-25 3M Innovative Properties Co Methods and compositions related to irm compounds and toll-like receptor 8
WO2004075865A2 (en) 2003-02-27 2004-09-10 3M Innovative Properties Company Selective modulation of tlr-mediated biological activity
WO2004078138A2 (en) 2003-03-04 2004-09-16 3M Innovative Properties Company Prophylactic treatment of uv-induced epidermal neoplasia
US7163947B2 (en) * 2003-03-07 2007-01-16 3M Innovative Properties Company 1-Amino 1H-imidazoquinolines
EP1605943A4 (en) 2003-03-07 2008-01-16 3M Innovative Properties Co 1-amino 1h-imidazoquinolines
ATE556711T1 (en) 2003-03-13 2012-05-15 3M Innovative Properties Co METHOD FOR IMPROVING SKIN QUALITY
EP1608282A4 (en) 2003-03-13 2010-12-08 3M Innovative Properties Co Methods for diagnosing skin lesions
WO2004080292A2 (en) * 2003-03-13 2004-09-23 3M Innovative Properties Company Method of tattoo removal
US20040192585A1 (en) 2003-03-25 2004-09-30 3M Innovative Properties Company Treatment for basal cell carcinoma
EP1613956A2 (en) 2003-03-25 2006-01-11 3M Innovative Properties Company Selective activation of cellular activities mediated through a common toll-like receptor
US7893096B2 (en) 2003-03-28 2011-02-22 Novartis Vaccines And Diagnostics, Inc. Use of small molecule compounds for immunopotentiation
US20040265351A1 (en) 2003-04-10 2004-12-30 Miller Richard L. Methods and compositions for enhancing immune response
WO2004091500A2 (en) 2003-04-10 2004-10-28 3M Innovative Properties Company Delivery of immune response modifier compounds
EP1617845A4 (en) 2003-04-28 2006-09-20 3M Innovative Properties Co Compositions and methods for induction of opioid receptors
AR044466A1 (en) 2003-06-06 2005-09-14 3M Innovative Properties Co PROCESS FOR THE PREPARATION OF IMIDAZO [4,5-C] PIRIDIN-4-AMINAS
WO2004110991A2 (en) 2003-06-06 2004-12-23 3M Innovative Properties Company PROCESS FOR IMIDAZO[4,5-c]PYRIDIN-4-AMINES
WO2005007672A2 (en) 2003-06-20 2005-01-27 Coley Pharmaceutical Gmbh Small molecule toll-like receptor (tlr) antagonists
MY157827A (en) 2003-06-27 2016-07-29 3M Innovative Properties Co Sulfonamide substituted imidazoquinolines
US20050106300A1 (en) 2003-06-30 2005-05-19 Purdue Research Foundation Method for producing a material having an increased solubility in alcohol
AU2004264336B2 (en) 2003-08-05 2010-12-23 3M Innovative Properties Company Formulations containing an immune response modifier
AR045260A1 (en) * 2003-08-12 2005-10-19 3M Innovative Properties Co COMPOUNDS CONTAINING IMIDAZO-OXIMA REPLACED
EP1660122A4 (en) * 2003-08-25 2007-10-24 3M Innovative Properties Co Immunostimulatory combinations and treatments
MXPA06002199A (en) * 2003-08-27 2006-05-22 3M Innovative Properties Co Aryloxy and arylalkyleneoxy substituted imidazoquinolines.
WO2005023190A2 (en) * 2003-09-05 2005-03-17 3M Innovative Properties Company Treatment for cd5+ b cell lymphoma
NZ545536A (en) 2003-09-05 2010-04-30 Anadys Pharmaceuticals Inc TLR7 ligands for the treatment of hepatitis C
GB0321615D0 (en) 2003-09-15 2003-10-15 Glaxo Group Ltd Improvements in vaccination
US20050059072A1 (en) * 2003-09-17 2005-03-17 3M Innovative Properties Company Selective modulation of TLR gene expression
US7687628B2 (en) 2003-10-01 2010-03-30 Taro Pharmaceuticals U.S.A., Inc. Method of preparing 4-amino-1H-imidazo(4,5-c)quinolines and acid addition salts thereof
US8871782B2 (en) * 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US7544697B2 (en) 2003-10-03 2009-06-09 Coley Pharmaceutical Group, Inc. Pyrazolopyridines and analogs thereof
US20090075980A1 (en) * 2003-10-03 2009-03-19 Coley Pharmaceutical Group, Inc. Pyrazolopyridines and Analogs Thereof
JP2007509987A (en) * 2003-10-31 2007-04-19 スリーエム イノベイティブ プロパティズ カンパニー Neutrophil activation by immune response modulator compounds
US20050239733A1 (en) 2003-10-31 2005-10-27 Coley Pharmaceutical Gmbh Sequence requirements for inhibitory oligonucleotides
ITMI20032121A1 (en) 2003-11-04 2005-05-05 Dinamite Dipharma Spa In Forma Abbr Eviata Dipharm PROCEDURE FOR THE PREPARATION OF IMIQUIMOD AND ITS INTERMEDIATES
CA2545774A1 (en) * 2003-11-14 2005-06-02 3M Innovative Properties Company Oxime substituted imidazo ring compounds
CU23404A1 (en) 2003-11-19 2009-08-04 Ct Ingenieria Genetica Biotech NEISSERIA MENINGITIDIS CAPSULAR POLYSACARIDS AS MUCOSOPT IMMUNOPOTENTIZERS AND RESULTING FORMULATIONS
CA2547020C (en) * 2003-11-25 2014-03-25 3M Innovative Properties Company 1h-imidazo[4,5-c]pyridine-4-amine derivatives as immune response modifier
US8778963B2 (en) 2003-11-25 2014-07-15 3M Innovative Properties Company Hydroxylamine and oxime substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
US20050226878A1 (en) 2003-12-02 2005-10-13 3M Innovative Properties Company Therapeutic combinations and methods including IRM compounds
WO2005055932A2 (en) 2003-12-02 2005-06-23 3M Innovative Properties Company Therapeutic combinations and methods including irm compounds
US7939526B2 (en) 2003-12-04 2011-05-10 3M Innovative Properties Company Sulfone substituted imidazo ring ethers
WO2005066170A1 (en) * 2003-12-29 2005-07-21 3M Innovative Properties Company Arylalkenyl and arylalkynyl substituted imidazoquinolines
CA2552101A1 (en) 2003-12-29 2005-07-21 3M Innovative Properties Company Piperazine, [1,4]diazepane, [1,4]diazocane, and [1,5]diazocane fused imidazo ring compounds
WO2005067500A2 (en) 2003-12-30 2005-07-28 3M Innovative Properties Company Enhancement of immune responses
JP2007517044A (en) * 2003-12-30 2007-06-28 スリーエム イノベイティブ プロパティズ カンパニー Imidazoquinolinyl, imidazopyridinyl, and imidazonaphthyridinylsulfonamide
WO2005065678A1 (en) 2003-12-30 2005-07-21 3M Innovative Properties Company Immunomodulatory combinations
WO2005094531A2 (en) 2004-03-24 2005-10-13 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
EP1735010A4 (en) 2004-04-09 2008-08-27 3M Innovative Properties Co Methods, compositions, and preparations for delivery of immune response modifiers
US20050267145A1 (en) 2004-05-28 2005-12-01 Merrill Bryon A Treatment for lung cancer
WO2005123079A2 (en) * 2004-06-14 2005-12-29 3M Innovative Properties Company Urea substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
US8017779B2 (en) 2004-06-15 2011-09-13 3M Innovative Properties Company Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
WO2006065280A2 (en) 2004-06-18 2006-06-22 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and methods
US20070259881A1 (en) 2004-06-18 2007-11-08 Dellaria Joseph F Jr Substituted Imidazo Ring Systems and Methods
US8026366B2 (en) 2004-06-18 2011-09-27 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
US20070259907A1 (en) 2004-06-18 2007-11-08 Prince Ryan B Aryl and arylalkylenyl substituted thiazoloquinolines and thiazolonaphthyridines
WO2006038923A2 (en) 2004-06-18 2006-04-13 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
US20090270443A1 (en) 2004-09-02 2009-10-29 Doris Stoermer 1-amino imidazo-containing compounds and methods
US20110070575A1 (en) 2004-12-08 2011-03-24 Coley Pharmaceutical Group, Inc. Immunomodulatory Compositions, Combinations and Methods
JP2008523084A (en) 2004-12-08 2008-07-03 スリーエム イノベイティブ プロパティズ カンパニー Immunostimulating combination and method
WO2006074003A2 (en) 2004-12-30 2006-07-13 3M Innovative Properties Company CHIRAL FUSED [1,2]IMIDAZO[4,5-c] RING COMPOUNDS
JP5313502B2 (en) * 2004-12-30 2013-10-09 スリーエム イノベイティブ プロパティズ カンパニー Substituted chiral condensed [1,2] imidazo [4,5-c] cyclic compounds
ZA200706251B (en) 2004-12-30 2008-11-26 Coley Pharm Group Inc Immune response modifier formulations and methods
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
WO2006086449A2 (en) 2005-02-09 2006-08-17 Coley Pharmaceutical Group, Inc. Alkyloxy substituted thiazoloquinolines and thiazolonaphthyridines
US8378102B2 (en) 2005-02-09 2013-02-19 3M Innovative Properties Company Oxime and hydroxylamine substituted thiazolo[4,5-c] ring compounds and methods
AU2006213745A1 (en) 2005-02-11 2006-08-17 Coley Pharmaceutical Group, Inc. Substituted fused [1,2]imidazo[4,5-c] ring compounds and methods
WO2006086634A2 (en) 2005-02-11 2006-08-17 Coley Pharmaceutical Group, Inc. Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US8658666B2 (en) * 2005-02-11 2014-02-25 3M Innovative Properties Company Substituted imidazoquinolines and imidazonaphthyridines
CA2598437A1 (en) * 2005-02-23 2006-08-31 Coley Pharmaceutical Group, Inc. Method of preferentially inducing the biosynthesis of interferon
WO2006091567A2 (en) 2005-02-23 2006-08-31 Coley Pharmaceutical Group, Inc. Hydroxyalkyl substituted imidazoquinoline compounds and methods
EP1851224A2 (en) * 2005-02-23 2007-11-07 3M Innovative Properties Company Hydroxyalkyl substituted imidazoquinolines
CA2598639A1 (en) 2005-02-23 2006-08-31 Coley Pharmaceutical Group, Inc. Hydroxyalkyl substituted imidazonaphthyridines
US7943610B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company Pyrazolopyridine-1,4-diamines and analogs thereof
US8168802B2 (en) 2005-04-01 2012-05-01 3M Innovative Properties Company Ring closing and related methods and intermediates
WO2006107771A2 (en) 2005-04-01 2006-10-12 Coley Pharmaceutical Group, Inc. PYRAZOLO[3,4-c]QUINOLINES, PYRAZOLO[3,4-c]NAPHTHYRIDINES, ANALOGS THEREOF, AND METHODS
AU2006232375A1 (en) 2005-04-01 2006-10-12 Coley Pharmaceutical Group, Inc. 1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
RS20080128A (en) 2005-09-02 2009-05-06 Pfizer Inc., Hydroxy substituted 1h-imidazopyridines and methods
EP1922317A4 (en) 2005-09-09 2009-04-15 Coley Pharm Group Inc Amide and carbamate derivatives of n-{2-ý4-amino-2- (ethoxymethyl)-1h-imidazoý4,5-c¨quinolin-1-yl¨-1,1-dimethylethyl}methanesulfonamide and methods
ZA200803029B (en) 2005-09-09 2009-02-25 Coley Pharm Group Inc Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods
CA2623541A1 (en) 2005-09-23 2007-03-29 Coley Pharmaceutical Group, Inc. Method for 1h-imidazo[4,5-c]pyridines and analogs thereof
US8088790B2 (en) 2005-11-04 2012-01-03 3M Innovative Properties Company Hydroxy and alkoxy substituted 1H-imidazoquinolines and methods
WO2007062043A1 (en) 2005-11-23 2007-05-31 Coley Pharmaceutical Group Inc. Method of activating murine toll-like receptor 8
MX2008007864A (en) 2005-12-16 2009-03-04 Coley Pharm Group Inc Substituted imidazoquinolines, imidazonaphthyridines, and imidazopyridines, compositions, and methods.
WO2007079169A2 (en) 2005-12-28 2007-07-12 Coley Pharmaceutical Group, Inc. Treatment for acute myeloid leukemia
WO2007079202A2 (en) 2005-12-28 2007-07-12 Coley Pharmaceutical Group, Inc. Treatment for acute lymhoblastic leukemia
EP1968582A4 (en) 2005-12-28 2011-02-16 3M Innovative Properties Co Treatment for cutaneous t cell lymphoma
WO2007079086A1 (en) 2005-12-28 2007-07-12 Coley Pharmaceutical Group, Inc. Pyrazoloalkyl substituted imidazo ring compounds and methods
WO2007079171A2 (en) 2005-12-28 2007-07-12 Coley Pharmaceutical Group, Inc. Treatment for hodgkin's lymphoma
WO2007079146A1 (en) 2005-12-28 2007-07-12 Coley Pharmaceutical Group, Inc Treatment for non-hodgkin's lymphoma
US20090306388A1 (en) 2006-02-10 2009-12-10 Pfizer Inc. Method for substituted ih-imidazo[4,5-c] pyridines
US8329721B2 (en) 2006-03-15 2012-12-11 3M Innovative Properties Company Hydroxy and alkoxy substituted 1H-imidazonaphthyridines and methods
WO2007106852A2 (en) 2006-03-15 2007-09-20 Coley Pharmaceutical Group, Inc. Substituted fused[1,2]imidazo[4,5-c] ring compounds and methods
WO2007143526A2 (en) 2006-06-05 2007-12-13 Coley Pharmaceutical Group, Inc. Substituted tetrahydroimidazonaphthyridines and methods
US7906506B2 (en) * 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
WO2008030511A2 (en) 2006-09-06 2008-03-13 Coley Pharmaceuticial Group, Inc. Substituted 3,4,6,7-tetrahydro-5h, 1,2a,4a,8-tetraazacyclopenta[cd]phenalenes
WO2008036312A1 (en) 2006-09-19 2008-03-27 Coley Pharmaceutical Group, Inc. Fungicidal methods using immune response modifier compounds
WO2008045543A1 (en) 2006-10-13 2008-04-17 Coley Pharmaceutical Group, Inc. Substituted 4h-imidazo [4, 5, 1-ij] [1, 6] naphthyridine-9-amines and their pharmaceutical use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP1682544A4 *

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7923429B2 (en) 2003-09-05 2011-04-12 3M Innovative Properties Company Treatment for CD5+ B cell lymphoma
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US7879849B2 (en) 2003-10-03 2011-02-01 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
EP1685129A4 (en) * 2003-11-14 2008-10-22 3M Innovative Properties Co Oxime substituted imidazo ring compounds
US7915281B2 (en) 2004-06-18 2011-03-29 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method
US8034938B2 (en) 2004-12-30 2011-10-11 3M Innovative Properties Company Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds
EP2394650A1 (en) 2004-12-30 2011-12-14 3M Innovative Properties Co. Use of resiquimod for the treatment of cutaneous metastases
US7943609B2 (en) 2004-12-30 2011-05-17 3M Innovative Proprerties Company Chiral fused [1,2]imidazo[4,5-C] ring compounds
WO2006080043A2 (en) * 2005-01-27 2006-08-03 Alma Mater Studiorum- Universita' Di Bologna Organic compounds useful for the treatment of alzheimer's disease, their use and method of preparation
WO2006080043A3 (en) * 2005-01-27 2006-09-08 Univ Bologna Alma Mater Organic compounds useful for the treatment of alzheimer's disease, their use and method of preparation
US7307083B2 (en) 2005-01-27 2007-12-11 Alma Mater Studiorum-Universita'di Bologna Tetrahydro-acridine and dithiolane derivatives
US10071156B2 (en) 2005-02-04 2018-09-11 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
WO2006086634A2 (en) * 2005-02-11 2006-08-17 Coley Pharmaceutical Group, Inc. Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US7968563B2 (en) 2005-02-11 2011-06-28 3M Innovative Properties Company Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
WO2006086634A3 (en) * 2005-02-11 2007-08-09 3M Innovative Properties Co Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US7943636B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company 1-substituted pyrazolo (3,4-C) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
US7943610B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company Pyrazolopyridine-1,4-diamines and analogs thereof
EP3085373A1 (en) 2006-02-22 2016-10-26 3M Innovative Properties Company Immune response modifier conjugates
US8951528B2 (en) 2006-02-22 2015-02-10 3M Innovative Properties Company Immune response modifier conjugates
US9221780B2 (en) 2006-03-17 2015-12-29 The Johns Hopkins University N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US9969684B2 (en) 2006-03-17 2018-05-15 Cardioxyl Pharmaceuticals, Inc. N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US11306056B2 (en) 2006-03-17 2022-04-19 Cardioxyl Pharmaceuticals, Inc. N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
CN103435524A (en) * 2006-03-17 2013-12-11 约翰斯·霍普金斯大学医学院 N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US10829445B2 (en) 2006-03-17 2020-11-10 Cardioxyl Pharmaceuticals, Inc. N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US10487049B2 (en) 2006-03-17 2019-11-26 Cardioxyl Pharmaceuticals, Inc. N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US10179765B2 (en) 2006-03-17 2019-01-15 Cardioxyl Pharmaceuticals, Inc. N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US9487498B2 (en) 2006-03-17 2016-11-08 The Johns Hopkins University N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US9725410B2 (en) 2006-03-17 2017-08-08 The Johns Hopkins University N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors
US7906506B2 (en) 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
US10144735B2 (en) 2006-12-22 2018-12-04 3M Innovative Properties Company Immune response modifier compositions and methods
WO2009118296A2 (en) * 2008-03-24 2009-10-01 4Sc Ag Novel substituted imidazoquinolines
EA023556B1 (en) * 2008-03-24 2016-06-30 4ЭсЦэ АГ 1,2-disubstituted-4-aminoimidazoquinolines
US9073913B2 (en) 2008-03-24 2015-07-07 4Sc Ag Substituted imidazoquinolines
US9908880B2 (en) 2008-03-24 2018-03-06 4Sc Ag Substituted imidazoquinolines
US9446040B2 (en) 2008-03-24 2016-09-20 4Sc Ag Substituted imidazoquinolines
WO2009118296A3 (en) * 2008-03-24 2009-12-03 4Sc Ag Novel substituted imidazoquinolines
EP3153180A1 (en) 2011-06-03 2017-04-12 3M Innovative Properties Company Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom
EP3756669A1 (en) 2013-01-07 2020-12-30 The Trustees of the University of Pennsylvania Compositions for use for treating cutaneous t cell lymphoma
WO2014107663A2 (en) 2013-01-07 2014-07-10 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cutaneous t cell lymphoma
US10434183B2 (en) 2013-12-02 2019-10-08 Altimmune UK Ltd. Immunogenic compound
US10849984B2 (en) 2013-12-02 2020-12-01 Altimmune Uk Limited Immunogenic compound
US9962453B2 (en) 2013-12-02 2018-05-08 Altimmune Uk Limited Immunogenic compound
US9932303B2 (en) 2014-01-17 2018-04-03 Cardioxyl Pharmaceuticals, Inc. N-hydroxymethanesulfonamide nitroxyl donors
WO2019166946A1 (en) 2018-02-28 2019-09-06 Pfizer Inc. Il-15 variants and uses thereof
WO2019224716A2 (en) 2018-05-23 2019-11-28 Pfizer Inc. Antibodies specific for gucy2c and uses thereof
WO2019224715A1 (en) 2018-05-23 2019-11-28 Pfizer Inc. Antibodies specific for cd3 and uses thereof
US11434292B2 (en) 2018-05-23 2022-09-06 Pfizer Inc. Antibodies specific for CD3 and uses thereof
WO2020128893A1 (en) 2018-12-21 2020-06-25 Pfizer Inc. Combination treatments of cancer comprising a tlr agonist
WO2021124073A1 (en) 2019-12-17 2021-06-24 Pfizer Inc. Antibodies specific for cd47, pd-l1, and uses thereof
WO2022013775A1 (en) 2020-07-17 2022-01-20 Pfizer Inc. Therapeutic antibodies and their uses

Also Published As

Publication number Publication date
JP2007511535A (en) 2007-05-10
CN1906192A (en) 2007-01-31
CA2545825A1 (en) 2005-06-02
AU2004291122A1 (en) 2005-06-02
US8598192B2 (en) 2013-12-03
WO2005048945A3 (en) 2006-03-23
EP1682544A2 (en) 2006-07-26
EP1682544A4 (en) 2009-05-06
US20090105295A1 (en) 2009-04-23

Similar Documents

Publication Publication Date Title
US8598192B2 (en) Hydroxylamine substituted imidazoquinolines
US7897767B2 (en) Oxime substituted imidazoquinolines
US8735421B2 (en) Imidazoquinolinyl sulfonamides
US8802853B2 (en) Arylalkenyl and arylalkynyl substituted imidazoquinolines
US7939526B2 (en) Sulfone substituted imidazo ring ethers
US8778963B2 (en) Hydroxylamine and oxime substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
US20090270443A1 (en) 1-amino imidazo-containing compounds and methods
MXPA06001669A (en) Oxime substituted imidazo-containing compounds.
EP1699792A1 (en) Piperazine, 1,4¨diazepane, 1,4¨diazocane, and 1,5¨diazocane fused imidazo ring compounds
WO2005051317A2 (en) Substituted imidazo ring systems and methods
US9550773B2 (en) Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 10595790

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2006539957

Country of ref document: JP

Ref document number: 2545825

Country of ref document: CA

Ref document number: 1680/CHENP/2006

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2004291122

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004810969

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2004291122

Country of ref document: AU

Date of ref document: 20041112

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004291122

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 200480040435.3

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2004810969

Country of ref document: EP